| 1 | Am. J. Med. Genet. 2000 Apr 96: 196-201 |
|---|---|
| PMID | 10893497 |
| Title | Haplotype transmission disequilibrium and evidence for linkage of the CHRNA7 gene region to schizophrenia in Southern African Bantu families. |
| Abstract | Recent reports have strongly linked markers near the alpha-7 nicotinic cholinergic receptor subunit gene on human chromosome 15q13-q14 to a sensory gating deficit common in schizophrenics, and have shown positive though non-significant results linking this region to the primary phenotype of schizophrenia in a sample of North American families. We therefore tested for linkage between markers in this region of chromosome 15q and schizophrenia in a sample of 15 multiply affected and 5 single case families with schizophrenia drawn from the Bantu-speaking black population of South Africa. An initial replication using markers from the original study gave an affected-only LOD score maximum of 1.08 under a recessive model at Theta=0.00 for D15S1360, a dinucleotide polymorphism found on the same YAC as the alpha-7 receptor gene. Nonparametric affected-only multipoint analysis gave a Z-score of 1. 29, P=0.098, for D15S1360, and Z=1.45, p=0.075 for D15S118. We then increased the resolution of the map with an extended set of 20 markers. Again, two peaks were observed, with NPL scores of 1.81, p=0.037, at D15S1043 and 1.79 at D15S1360 and 1.80 at D15S1010, both p=0.037. Transmission disequilibrium testing of data from D15S1360 gave an allele-wise and genotype-wise chi(2) of 6.59, 2 df, p=0.037. Haplotype transmission disequilibrium testing using a restricted allele and haplotype set from D15S1043 and D15S1360 gave a global chi(2) of 10.647, 4 df, P=0.007, and a maximum chi(2) of 6.567, 1 df, P=0.004 for excess transmission of the 1.2 haplotype into affected offspring. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:196-201, 2000. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Am. J. Med. Genet. 2000 Apr 96: 196-201 |
| PMID | 10893497 |
| Title | Haplotype transmission disequilibrium and evidence for linkage of the CHRNA7 gene region to schizophrenia in Southern African Bantu families. |
| Abstract | Recent reports have strongly linked markers near the alpha-7 nicotinic cholinergic receptor subunit gene on human chromosome 15q13-q14 to a sensory gating deficit common in schizophrenics, and have shown positive though non-significant results linking this region to the primary phenotype of schizophrenia in a sample of North American families. We therefore tested for linkage between markers in this region of chromosome 15q and schizophrenia in a sample of 15 multiply affected and 5 single case families with schizophrenia drawn from the Bantu-speaking black population of South Africa. An initial replication using markers from the original study gave an affected-only LOD score maximum of 1.08 under a recessive model at Theta=0.00 for D15S1360, a dinucleotide polymorphism found on the same YAC as the alpha-7 receptor gene. Nonparametric affected-only multipoint analysis gave a Z-score of 1. 29, P=0.098, for D15S1360, and Z=1.45, p=0.075 for D15S118. We then increased the resolution of the map with an extended set of 20 markers. Again, two peaks were observed, with NPL scores of 1.81, p=0.037, at D15S1043 and 1.79 at D15S1360 and 1.80 at D15S1010, both p=0.037. Transmission disequilibrium testing of data from D15S1360 gave an allele-wise and genotype-wise chi(2) of 6.59, 2 df, p=0.037. Haplotype transmission disequilibrium testing using a restricted allele and haplotype set from D15S1043 and D15S1360 gave a global chi(2) of 10.647, 4 df, P=0.007, and a maximum chi(2) of 6.567, 1 df, P=0.004 for excess transmission of the 1.2 haplotype into affected offspring. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:196-201, 2000. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Am. J. Med. Genet. 2000 Apr 96: 173-7 |
| PMID | 10893492 |
| Title | Schizophrenia and smoking: evidence for a common neurobiological basis? |
| Abstract | Several previous investigations have suggested that the gene for the alpha 7-nicotinic receptor may play a role in the pathogenesis of schizophrenia and may be responsible for the heavy smoking among schizophrenic patients. In a study of 129 healthy controls and 127 schizophrenic, schizoaffective, and bipolar patients we have aimed 1) to confirm the potential association between schizophrenia and the alpha 7-nicotinic receptor, 2) to test the diagnostic specificity of alpha 7-receptor subunits with respect to psychiatric diagnoses, and 3) to investigate potential receptor differences between smokers and nonsmokers in the general population. Our analysis included the two dinucleotide polymorphisms D15S1360 and L76630 that are localized in a genomic fragment containing the alpha 7-nicotinic receptor gene CHRNA7. Highly significant differences (P < 0.0001) between the allele distributions of patients and controls were detected for these two markers with all three diagnostic subgroups contributing to the discrimination. An independently ascertained replication sample of 24 patients confirmed this finding. Our results suggested an unspecific vulnerability that depended on the severity of overall psychopathology in terms of the co-occurrence of psychopathology with no clear-cut boundary between the diagnostic entities. In comparison with healthy controls, this vulnerability was lowest among schizophrenics, intermediate among bipolars, and highest among schizoaffectives. As to the question of alpha 7-receptor differences between smokers and nonsmokers among the healthy control subjects, our analysis revealed no significant differences, thus indicating that the differences between patients and controls are more than just a smoker/nonsmoker distinction. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:173-177, 2000. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Am. J. Med. Genet. 2000 Apr 96: 173-7 |
| PMID | 10893492 |
| Title | Schizophrenia and smoking: evidence for a common neurobiological basis? |
| Abstract | Several previous investigations have suggested that the gene for the alpha 7-nicotinic receptor may play a role in the pathogenesis of schizophrenia and may be responsible for the heavy smoking among schizophrenic patients. In a study of 129 healthy controls and 127 schizophrenic, schizoaffective, and bipolar patients we have aimed 1) to confirm the potential association between schizophrenia and the alpha 7-nicotinic receptor, 2) to test the diagnostic specificity of alpha 7-receptor subunits with respect to psychiatric diagnoses, and 3) to investigate potential receptor differences between smokers and nonsmokers in the general population. Our analysis included the two dinucleotide polymorphisms D15S1360 and L76630 that are localized in a genomic fragment containing the alpha 7-nicotinic receptor gene CHRNA7. Highly significant differences (P < 0.0001) between the allele distributions of patients and controls were detected for these two markers with all three diagnostic subgroups contributing to the discrimination. An independently ascertained replication sample of 24 patients confirmed this finding. Our results suggested an unspecific vulnerability that depended on the severity of overall psychopathology in terms of the co-occurrence of psychopathology with no clear-cut boundary between the diagnostic entities. In comparison with healthy controls, this vulnerability was lowest among schizophrenics, intermediate among bipolars, and highest among schizoaffectives. As to the question of alpha 7-receptor differences between smokers and nonsmokers among the healthy control subjects, our analysis revealed no significant differences, thus indicating that the differences between patients and controls are more than just a smoker/nonsmoker distinction. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:173-177, 2000. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Am. J. Med. Genet. 2000 Apr 96: 173-7 |
| PMID | 10893492 |
| Title | Schizophrenia and smoking: evidence for a common neurobiological basis? |
| Abstract | Several previous investigations have suggested that the gene for the alpha 7-nicotinic receptor may play a role in the pathogenesis of schizophrenia and may be responsible for the heavy smoking among schizophrenic patients. In a study of 129 healthy controls and 127 schizophrenic, schizoaffective, and bipolar patients we have aimed 1) to confirm the potential association between schizophrenia and the alpha 7-nicotinic receptor, 2) to test the diagnostic specificity of alpha 7-receptor subunits with respect to psychiatric diagnoses, and 3) to investigate potential receptor differences between smokers and nonsmokers in the general population. Our analysis included the two dinucleotide polymorphisms D15S1360 and L76630 that are localized in a genomic fragment containing the alpha 7-nicotinic receptor gene CHRNA7. Highly significant differences (P < 0.0001) between the allele distributions of patients and controls were detected for these two markers with all three diagnostic subgroups contributing to the discrimination. An independently ascertained replication sample of 24 patients confirmed this finding. Our results suggested an unspecific vulnerability that depended on the severity of overall psychopathology in terms of the co-occurrence of psychopathology with no clear-cut boundary between the diagnostic entities. In comparison with healthy controls, this vulnerability was lowest among schizophrenics, intermediate among bipolars, and highest among schizoaffectives. As to the question of alpha 7-receptor differences between smokers and nonsmokers among the healthy control subjects, our analysis revealed no significant differences, thus indicating that the differences between patients and controls are more than just a smoker/nonsmoker distinction. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:173-177, 2000. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Am. J. Med. Genet. 2001 Jan 105: 20-2 |
| PMID | 11424985 |
| Title | Linkage disequilibrium for schizophrenia at the chromosome 15q13-14 locus of the alpha7-nicotinic acetylcholine receptor subunit gene (CHRNA7). |
| Abstract | The transmission/disequilibrium test was used for fine mapping of the linkage of schizophrenia to the chromosome 15q13-14 region, the site of a candidate gene, the alpha7 nicotinic acetylcholine receptor subunit gene (CHRNA7), in parent-child triads from the NIMH schizophrenia Genetics Initiative families. This candidate gene was identified from neurobiological studies of deficits in schizophrenics of the inhibitory gating of the P50 auditory evoked potential. The neurobiological deficit was also used as a phenotype for subsequent linkage analysis. In the present study, significant genotype-wise disequilibrium (P < 0.007) was found at D15S165, a polymorphic simple sequence marker physically located within 1 megabase of both CHRNA7 and a partially duplicated, expressed sequence that includes exons 5-10 of CHRNA7. Replication of this result was found in an additional set of families. The results support this region as a chromosomal location involved in the genetic transmission of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Am. J. Med. Genet. 2001 Jan 105: 20-2 |
| PMID | 11424985 |
| Title | Linkage disequilibrium for schizophrenia at the chromosome 15q13-14 locus of the alpha7-nicotinic acetylcholine receptor subunit gene (CHRNA7). |
| Abstract | The transmission/disequilibrium test was used for fine mapping of the linkage of schizophrenia to the chromosome 15q13-14 region, the site of a candidate gene, the alpha7 nicotinic acetylcholine receptor subunit gene (CHRNA7), in parent-child triads from the NIMH schizophrenia Genetics Initiative families. This candidate gene was identified from neurobiological studies of deficits in schizophrenics of the inhibitory gating of the P50 auditory evoked potential. The neurobiological deficit was also used as a phenotype for subsequent linkage analysis. In the present study, significant genotype-wise disequilibrium (P < 0.007) was found at D15S165, a polymorphic simple sequence marker physically located within 1 megabase of both CHRNA7 and a partially duplicated, expressed sequence that includes exons 5-10 of CHRNA7. Replication of this result was found in an additional set of families. The results support this region as a chromosomal location involved in the genetic transmission of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Am. J. Med. Genet. 2001 Dec 105: 686-9 |
| PMID | 11803515 |
| Title | No association between CHRNA7 microsatellite markers and attention-deficit hyperactivity disorder. |
| Abstract | Attention-deficit hyperactivity disorder (ADHD) is a highly heritable, common psychiatric disorder of childhood that probably involves several genes. There are several lines of evidence suggesting that the nicotinic system may be functionally significant in ADHD. First, nicotine promotes the release of dopamine and has been shown to improve attention in adults with ADHD, smokers, and nonsmokers. Second, ADHD is a significant risk factor for early initiation of cigarette smoking in children and maternal cigarette smoking appears to be a risk factor for ADHD. Finally, animal studies in rats and monkeys also suggest that nicotine may be involved in attentional systems and locomotor activity. The nicotinic system has previously been studied in schizophrenia where the neuronal nicotinic acetylcholine receptor alpha 7 subunit gene (CHRNA7) has been implicated in decreased P50 inhibition and attentional disturbances in patients with schizophrenia and in many of their nonschizophrenic relatives. Three known microsatellite markers (D15S165, D15S1043, and D15S1360) near the nicotinic acetylcholine alpha 7 receptor gene, CHRNA7, were studied in 206 ADHD parent-proband trios of children aged 5-16 with ADHD according to DSM-IV criteria. Children with known major medical or psychiatric conditions or mental retardation (IQ < 70) were excluded from the study. Markers D15S165 and D15S1360 were in linkage disequilibrium. The extended Transmission Disequilibrium Test analyses demonstrated no evidence that variation at the microsatellite markers D15S1360, D15S1043, and D15S165 influences susceptibility to ADHD. However, it remains possible that the CHRNA7 gene and other nicotinic system genes may be involved in conferring susceptibility to ADHD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Am. J. Med. Genet. 2001 Dec 105: 669-74 |
| PMID | 11803513 |
| Title | Evidence for linkage disequilibrium between the alpha 7-nicotinic receptor gene (CHRNA7) locus and schizophrenia in Azorean families. |
| Abstract | Recent studies have suggested that the alpha 7-nicotinic receptor gene (CHRNA7) may play a role in the pathogenesis of schizophrenia. The alpha 7-nicotinic receptor gene (CHRNA7) is involved in P50 auditory sensory gating deficits, and the genomic locus for this gene lies in the chromosome 15q13-14 regions. The human gene is partially duplicated (exons 5-10) with four novel upstream exons. The marker D15S1360 has been shown to be significantly linked with the phenotype of abnormal P50 suppression in schizophrenia families. The marker L76630 is 3 kb in the 3' direction from the last exon of the CHRNA7 gene and is located in the duplicated region. The function of the two L76630 copies is unknown. We genotyped three polymorphic markers D15S1360, D15S165, and L76630 that are localized in a genomic fragment containing the CHRNA7 in 31 Azorean schizophrenia families/trios (including 41 schizophrenia individuals and 97 unaffected families members). An overall analysis utilizing the family-based association test revealed significant linkage disequilibrium between L76630 and schizophrenia (P = 0.0004). Using the extended transmission disequilibrium test and limiting the analysis to one triad per family, transmission disequilibrium of D15S1360 was near significance (P = 0.078). The 15q13 region overlaps with the location of two well-known genomically imprinted disorders: Angelman syndrome and Prader-Willi syndrome. Therefore, we investigated maternal and paternal meioses. We found significant transmission disequilibrium for D15S1360 through paternal transmission (P = 0.0006) in our schizophrenia families. The L76630 marker showed a significant disequilibrium in maternal transmissions (P = 0.028). No parent-of-origin effect was found in D15S165. Overall, our results suggest that the CHRNA7 may play a role in schizophrenia in these families. A parent of origin effect may be present and requires further study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Am. J. Med. Genet. 2001 Dec 105: 662-8 |
| PMID | 11803512 |
| Title | Examination of genetic linkage of chromosome 15 to schizophrenia in a large Veterans Affairs Cooperative Study sample. |
| Abstract | Previous studies have reported genetic linkage evidence for a schizophrenia gene on chromosome 15q. Here, chromosome 15 was examined by genetic linkage analysis using 166 schizophrenia families, each with two or more affected subjects. The families, assembled from multiple centers by the Department of Veterans Affairs Cooperative Study Program, consisted of 392 sampled affected subjects and 216 affected sibling pairs. By DSM-III-R criteria, 360 subjects (91.8%) had a diagnosis of schizophrenia and 32 (8.2%) were classified as schizo-affective disorder, depressed. Participating families had diverse ethnic backgrounds. The largest single group were northern European American families (n = 62, 37%), but a substantial proportion was African American kindreds (n = 60, 36%). The chromosome 15 markers tested were spaced at intervals of approximately 10 cM over the entire chromosome and 2-5 cM for the region surrounding the alpha-7 nicotinic cholinergic receptor subunit gene (CHRNA7). These markers were genotyped and the data analyzed using semiparametric affecteds-only linkage analysis. In the European American families, there was a maximum Z-score of 1.65 between markers D15S165 and D15S1010. These markers are within 1 cM from CHRNA-7, the site previously implicated in schizophrenia. However, there was no evidence for linkage to this region in the African America kindreds. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Cell. Mol. Life Sci. 2002 Feb 59: 331-48 |
| PMID | 11915947 |
| Title | Recent advances in the genetics of schizophrenia. |
| Abstract | The genetic etiology of schizophrenia, a common and debilitating psychiatric disorder, is supported by a wealth of data. Review of the current findings suggests that considerable progress has been made in recent years, with a number of chromosomal regions consistently implicated by linkage analysis. Three groups have shown linkage to 1q21-22 using similar models, with HLOD scores of 6.5, 3.2, and 2.4. Other replicated loci include 13q32 that has been implicated by two independent groups with significant HLOD scores (4.42) or NPL values (4.18), and 5pl4.1-13.1, 5q21-33, 8p2l-22, and 10p11-15, each of which have been reported as suggestive by at least three separate groups. Different studies have also replicated evidence for a modest number of candidate genes that were not ascertained through linkage. Of these, the greatest support exists for the DRD3 (3q13.3), HTR2A (13q14.2), and CHRNA7 (15q13-q14) genes. The refinement of phenotypes, the use of endophenotypes, reduction of heterogeneity, and extensive genetic mapping have all contributed to this progress. The rapid expansion of information from the human genome project will likely further accelerate this progress and assist in the discovery of susceptibility genes for schizophrenia. A greater understanding of disease mechanisms and the application of pharmacogenetics should also lead to improvements in therapeutic interventions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Mol. Psychiatry 2002 -1 7: 220-3 |
| PMID | 11840317 |
| Title | Exclusion of the neuronal nicotinic acetylcholine receptor alpha7 subunit gene as a candidate for catatonic schizophrenia in a large family supporting the chromosome 15q13-22 locus. |
| Abstract | The gene encoding the neuronal nicotinic acetylcholine receptor alpha7 subunit (CHRNA7) is located on chromosome 15q13.2. This region was suggested to be involved in the etiopathogenesis of: (a) schizophrenia combined with a neurophysiological deficit; (b) lithium-responsive bipolar disorder; and (c) familial catatonic schizophrenia (periodic catatonia). Therefore, members of a large family with periodic catatonia strongly supporting the chromosome 15q13-22 region were genotyped with polymorphic markers localized around the CHRNA7 locus. A recombination event distally of marker D15S144 leading to the exclusion of the CHRNA7 locus from this candidate region was detected in one branch of the pedigree. This result provides strong evidence that a gene located telomeric to CHRNA7 is causative for the pathogenesis of catatonic schizophrenia in this family. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Arch. Gen. Psychiatry 2002 Dec 59: 1085-96 |
| PMID | 12470124 |
| Title | Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia. |
| Abstract | The alpha7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) has been implicated as a candidate gene for schizophrenia, and for an auditory sensory processing deficit found in the disease, by both genetic linkage at 15q14 and biochemical data. The expression of CHRNA7 is reduced in several brain regions in schizophrenic subjects compared with control subjects. This study presents DNA sequence analysis of the core promoter region for CHRNA7 in schizophrenic and control subjects. Single-strand conformation polymorphism analysis and DNA sequencing were used for mutation screening of the core promoter in the CHRNA7 gene. The sample included subjects from 166 schizophrenic families and 165 controls. Controls had no evidence of current or past psychosis and had auditory evoked potentials recorded. Multiple polymorphic patterns were identified in the CHRNA7 core promoter in both schizophrenic and control subjects. Functional analysis of polymorphisms indicated that transcription was reduced. The prevalence of functional promoter variants was statistically greater in schizophrenic subjects than in the controls. Presence of an alpha7 promoter polymorphism in controls was associated with failure to inhibit the P50 auditory evoked potential response. Although linkage disequilibrium with other genetic alterations cannot be excluded, the CHRNA7 core promoter variants, found in this study, may contribute to a common pathophysiologic feature of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Arch. Gen. Psychiatry 2002 Dec 59: 1085-96 |
| PMID | 12470124 |
| Title | Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia. |
| Abstract | The alpha7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) has been implicated as a candidate gene for schizophrenia, and for an auditory sensory processing deficit found in the disease, by both genetic linkage at 15q14 and biochemical data. The expression of CHRNA7 is reduced in several brain regions in schizophrenic subjects compared with control subjects. This study presents DNA sequence analysis of the core promoter region for CHRNA7 in schizophrenic and control subjects. Single-strand conformation polymorphism analysis and DNA sequencing were used for mutation screening of the core promoter in the CHRNA7 gene. The sample included subjects from 166 schizophrenic families and 165 controls. Controls had no evidence of current or past psychosis and had auditory evoked potentials recorded. Multiple polymorphic patterns were identified in the CHRNA7 core promoter in both schizophrenic and control subjects. Functional analysis of polymorphisms indicated that transcription was reduced. The prevalence of functional promoter variants was statistically greater in schizophrenic subjects than in the controls. Presence of an alpha7 promoter polymorphism in controls was associated with failure to inhibit the P50 auditory evoked potential response. Although linkage disequilibrium with other genetic alterations cannot be excluded, the CHRNA7 core promoter variants, found in this study, may contribute to a common pathophysiologic feature of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Mol. Psychiatry 2002 -1 7: 1006-11 |
| PMID | 12399955 |
| Title | The -2 bp deletion in exon 6 of the 'alpha 7-like' nicotinic receptor subunit gene is a risk factor for the P50 sensory gating deficit. |
| Abstract | Abnormality in the P50 auditory-evoked potential gating is an endophenotype associated with schizophrenia. Biochemical and genetic studies have suggested that the alpha 7 nicotinic acetylcholine receptor (nAChR) is involved in this sensory gating deficit. Two related alpha 7 genes (CHRNA7 and CHRNA7-like gene) resulting from a partial duplication (from exon 5 to exon 10) are present in the human genome. Two types of genetic variation, a large deletion and a -2 base-pair deletion in exon 6 resulting in a truncation of the open reading frame, affect specifically the CHRNA7-like gene. We developed a simple multiplex PCR assay on genomic DNA, allowing the quantification of the number of exons 6 and the distinction of all possible exon 6 genotypes. Genotyping of 70 schizophrenic patients and 77 controls showed that carrying at least one -2 bp deletion of exon 6 did not constitute a risk factor for schizophrenia. In contrast, the distribution of genotypes differed significantly between subjects with normal and abnormal P50 ratios, with an over-representation of genotypes carrying at least one -2 bp deletion of exon 6 among subjects exhibiting an abnormal P50 ratio. We thus conclude that the -2 bp deletion within the CHRNA7-like gene is a risk factor for P50 sensory gating deficit. Interestingly, most of the effect came from the non schizophrenic group, which may suggest that in schizophrenic patients other risk factors account for the large proportion of subjects exhibiting an abnormal P50 ratio. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Mol. Psychiatry 2002 -1 7: 1006-11 |
| PMID | 12399955 |
| Title | The -2 bp deletion in exon 6 of the 'alpha 7-like' nicotinic receptor subunit gene is a risk factor for the P50 sensory gating deficit. |
| Abstract | Abnormality in the P50 auditory-evoked potential gating is an endophenotype associated with schizophrenia. Biochemical and genetic studies have suggested that the alpha 7 nicotinic acetylcholine receptor (nAChR) is involved in this sensory gating deficit. Two related alpha 7 genes (CHRNA7 and CHRNA7-like gene) resulting from a partial duplication (from exon 5 to exon 10) are present in the human genome. Two types of genetic variation, a large deletion and a -2 base-pair deletion in exon 6 resulting in a truncation of the open reading frame, affect specifically the CHRNA7-like gene. We developed a simple multiplex PCR assay on genomic DNA, allowing the quantification of the number of exons 6 and the distinction of all possible exon 6 genotypes. Genotyping of 70 schizophrenic patients and 77 controls showed that carrying at least one -2 bp deletion of exon 6 did not constitute a risk factor for schizophrenia. In contrast, the distribution of genotypes differed significantly between subjects with normal and abnormal P50 ratios, with an over-representation of genotypes carrying at least one -2 bp deletion of exon 6 among subjects exhibiting an abnormal P50 ratio. We thus conclude that the -2 bp deletion within the CHRNA7-like gene is a risk factor for P50 sensory gating deficit. Interestingly, most of the effect came from the non schizophrenic group, which may suggest that in schizophrenic patients other risk factors account for the large proportion of subjects exhibiting an abnormal P50 ratio. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Mol. Psychiatry 2003 Mar 8: 259-60 |
| PMID | 12660798 |
| Title | A second large family with catatonic schizophrenia supports the region distally of CHRNA7 on chromosome 15q14-15. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | Mol. Psychiatry 2003 Feb 8: 145-6 |
| PMID | 12610645 |
| Title | Recombination in a schizophrenic proband fails to exclude CHRNA7 at chromosome 15q14. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Nov 123B: 39-49 |
| PMID | 14582144 |
| Title | Comparison of polymorphisms in the alpha7 nicotinic receptor gene and its partial duplication in schizophrenic and control subjects. |
| Abstract | The hypothesis that the 15q13-15 region of chromosome 15 contains a gene that contributes to the etiology of schizophrenia is supported by multiple genetic linkage studies. The alpha7 neuronal nicotinic acetylcholine receptor (CHRNA7) gene was selected as the best candidate gene in this region for molecular investigation, based on these linkage findings and biological evidence in both human and rodent models. CHRNA7 receptors are decreased in expression in postmortem brain of schizophrenic subjects. A dinucleotide marker, D15S1360, in intron two of the CHRNA7 gene is genetically linked to an auditory gating deficit found in schizophrenics and half of the first-degree relatives of patients. Single strand conformation polymorphism (SSCP) and sequence analyses of DNA from schizophrenic and control individuals identified 33 variants in the coding region and intron/exon borders of the CHRNA7 gene and its partial duplication, dupCHRNA7; common polymorphisms were mapped. Twenty-one variants were found in the exons, but non-synonymous changes were rare. Although the expression of CHRNA7 is decreased in schizophrenia, the general structure of the remaining receptors is likely to be normal. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Nov 123B: 39-49 |
| PMID | 14582144 |
| Title | Comparison of polymorphisms in the alpha7 nicotinic receptor gene and its partial duplication in schizophrenic and control subjects. |
| Abstract | The hypothesis that the 15q13-15 region of chromosome 15 contains a gene that contributes to the etiology of schizophrenia is supported by multiple genetic linkage studies. The alpha7 neuronal nicotinic acetylcholine receptor (CHRNA7) gene was selected as the best candidate gene in this region for molecular investigation, based on these linkage findings and biological evidence in both human and rodent models. CHRNA7 receptors are decreased in expression in postmortem brain of schizophrenic subjects. A dinucleotide marker, D15S1360, in intron two of the CHRNA7 gene is genetically linked to an auditory gating deficit found in schizophrenics and half of the first-degree relatives of patients. Single strand conformation polymorphism (SSCP) and sequence analyses of DNA from schizophrenic and control individuals identified 33 variants in the coding region and intron/exon borders of the CHRNA7 gene and its partial duplication, dupCHRNA7; common polymorphisms were mapped. Twenty-one variants were found in the exons, but non-synonymous changes were rare. Although the expression of CHRNA7 is decreased in schizophrenia, the general structure of the remaining receptors is likely to be normal. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Nov 123B: 39-49 |
| PMID | 14582144 |
| Title | Comparison of polymorphisms in the alpha7 nicotinic receptor gene and its partial duplication in schizophrenic and control subjects. |
| Abstract | The hypothesis that the 15q13-15 region of chromosome 15 contains a gene that contributes to the etiology of schizophrenia is supported by multiple genetic linkage studies. The alpha7 neuronal nicotinic acetylcholine receptor (CHRNA7) gene was selected as the best candidate gene in this region for molecular investigation, based on these linkage findings and biological evidence in both human and rodent models. CHRNA7 receptors are decreased in expression in postmortem brain of schizophrenic subjects. A dinucleotide marker, D15S1360, in intron two of the CHRNA7 gene is genetically linked to an auditory gating deficit found in schizophrenics and half of the first-degree relatives of patients. Single strand conformation polymorphism (SSCP) and sequence analyses of DNA from schizophrenic and control individuals identified 33 variants in the coding region and intron/exon borders of the CHRNA7 gene and its partial duplication, dupCHRNA7; common polymorphisms were mapped. Twenty-one variants were found in the exons, but non-synonymous changes were rare. Although the expression of CHRNA7 is decreased in schizophrenia, the general structure of the remaining receptors is likely to be normal. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Neuropsychobiology 2004 -1 50: 124-7 |
| PMID | 15292665 |
| Title | Linkage of M5 muscarinic and alpha7-nicotinic receptor genes on 15q13 to schizophrenia. |
| Abstract | Most antipsychotic drugs act on the forebrain by blocking dopamine receptors. In rodents, the M5 muscarinic receptor (CHRM5) is important for prolonged dopamine release. We typed polymorphisms in CHRM5 and alpha7-nicotinic receptor (CHRNA7) genes on 15q13 in 82 Canadian families having at least 1 schizophrenic patient. Using the Family-Based Association Test, we performed haplotype analysis of the 2 loci and found biased transmission in schizophrenia (z = -2.651, p = 0.008). In the families tested, the 2 cholinergic genes interacted to affect schizophrenia in combination, while neither was sufficiently alone to confer susceptibility. Our present study provided the first line of direct evidence suggesting that the CHRM5 gene combined with the CHRNA7 gene may be linked to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Hum. Hered. 2004 -1 57: 59-68 |
| PMID | 15192278 |
| Title | A novel permutation testing method implicates sixteen nicotinic acetylcholine receptor genes as risk factors for smoking in schizophrenia families. |
| Abstract | Smoking is a common correlate of schizophrenia, which leads to medical morbidity. Although twin and adoption studies have consistently implicated genes in the etiology of both smoking and schizophrenia, finding genes has been difficult. Several authors have suggested that clinical or neurobiological features associated with schizophrenia, such as smoking, might improve the ability to detect schizophrenia susceptibility genes by identifying genes related to the etiology of that feature. The objective of this study is to assess evidence for linkage of sixteen nicotinic acetylcholine receptor genes and smoking in schizophrenia families, using data from the NIMH Genetics Initiative for schizophrenia. Sixteen nicotinic acetylcholine receptor genes were selected prior to analysis. We used a multipoint sibling pair linkage analysis program, SIBPAL2, with a smoking trait in schizophrenia families. The significance of the group of candidate genes, in addition to each individual candidate gene, was assessed using permutation testing, which adjusted for multiple comparisons. The group of genes showed significant linkage to the smoking trait after adjusting for multiple comparisons through permutation testing (p = 0.039). In addition, two of the individual candidate genes were significant (CHRNA2, p = 0.044) and (CHRNB2, p = 0.015) and two genes were marginally significant (CHRNA7, p = 0.095; CHRNA1, p = 0.076). The significance of the complex hypothesis, involving sixteen genes, implicates the nicotinic system in smoking for schizophrenic families. Individual gene analysis suggests that CHRNA2 and CHRNB2 may play a particular role in this involvement. Such findings help prioritize genes for future case control studies. In addition, we provide a novel permutation method that is useful in future analyses involving a single hypothesis, with multiple candidate genes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Mol. Psychiatry 2004 Mar 9: 320-2 |
| PMID | 14569275 |
| Title | The promoter -194 C polymorphism of the nicotinic alpha 7 receptor gene has a protective effect against the P50 sensory gating deficit. |
| Abstract | As suggested by several studies, abnormal sensory gating measured by the P50 paradigm could be an endophenotype predisposing to schizophrenia. In a previous work, we have shown a significant association between the presence of at least one -2 bp deletion located within exon 6 of the CHRNA7-like gene and the P50 abnormality in the general population. A recent study involved polymorphisms located in the core promoter region of the CHRNA7 gene as risk factors for the P50 inhibitory deficit. Screening for promoter variants in a large population of schizophrenic patients (n=111) and control subjects (85), for whom auditory-evoked potentials had been recorded did not allow us to replicate these results. By contrast, we showed a significant association between the -194 C allele and a T/C ratio <0.45, thus demonstrating a protective effect of this variant for the sensory gating deficit. Such conflicting results can be reconciled if we consider that the -194 C polymorphism has no causative effect, but is in linkage disequilibrium with other causal variations for the P50 sensory gating deficit, and that different alleles are in disequilibrium in different populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | Neuropsychobiology 2004 -1 50: 124-7 |
| PMID | 15292665 |
| Title | Linkage of M5 muscarinic and alpha7-nicotinic receptor genes on 15q13 to schizophrenia. |
| Abstract | Most antipsychotic drugs act on the forebrain by blocking dopamine receptors. In rodents, the M5 muscarinic receptor (CHRM5) is important for prolonged dopamine release. We typed polymorphisms in CHRM5 and alpha7-nicotinic receptor (CHRNA7) genes on 15q13 in 82 Canadian families having at least 1 schizophrenic patient. Using the Family-Based Association Test, we performed haplotype analysis of the 2 loci and found biased transmission in schizophrenia (z = -2.651, p = 0.008). In the families tested, the 2 cholinergic genes interacted to affect schizophrenia in combination, while neither was sufficiently alone to confer susceptibility. Our present study provided the first line of direct evidence suggesting that the CHRM5 gene combined with the CHRNA7 gene may be linked to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | Mol. Psychiatry 2004 Mar 9: 320-2 |
| PMID | 14569275 |
| Title | The promoter -194 C polymorphism of the nicotinic alpha 7 receptor gene has a protective effect against the P50 sensory gating deficit. |
| Abstract | As suggested by several studies, abnormal sensory gating measured by the P50 paradigm could be an endophenotype predisposing to schizophrenia. In a previous work, we have shown a significant association between the presence of at least one -2 bp deletion located within exon 6 of the CHRNA7-like gene and the P50 abnormality in the general population. A recent study involved polymorphisms located in the core promoter region of the CHRNA7 gene as risk factors for the P50 inhibitory deficit. Screening for promoter variants in a large population of schizophrenic patients (n=111) and control subjects (85), for whom auditory-evoked potentials had been recorded did not allow us to replicate these results. By contrast, we showed a significant association between the -194 C allele and a T/C ratio <0.45, thus demonstrating a protective effect of this variant for the sensory gating deficit. Such conflicting results can be reconciled if we consider that the -194 C polymorphism has no causative effect, but is in linkage disequilibrium with other causal variations for the P50 sensory gating deficit, and that different alleles are in disequilibrium in different populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | Hum. Hered. 2004 -1 57: 59-68 |
| PMID | 15192278 |
| Title | A novel permutation testing method implicates sixteen nicotinic acetylcholine receptor genes as risk factors for smoking in schizophrenia families. |
| Abstract | Smoking is a common correlate of schizophrenia, which leads to medical morbidity. Although twin and adoption studies have consistently implicated genes in the etiology of both smoking and schizophrenia, finding genes has been difficult. Several authors have suggested that clinical or neurobiological features associated with schizophrenia, such as smoking, might improve the ability to detect schizophrenia susceptibility genes by identifying genes related to the etiology of that feature. The objective of this study is to assess evidence for linkage of sixteen nicotinic acetylcholine receptor genes and smoking in schizophrenia families, using data from the NIMH Genetics Initiative for schizophrenia. Sixteen nicotinic acetylcholine receptor genes were selected prior to analysis. We used a multipoint sibling pair linkage analysis program, SIBPAL2, with a smoking trait in schizophrenia families. The significance of the group of candidate genes, in addition to each individual candidate gene, was assessed using permutation testing, which adjusted for multiple comparisons. The group of genes showed significant linkage to the smoking trait after adjusting for multiple comparisons through permutation testing (p = 0.039). In addition, two of the individual candidate genes were significant (CHRNA2, p = 0.044) and (CHRNB2, p = 0.015) and two genes were marginally significant (CHRNA7, p = 0.095; CHRNA1, p = 0.076). The significance of the complex hypothesis, involving sixteen genes, implicates the nicotinic system in smoking for schizophrenic families. Individual gene analysis suggests that CHRNA2 and CHRNB2 may play a particular role in this involvement. Such findings help prioritize genes for future case control studies. In addition, we provide a novel permutation method that is useful in future analyses involving a single hypothesis, with multiple candidate genes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | Dialogues Clin Neurosci 2005 -1 7: 17-29 |
| PMID | 16060593 |
| Title | Early biomarkers of psychosis. |
| Abstract | Biological traits that are predictive of the later development of psychosis have not yet been identified. The complex, multidetermined nature of schizophrenia and other psychoses makes it unlikely that any single biomarker will be both sensitive and specific enough to unambiguously identify individuals who will later become psychotic. However, current genetic research has begun to identify genes associated with schizophrenia, some of which have phenotypes that appear early in life. While these phenotypes have low predictive power for identifying individuals who will become psychotic, they do serve as biomarkers for pathophysiological processes that can become the targets of prevention strategies. Examples are given from work on the role of the alpha(T)nicotinic receptor and its gene CHRNA7 on chromosome 15 in the neurobiology and genetic transmission of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | BMC Genomics 2005 -1 6: 157 |
| PMID | 16280085 |
| Title | Genetic mapping of putative Chrna7 and Luzp2 neuronal transcriptional enhancers due to impact of a transgene-insertion and 6.8 Mb deletion in a mouse model of Prader-Willi and Angelman syndromes. |
| Abstract | Prader-Willi and Angelman syndrome (PWS and AS) patients typically have an approximately 5 Mb deletion of human chromosome 15q11-q13, of opposite parental origin. A mouse model of PWS and AS has a transgenic insertion-deletion (TgPWS/TgAS) of chromosome 7B/C subsequent to paternal or maternal inheritance, respectively. In this study, we define the deletion endpoints and examine the impact on expression of flanking genes. Using molecular and cytological methods we demonstrate that 13 imprinted and 11 non-imprinted genes are included in the TgPWS/TgAS deletion. Normal expression levels were found in TgPWS brain for genes extending 9.1- or 5.6-Mb centromeric or telomeric of the deletion, respectively. Our molecular cytological studies map the proximal deletion breakpoint between the Luzp2 and Siglec-H loci, and we show that overall mRNA levels of Luzp2 in TgPWS and TgAS brain are significantly reduced by 17%. Intriguingly, 5' CHRNA7 shows 1.7-fold decreased levels in TgPWS and TgAS brain whereas there is a > or =15-fold increase in expression in neonatal liver and spleen of these mouse models. By isolating a CHRNA7-Tg fusion transcript from TgAS mice, we mapped the telomeric deletion breakpoint in CHRNA7 intron 4. Based on the extent of the deletion, TgPWS/TgAS mice are models for PWS/AS class I deletions. Other than for the first gene promoters immediately outside the deletion, since genes extending 5.6-9.1 Mb away from each end of the deletion show normal expression levels in TgPWS brain, this indicates that the transgene array does not induce silencing and there are no additional linked rearrangements. Using gene expression, non-coding conserved sequence (NCCS) and synteny data, we have genetically mapped a putative Luzp2 neuronal enhancer responsible for approximately 33% of allelic transcriptional activity. The CHRNA7 results are explained by hypothesizing loss of an essential neuronal transcriptional enhancer required for approximately 80% of allelic CHRNA7 promoter activity, while the CHRNA7 promoter is upregulated in B lymphocytes by the transgene immunoglobulin enhancer. The mapping of a putative CHRNA7 neuronal enhancer inside the deletion has significant implications for understanding the transcriptional regulation of this schizophrenia-susceptibility candidate gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | Schizophr. Res. 2006 Jun 84: 253-71 |
| PMID | 16632332 |
| Title | Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia. |
| Abstract | Neurodevelopmental changes may underlie the brain dysfunction seen in schizophrenia. While advances have been made in our understanding of the genetics of schizophrenia, little is known about how non-genetic factors interact with genes for schizophrenia. The present analysis of genes potentially associated with schizophrenia is based on the observation that hypoxia prevails in the embryonic and fetal brain, and that interactions between neuronal genes, molecular regulators of hypoxia, such as hypoxia-inducible factor 1 (HIF-1), and intrinsic hypoxia occur in the developing brain and may create the conditions for complex changes in neurodevelopment. Consequently, we searched the literature for currently hypothesized candidate genes for susceptibility to schizophrenia that may be subject to ischemia-hypoxia regulation and/or associated with vascular expression. Genes were considered when at least two independent reports of a significant association with schizophrenia had appeared in the literature. The analysis showed that more than 50% of these genes, particularly AKT1, BDNF, CAPON, CCKAR, CHRNA7, CNR1, COMT, DNTBP1, GAD1, GRM3, IL10, MLC1, NOTCH4, NRG1, NR4A2/NURR1, PRODH, RELN, RGS4, RTN4/NOGO and TNF, are subject to regulation by hypoxia and/or are expressed in the vasculature. Future studies of genes proposed as candidates for susceptibility to schizophrenia should include their possible regulation by physiological or pathological hypoxia during development as well as their potential role in cerebral vascular function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 31 | Psychiatr Hung 2006 -1 21: 404-12 |
| PMID | 17438657 |
| Title | [Gene polymorphism and gene expression in schizophrenia]. |
| Abstract | The author reviews relevant data on the neuropathology and molecular genetics of schizophrenia. Anatomical alterations are localized mainly in the hippocampus, dorsal thalamus and dorsolateral prefrontal cortex, and involve the morphology and molecular structure of the neurons and synapses. Several susceptibility genes [including COMT, dysbindin, neuregulin, DISCI, RGS4, GRM3, G72, PPP3CC, CHRNA7, PRODH2, Aktl, 5qGABA(A)] having physiological function in the brain have been identified and this supports the view of schizophrenia as a disorder of cerebral synaptic function. NMDA receptor-mediated glutamate transmission may be particularly involved, but disturbances of dopamine and GABA signalling seem to be linked as well. Based on recent data, an agreement is emerging between the roles of the genes on the molecular and synaptic levels and the understanding of the disorder at the neural systems level. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 32 | Am J Psychiatry 2006 Oct 163: 1832-4 |
| PMID | 17012698 |
| Title | Episodic memory performance predicted by the 2bp deletion in exon 6 of the "alpha 7-like" nicotinic receptor subunit gene. |
| Abstract | There is evidence of linkage between chromosome 15q14 and the P50 auditory evoked response, a heritable neuropsychological marker associated with increased risk of schizophrenia. Chromosome 15q14 harbors the alpha-7 nicotinic receptor subunit gene (CHRNA7) and a hybrid gene of unknown function (CHRFAM7A). CHRNA7 is involved in memory formation, a core dysfunction in schizophrenia. The authors set out to determine if this locus is associated with memory dysfunction in schizophrenia. A 2bp deletion in exon 6 of CHRFAM7A, which disrupts the hybrid gene and has previously been associated with P50 deficit, was genotyped in 251 individuals from the Maudsley Family Study of schizophrenia. Episodic memory function was assessed using the Wechsler Memory Scale. Significant associations were identified with delayed recall and percentage retained, with the presence of the deletion predicting worse performance. These observations indicate that episodic memory function is a schizophrenia endophenotype and implicate the CHRFAM7A/CHRNA7 locus in modulating its function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 33 | Genes Brain Behav. 2006 Aug 5: 433-40 |
| PMID | 16923147 |
| Title | Performance deficit of alpha7 nicotinic receptor knockout mice in a delayed matching-to-place task suggests a mild impairment of working/episodic-like memory. |
| Abstract | Patients with schizophrenia exhibit deficits in a range of cognitive functions, particularly working and episodic memory, which are thought to be core features of the disorder. Memory dysfunction in schizophrenia is familial and thus a promising endophenotype for genetic studies. Both human and animal studies suggest a role for the neural nicotinic acid receptor family in cognition and specifically the alpha7-receptor subunit in schizophrenia and its endophenotypes. Consequently, we tested mice lacking the alpha7 subunit of the neural nicotinic receptor (B6.129S7-CHRNA7(tm1Bay)/J) in the delayed matching-to-place (DMP) task of the Morris water maze, a measure of working/episodic memory akin to human episodic memory. We report that a minor impairment in alpha7 knockout mice was observed in the DMP task, with knockout mice taking longer to find the hidden platform than their wildtype controls. This suggests a role for the alpha7 subunit in working/episodic memory and a potential role for the alpha7 neural nicotinic receptor gene (CHRNA7) in schizophrenia and its endophenotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 34 | Acta Psychiatr Scand 2006 Sep 114: 211-5 |
| PMID | 16889592 |
| Title | Regulation of alpha7-nicotinic receptor subunit and alpha7-like gene expression in the prefrontal cortex of patients with bipolar disorder and schizophrenia. |
| Abstract | The alpha7-nicotinic receptor subunit gene (CHRNA7) is located at chromosome 15q13-14, a region previously linked with schizophrenia. Genetic association and mRNA expression studies also implicate CHRNA7 in schizophrenia. The CHRNA7 gene has a partial duplication that constitutes the alpha7-like nicotinic receptor gene (CHRFAM7A). We hypothesized that major psychoses could affect the expression of both CHRNA7 and CHRFAM7A. CHRNA7 and CHRFAM7A mRNA levels were measured in postmortem prefrontal cortex (donated by the Stanley Foundation) from subjects with schizophrenia, bipolar disorder and unaffected controls (n = 35 each). The mRNA levels of alpha7 and alpha7-like genes have a positive correlation overall (r = 0.25; P = 0.009), however, there is no significant difference in the expression of CHRNA7 among the three diagnostic groups. This correlation is driven by the bipolar group (r = 0.43; P = 0.009), and is absent in schizophrenia and unaffected controls, suggesting an alteration in the CHRNA7:CHRFAM7A ratio in bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 35 | Biol. Psychiatry 2006 Jul 60: 115-22 |
| PMID | 16843094 |
| Title | Genetics of chromosome 15q13-q14 in schizophrenia. |
| Abstract | Positive genetic linkage to the 15q13-q14 region has been found in 11 studies, and several association reports support this locus as a candidate region for schizophrenia. The locus is unusual in that it was first linked to an endophenotype found in schizophrenia, the P50 deficit, and subsequently to schizophrenia. There is also biological data showing that a candidate gene in the region, the alpha7 nicotinic receptor CHRNA7, plays a seminal role in the linked endophenotype, and is decreased in expression in the patient population. The 15q13-q14 region is complicated by a partial duplication of the CHRNA7 gene that includes exons 5-10 and considerable sequence downstream. Evidence from multiple studies supports a broad region of genetic linkage around the marker D15S1360. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 36 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Sep 141B: 571-5 |
| PMID | 16823804 |
| Title | Association study of CHRFAM7A copy number and 2 bp deletion polymorphisms with schizophrenia and bipolar affective disorder. |
| Abstract | schizophrenia and bipolar disorder are major psychiatric diseases that have a strong genetic element. Markers in the vicinity of the CHRNA7 gene at 15q13-q14 have been linked with an endophenotype of schizophrenia, P50 sensory gating disorder, with schizophrenia itself and with bipolar disorder. We have measured the copy number of the polymorphic partial duplication of CHRNA7 (CHRFAM7A) and genotyped a polymorphic 2 bp deletion within exon 6 of CHRFAM7A. In this study, 208 probands with a primary diagnosis of schizophrenia, 217 with a diagnosis of bipolar affective disorder and 28 with schizoaffective or other psychotic disorders were examined together with 197 controls recruited from the same region in Scotland. No significant association was seen for schizophrenia and bipolar disorder by genotype or allele overall for either polymorphism, but a mildly significant association by genotype (P = 0.04) was observed for absence of CHRFAM7A when the sample was analyzed as a single psychosis phenotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 37 | Schizophr. Res. 2006 Jun 84: 222-7 |
| PMID | 16563701 |
| Title | Population-based and family-based association studies of an (AC)n dinucleotide repeat in alpha-7 nicotinic receptor subunit gene and schizophrenia. |
| Abstract | The human alpha-7 neuronal nicotinic receptor subunit (CHRNA7) gene, located at chromosome 15q13.2, represents a strong candidate gene for schizophrenia. We have examined an (AC)n dinucleotide repeat in intron 2 of the CHRNA7 gene, which was previously shown to be strongly linked with schizophrenia, using both population-based and family-based association studies. In the population-based study, no significant differences between the genotype and allele frequency distributions in schizophrenia patients and control subjects were observed after correction for multiple testing, although a nominally significant association between the most common allele and schizophrenia was observed (P = 0.023, uncorrected for multiple testing). In the family-based study, there is no significant over-transmission (Transmitted/Non-transmitted: 61/50) of the same allele in 160 family trios. Overall, our results do not support a major role for the (AC)n dinucleotide repeat in schizophrenia susceptibility in Han Chinese. Further large-scale genetic studies based on a set of single nucleotide polymorphisms (SNPs) that fully characterize the linkage disequilibrium patterns at the CHRNA7 gene are necessary to determine the relevance of this gene as a risk factor for schizophrenia susceptibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 38 | Genes Brain Behav. 2006 -1 5 Suppl 1: 14-22 |
| PMID | 16417613 |
| Title | Characterization of allelic variants at chromosome 15q14 in schizophrenia. |
| Abstract | Evidence of genetic linkage for schizophrenia at chromosome 15q14 has been reported in nine independent studies, but the molecular variants responsible for transmission of genetic risk are unknown. National Institute of Mental Health schizophrenia Genetics Initiative families were genotyped for single nucleotide polymorphisms (SNPs) and dinucleotide repeat markers in the 15q14 linkage region and analyzed based on the presence of particular alleles of the dinucleotide repeat marker D15S165 in the 15q14 region. Two alleles showed both familial transmission disequilibrium and population-wide association with schizophrenia. The two groups identified by these two D15S165 alleles differ in age of onset, number of hospitalizations and intensity of nicotine abuse, as well as in predominant ethnicity. Variations in the frequency of SNPs in CHRNA7, the alpha-7-nicotinic acetylcholine receptor subunit gene at 15q14, were found in each group. Further sequencing in these two groups may yield more definitive identification of the molecular pathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 39 | Arch. Gen. Psychiatry 2006 Jun 63: 630-8 |
| PMID | 16754836 |
| Title | Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. |
| Abstract | The alpha7 nicotinic acetylcholine receptor gene, CHRNA7, is associated with genetic transmission of schizophrenia and related cognitive and neurophysiological sensory gating deficits. Cognitive dysfunction is responsible for significant psychosocial disability in schizophrenia. Nicotine, a low-potency agonist at the alpha7 receptor, has some positive effects on neurophysiological and neurocognitive deficits associated with schizophrenia, which suggests that more effective receptor activation might meaningfully enhance cognition in schizophrenia. To determine if 3-[(2,4-dimethoxy)benzylidene]anabaseine (DMXB-A), a natural alkaloid derivative and a partial alpha7 nicotinic cholinergic agonist, significantly improves neurocognition, and to assess, by effects on P50 auditory evoked potential inhibition, whether its neurobiological actions are consistent with activation of alpha7 nicotinic receptors. Randomized, double-blind crossover trial of 2 drug doses and 1 placebo. General clinical research center. Twelve persons with schizophrenia who did not smoke and were concurrently treated with antipsychotic drugs. One person was withdrawn because of a transient decrease in white blood cell count. Administration of DMXB-A. Total scale score of the Repeatable Battery for the Assessment of Neuropsychological Status and P50 inhibitory gating. Significant neurocognitive improvement was found on the Repeatable Battery for the Assessment of Neuropsychological Status total scale score, particularly for the lower DMXB-A dose compared with placebo. Effects were greater than those of nicotine in a similar study. Significant improvement in P50 inhibition also occurred. Patients generally tolerated the drug well. An alpha7 nicotinic agonist appears to have positive effects on neurocognition in persons with schizophrenia. Longer trials are needed to determine the clinical utility of this novel treatment strategy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 40 | J Psychiatry Neurosci 2007 Nov 32: 412-6 |
| PMID | 18043764 |
| Title | Association of alpha4beta2 nicotinic receptor and heavy smoking in schizophrenia. |
| Abstract | Previously we suggested that the CHRNA7 polymorphism in nicotinic receptor genes, in particular the D15S1360 in CHRNA7, is associated with smoking in schizophrenia. schizophrenia patients are usually heavy smokers. In this study we hypothesized that high-affinity nicotinic receptors are associated with smoking in such patients. To investigate the role of alpha4 (Ch 20) and beta2 (Ch 1) genes in conferring a risk for smoking and for smoking a large number of cigarettes daily in subjects with schizophrenia. Our study sample consisted of 241 white European schizophrenia patients (157 smokers and 84 nonsmokers) from the Toronto area. Current smoking status was assessed by the medical history. We investigated 4 markers located in the CHRNA4 gene and 3 markers located in the CHRNB2 gene. There was no difference in age or ethnicity between the 2 groups and the population was not stratified (lambda=0.4527). We found a significant association between the CHRNA4 rs3746372 allele 1 and a large number of cigarettes smoked daily (p=0.0203). The intragenic interaction between rs3787116 and rs3746372 (p = 0.0050) in CHRNA4 showed a significant interaction for the number of cigarettes smoked. Although our findings suggest an association between rs3746372 allele 1 and heavy smoking, further study is warranted to investigate the relation between smoking and high-affinity nicotinic receptor genes in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 41 | Br J Psychiatry 2007 Nov 191: 402-7 |
| PMID | 17978319 |
| Title | Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use. |
| Abstract | Genetic variations might modify associations between schizophrenia and cannabis or tobacco use. To examine whether variants within the cannabinoid receptor (CNR1) and alpha(7) nicotinic receptor (CHRNA7) genes are associated with schizophrenia, and whether these effects vary according to cannabis or tobacco use. We also examined a putative interaction between cannabis and Val(158)Met within the catechol-O-methyltransferase gene (COMT). Genotype effects of CHRNA7 and CNR1were studied in a case-control sample of 750 individuals with schizophrenia and 688 controls, with interactions for these genes studied in small subsamples. A case-only design of 493 ofthe schizophrenia group was used to examine interactions between cannabis use and COMT. There was no evidence of association between schizophrenia and CNR1 (OR=0.97, 95% CI 0.82-1.13) or CHRNA7 (OR=1.07, 95% CI 0.77-1.49) genotypes, or of interactions between tobacco use and CHRNA7, or cannabis use and CNR1or COMT genotypes. Neither CNR1 nor CHRNA7 variation appears to alter the risk of schizophrenia. Furthermore, our results do not support the presence of different effects of cannabis use on schizophrenia according to variation within COMT. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 42 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Jul 144B: 611-4 |
| PMID | 17192894 |
| Title | Sensory gating and alpha-7 nicotinic receptor gene allelic variants in schizoaffective disorder, bipolar type. |
| Abstract | Single nucleotide allelic variants in the promoter region of the chromosome 15 alpha-7 acetylcholine nicotinic receptor gene (CHRNA7) are associated with both schizophrenia and the P50 auditory evoked potential sensory gating deficit. The purpose of this study was to determine if CHRNA7 promoter allelic variants are also associated with abnormal P50 ratios in persons with schizoaffective disorder, bipolar type. P50 auditory evoked potentials were recorded in a paired stimulus paradigm in 17 subjects with schizoaffective disorder, bipolar type. The P50 test to conditioning ratio was used as the measure of sensory gating. Mutation screening of the CHRNA7 promoter region was performed on the subjects' DNA samples. Comparisons to previously obtained data from persons with schizophrenia and controls were made. Subjects with schizophrenia, regardless of allele status, had an abnormal mean P50 ratio. Subjects with schizoaffective disorder, bipolar type and a variant allele had an abnormal mean P50 ratio, whereas those schizoaffective subjects with the common alleles had a normal mean P50 ratio. Normal control subjects had a normal mean ratio, but controls with variant alleles had higher P50 ratios. In persons with bipolar type schizoaffective disorder, CHRNA7 promoter region allelic variants are linked to the capacity to inhibit the P50 auditory evoked potential and thus are associated with a type of illness genetically and biologically more similar to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 43 | Neurosci. Res. 2007 Feb 57: 194-202 |
| PMID | 17113175 |
| Title | Linkage disequilibrium analysis of the CHRNA7 gene and its partially duplicated region in schizophrenia. |
| Abstract | Several previous studies have reported a significant linkage between markers in the alpha 7 nicotinic cholinergic receptor subunit (CHRNA7) gene and either schizophrenia or the P50 sensory gating deficit, a schizophrenia endophenotype. However, CHRFAM7A, a partially duplicated gene 1.6Mb upstream of the CHRNA7 gene, has complicated further genetic analysis. We genotyped 14 polymorphic markers throughout the full-length CHRNA7 gene and the duplicated region in 188 unrelated Han Chinese patients with schizophrenia and 188 controls. The duplicated regions were assessed by genotyping up- and down-stream polymorphic markers in the vicinity of each region and analyzing the linkage disequilibrium (LD) between each pair of markers. No evidence of risk variants for schizophrenia in either the CHRNA7 gene or the partially duplicated region was found in the LD analysis. A significant deviation from the Hardy-Weinberg equilibrium (HWE) was found only in the genotypic distribution of SNP9 (IVS4-1912) in patients (p=0.00829), but not in controls. In conclusion, our LD analysis did not reveal any association between schizophrenia in our Han Chinese population and the CHRNA7 gene or its partially duplicated region. However, we could not exclude the possibility of a weak genetic effect due to the small sample size. Analyses of larger samples and higher-density markers, particularly around SNP9 (IVS4-1912), are still needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 44 | Am J Psychiatry 2008 Apr 165: 497-506 |
| PMID | 18198266 |
| Title | No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. |
| Abstract | The authors carried out a genetic association study of 14 schizophrenia candidate genes (RGS4, DISC1, DTNBP1, STX7, TAAR6, PPP3CC, NRG1, DRD2, HTR2A, DAOA, AKT1, CHRNA7, COMT, and ARVCF). This study tested the hypothesis of association of schizophrenia with common single nucleotide polymorphisms (SNPs) in these genes using the largest sample to date that has been collected with uniform clinical methods and the most comprehensive set of SNPs in each gene. The sample included 1,870 cases (schizophrenia and schizoaffective disorder) and 2,002 screened comparison subjects (i.e. controls), all of European ancestry, with ancestral outliers excluded based on analysis of ancestry-informative markers. The authors genotyped 789 SNPs, including tags for most common SNPs in each gene, SNPs previously reported as associated, and SNPs located in functional domains of genes such as promoters, coding exons (including nonsynonymous SNPs), 3' untranslated regions, and conserved noncoding sequences. After extensive data cleaning, 648 SNPs were analyzed for association of single SNPs and of haplotypes. Neither experiment-wide nor gene-wide statistical significance was observed in the primary single-SNP analyses or in secondary analyses of haplotypes or of imputed genotypes for additional common HapMap SNPs. Results in SNPs previously reported as associated with schizophrenia were consistent with chance expectation, and four functional polymorphisms in COMT, DRD2, and HTR2A did not produce nominally significant evidence to support previous evidence for association. It is unlikely that common SNPs in these genes account for a substantial proportion of the genetic risk for schizophrenia, although small effects cannot be ruled out. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 45 | Mol. Psychiatry 2008 Sep 13: 873-7 |
| PMID | 18195713 |
| Title | Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk. |
| Abstract | The etiology of schizophrenia is thought to include both epistasis and gene-environment interactions. We sought to test whether a set of schizophrenia candidate genes regulated by hypoxia or involved in vascular function in the brain (AKT1, BDNF, CAPON, CHRNA7, COMT, DTNBP1, GAD1, GRM3, NOTCH4, NRG1, PRODH, RGS4, TNF-alpha) interacted with serious obstetric complications to influence risk for schizophrenia. A family-based study of transmission disequilibrium was conducted in 116 trios. Twenty-nine probands had at least one serious obstetric complication (OC) using the McNeil-Sjostrom Scale, and many of the OCs reported were associated with the potential for fetal hypoxia. Analyses were conducted using conditional logistic regression and a likelihood ratio test (LRT) between nested models was performed to assess significance. Of the 13 genes examined, four (AKT1 (three SNPs), BDNF (two SNPs), DTNBP1 (one SNP) and GRM3 (one SNP)) showed significant evidence for gene-by-environment interaction (LRT P-values ranged from 0.011 to 0.037). Although our sample size was modest and the power to detect interactions was limited, we report significant evidence for genes involved in neurovascular function or regulated by hypoxia interacting with the presence of serious obstetric complications to increase risk for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 46 | Neuromolecular Med. 2008 -1 10: 377-84 |
| PMID | 18696274 |
| Title | Genetic variation in the alpha 7 nicotinic acetylcholine receptor is associated with delusional symptoms in Alzheimer's disease. |
| Abstract | Psychotic symptoms are common in Alzheimer's disease (AD) and have a negative impact on quality of life. It is suggested that psychotic symptoms may be attributed to genetic risk factors which are revealed during neurodegeneration. CHRNA7, the gene for the alpha 7 nicotinic acetylcholine receptor, has been associated with schizophrenia in linkage and association studies. Hence we investigated single SNPs and haplotypes in CHRNA7 in relation to AD with psychosis in a large, well-characterised and previously described cohort within the Northern Ireland population. A significant association between delusions and the T allele of rs6494223 (P = 0.014, OR = 1.63, CI = 1.22-2.17) was found. This suggests that the alpha 7 receptor may be a suitable target for the treatment of AD with psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 47 | Eur. J. Hum. Genet. 2008 Nov 16: 1364-71 |
| PMID | 18545269 |
| Title | The copy number variant involving part of the alpha7 nicotinic receptor gene contains a polymorphic inversion. |
| Abstract | The alpha7 nicotinic acetylcholine receptor gene (CHRNA7) is located at 15q13-q14 in a region that is strongly linked to the P50 sensory gating deficit, an endophenotype of schizophrenia and bipolar disorder. Part of the gene is a copy number variant, due to a duplication of exons 5-10 and 3' sequence in CHRFAM7A, which is present in many but not all humans. Maps of this region show that the two genes are in opposite orientation in the individual mainly represented in the public access human DNA sequence database (Build 36), suggesting that an inversion had occurred since the duplication. We have used fluorescent in situ hybridization to investigate this putative inversion. Analysis of interphase chromosomes in 12 individuals confirms the occurrence of an inversion and indicates that CHRFAM7A exists in both orientations with similar frequency. We showed that the 2 bp deletion polymorphism in exon 6 of CHRFAM7A is in strong linkage disequilibrium with the inversion polymorphism (r(2)=0.82, CI 0.53-1.00, P=0.00003), which can therefore be used as a surrogate marker. Previous associations of endophenotypes of schizophrenia with the 2 bp deletion might therefore be due to the orientation of the duplicon containing CHRFAM7A. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 48 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2008 Apr 25: 154-8 |
| PMID | 18393235 |
| Title | [The transmission disequilibrium analysis between neuronal nicotinic acetylcholine receptor alpha 7 subunit gene polymorphisms and schizophrenia]. |
| Abstract | To investigate the association between neuronal nicotinic acetylcholine receptor alpha 7 subunit (CHRNA7) gene and schizophrenia. The three polymorphisms rs2337980, rs1909884, rs883473 in CHRNA7 gene were detected based on PCR and polyacrylamide gel microarray in 129 schizophrenic trios. The results of genotyping were analyzed by haplotype relative risk analysis based on haplotype(HHRR), transmission disequilibrium test(TDT) and hyplotype analysis. (1)The HHRR analysis suggested that there was significant differences in rs2337980 allele frequencies between schizophrenia group and dummy control group(P= 0.017); (2)In TDT test, there may be transmission disequilibrium between rs2337980 and schizophrenia, the heterozygous parents excessively transferred the C allele to patients (P= 0.021); (3)The haplotype between rs2337980 and rs1909884 as well as the hyplotype among rs2337980, rs1909884 and rs883473 may have significant association with schizophrenia (global P= 0.034; global P= 0.027), the T-C and T-C-T hyplotype may have transmission disequilibrium with schizophrenia. There may be association between CHRNA7 gene polymorphisms and schizophrenia, the variant allele T in rs2337980 may have a protective effect to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 49 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2008 Apr 25: 154-8 |
| PMID | 18393235 |
| Title | [The transmission disequilibrium analysis between neuronal nicotinic acetylcholine receptor alpha 7 subunit gene polymorphisms and schizophrenia]. |
| Abstract | To investigate the association between neuronal nicotinic acetylcholine receptor alpha 7 subunit (CHRNA7) gene and schizophrenia. The three polymorphisms rs2337980, rs1909884, rs883473 in CHRNA7 gene were detected based on PCR and polyacrylamide gel microarray in 129 schizophrenic trios. The results of genotyping were analyzed by haplotype relative risk analysis based on haplotype(HHRR), transmission disequilibrium test(TDT) and hyplotype analysis. (1)The HHRR analysis suggested that there was significant differences in rs2337980 allele frequencies between schizophrenia group and dummy control group(P= 0.017); (2)In TDT test, there may be transmission disequilibrium between rs2337980 and schizophrenia, the heterozygous parents excessively transferred the C allele to patients (P= 0.021); (3)The haplotype between rs2337980 and rs1909884 as well as the hyplotype among rs2337980, rs1909884 and rs883473 may have significant association with schizophrenia (global P= 0.034; global P= 0.027), the T-C and T-C-T hyplotype may have transmission disequilibrium with schizophrenia. There may be association between CHRNA7 gene polymorphisms and schizophrenia, the variant allele T in rs2337980 may have a protective effect to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 50 | Brain Res. 2009 Sep 1291: 1-11 |
| PMID | 19631623 |
| Title | A 2-base pair deletion polymorphism in the partial duplication of the alpha7 nicotinic acetylcholine gene (CHRFAM7A) on chromosome 15q14 is associated with schizophrenia. |
| Abstract | Multiple genetic linkage studies support the hypothesis that the 15q13-14 chromosomal region contributes to the etiology of schizophrenia. Among the putative candidate genes in this area are the alpha7 nicotinic acetylcholine receptor gene (CHRNA7) and its partial duplication, CHRFAM7A. A large chromosomal segment including the CHRFAM7A gene locus, but not the CHRNA7 locus, is deleted in some individuals. The CHRFAM7A gene contains a polymorphism consisting of a 2 base pair (2 bp) deletion at position 497-498 bp of exon 6. We employed PCR-based methods to quantify the copy number of CHRFAM7A and the presence of the 2 bp polymorphism in a large, multi-ethnic population. The 2 bp polymorphism was associated with schizophrenia in African Americans (genotype p=0.005, allele p=0.015), and in Caucasians (genotype p=0.015, allele p=0.009). We conclude that the presence of the 2 bp polymorphism at the CHRFAM7A locus may have a functional significance in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 51 | Schizophr. Res. 2009 Apr 109: 102-12 |
| PMID | 19181484 |
| Title | Association of the 5'-upstream regulatory region of the alpha7 nicotinic acetylcholine receptor subunit gene (CHRNA7) with schizophrenia. |
| Abstract | The alpha7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) is localized in a chromosomal region (15q14) linked to schizophrenia in multiple independent studies. CHRNA7 was selected as the best candidate gene in the region for a well-documented endophenotype of schizophrenia, the P50 sensory processing deficit, by genetic linkage and biochemical studies. Subjects included Caucasian-Non Hispanic and African-American case-control subjects collected in Denver, and schizophrenic subjects from families in the NIMH Genetics Initiative on schizophrenia. Thirty-five single nucleotide polymorphisms (SNPs) in the 5'-upstream regulatory region of CHRNA7 were genotyped for association with schizophrenia, and for smoking in schizophrenia. The rs3087454 SNP, located at position -1831 bp in the upstream regulatory region of CHRNA7, was significantly associated with schizophrenia in the case-control samples after multiple-testing correction (P=0.0009, African American; P=0.013, Caucasian-Non Hispanic); the association was supported in family members. There was nominal association of this SNP with smoking in schizophrenia. The data support association of regulatory region polymorphisms in the CHRNA7 gene with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 52 | Int. J. Neuropsychopharmacol. 2009 Mar 12: 267-73 |
| PMID | 19149910 |
| Title | CHRFAM7A copy number and 2-bp deletion polymorphisms and antisaccade performance. |
| Abstract | Chromosome 15q13-q14 harbours the gene for the alpha7 nicotinic acetylcholine receptor subunit (CHRNA7) and a related gene (CHRFAM7A) which arises from a partly duplicated portion of CHRNA7. Recent evidence suggests that CHRFAM7A is a locus with a possible role in schizophrenia and cognitive functioning. We studied an antisaccade task as a fronto-parietal measure of executive function that reflects risk for schizophrenia. Association of CHRFAM7A genotype with antisaccade performance was assessed in 103 healthy Caucasian individuals. No significant associations of 2-bp deletion or CHRFAM7A copy number with antisaccade performance parameters were observed. The failure to observe an association between antisaccade performance and polymorphisms in CHRFAM7A gene is consistent with specificity of the gene effects on hippocampal and memory functions as previously demonstrated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 53 | Nat. Genet. 2009 Feb 41: 160-2 |
| PMID | 19136953 |
| Title | 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. |
| Abstract | We identified 15q13.3 microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with idiopathic generalized epilepsy (IGE), which were not detected in 3,699 controls (joint P = 5.32 x 10(-8)). Most deletion carriers showed common IGE syndromes without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia. Our results indicate that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified to date. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 54 | Schizophr. Res. 2009 Apr 109: 102-12 |
| PMID | 19181484 |
| Title | Association of the 5'-upstream regulatory region of the alpha7 nicotinic acetylcholine receptor subunit gene (CHRNA7) with schizophrenia. |
| Abstract | The alpha7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) is localized in a chromosomal region (15q14) linked to schizophrenia in multiple independent studies. CHRNA7 was selected as the best candidate gene in the region for a well-documented endophenotype of schizophrenia, the P50 sensory processing deficit, by genetic linkage and biochemical studies. Subjects included Caucasian-Non Hispanic and African-American case-control subjects collected in Denver, and schizophrenic subjects from families in the NIMH Genetics Initiative on schizophrenia. Thirty-five single nucleotide polymorphisms (SNPs) in the 5'-upstream regulatory region of CHRNA7 were genotyped for association with schizophrenia, and for smoking in schizophrenia. The rs3087454 SNP, located at position -1831 bp in the upstream regulatory region of CHRNA7, was significantly associated with schizophrenia in the case-control samples after multiple-testing correction (P=0.0009, African American; P=0.013, Caucasian-Non Hispanic); the association was supported in family members. There was nominal association of this SNP with smoking in schizophrenia. The data support association of regulatory region polymorphisms in the CHRNA7 gene with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 55 | J. Mol. Neurosci. 2010 Jan 40: 185-95 |
| PMID | 19680823 |
| Title | Differential regulation of alpha7 nicotinic receptor gene (CHRNA7) expression in schizophrenic smokers. |
| Abstract | The alpha7 neuronal nicotinic receptor gene (CHRNA7) has been implicated in the pathophysiology of schizophrenia by genetic and pharmacological studies. Expression of the alpha7* receptor, as measured by [(125)I]alpha-bungarotoxin autoradiography, is decreased in postmortem brain of schizophrenic subjects compared to non-mentally ill controls. Most schizophrenic patients are heavy smokers, with high levels of serum cotinine. Smoking changes the expression of multiple genes and differentially regulates gene expression in schizophrenic hippocampus. We examined the effects of smoking on CHRNA7 expression in the same tissue and find that smoking differentially regulates expression of both mRNA and protein for this gene. CHRNA7 mRNA and protein levels are significantly lower in schizophrenic nonsmokers compared to control nonsmokers and are brought to control levels in schizophrenic smokers. Sufficient protein but low surface expression of the alpha7* receptor, seen in the autoradiographic studies, suggests aberrant assembly or trafficking of the receptor. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 56 | J. Mol. Neurosci. 2010 Jan 40: 185-95 |
| PMID | 19680823 |
| Title | Differential regulation of alpha7 nicotinic receptor gene (CHRNA7) expression in schizophrenic smokers. |
| Abstract | The alpha7 neuronal nicotinic receptor gene (CHRNA7) has been implicated in the pathophysiology of schizophrenia by genetic and pharmacological studies. Expression of the alpha7* receptor, as measured by [(125)I]alpha-bungarotoxin autoradiography, is decreased in postmortem brain of schizophrenic subjects compared to non-mentally ill controls. Most schizophrenic patients are heavy smokers, with high levels of serum cotinine. Smoking changes the expression of multiple genes and differentially regulates gene expression in schizophrenic hippocampus. We examined the effects of smoking on CHRNA7 expression in the same tissue and find that smoking differentially regulates expression of both mRNA and protein for this gene. CHRNA7 mRNA and protein levels are significantly lower in schizophrenic nonsmokers compared to control nonsmokers and are brought to control levels in schizophrenic smokers. Sufficient protein but low surface expression of the alpha7* receptor, seen in the autoradiographic studies, suggests aberrant assembly or trafficking of the receptor. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 57 | Psychiatry Investig 2010 Sep 7: 196-201 |
| PMID | 20927308 |
| Title | Genetic Association Study of the Alpha 7 Nicotinic Receptor (CHRNA7) with the Development of Schizophrenia and Bipolar Disorder in Korean Population. |
| Abstract | CHRNA7 has been shown to be a strong candidate gene for schizophrenia and bipolar disorder. It is located on chromosome 15q13-q14, which is one of the replicated linkage spots for schizophrenia and bipolar disorder. We conducted an association study to determine whether previous positive association is replicable in the Korean population. We included 254 patients with schizophrenia, 193 patients with bipolar disorder type I, 38 patients with bipolar disorder type II, 64 schizoaffective disorder patients, and 349 controls. All subjects were ethnically Korean. A total of 898 subjects were included, and genotyping was done for three single nucleotide polymorphisms (SNPs) of CHRNA7. These three intronic SNPs were rs2337506 (A/G), rs6494223 (C/T), and rs12916879 (A/G). There was only one marginally significant association; this association was between rs12916879 and bipolar disorder type I in the male subgroup. In both the allele and genotype distributions, we found a weak signal (Chi-squared=3.57, df=1, p=0.06 for allele, Chi-squared=7.50, df=2, p=0.02 for genotype) only. Unphased haplotype analysis could not provide additional support for this finding. No SNP was associated with schizophrenia or any other affected groups in this Korean sample. The associative finding is marginal and inconclusive. We could not replicate positive association in other ethnic groups previously studied. This suggests possible heterogeneity in the genes associated with schizophrenia and bipolar disorders. Because of structural complexity of the CHRNA7 gene and the limited statistical power of this study, further genetic studies with more SNPs and larger samples covering various populations, along with more fine molecular exploration of the CHRNA7 gene structure, are required. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 58 | Psychiatr. Genet. 2010 Dec 20: 289-97 |
| PMID | 20463630 |
| Title | Evidence for association of the non-duplicated region of CHRNA7 gene with bipolar disorder but not with Schizophrenia. |
| Abstract | Biological evidence in both human and animal studies suggests ?7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) as a suitable functional candidate for genetic studies in psychiatric populations. This gene maps to chromosome 15q13-14, a major linkage hotspot for schizophrenia (SCH) and bipolar disorder (BD). In this study we examine the role of CHRNA7 in influencing the risk of SCH and BD. In the present investigation four SNPs of the non-duplicated region of CHRNA7 were genotyped: -86C/T variant, located in the 5'-upstream regulatory region; and three intronic polymorphisms (rs883473, rs6494223 and rs904952). Genetic analysis was performed on 510 patients diagnosed with SCH, 245 with BD and on 793 unrelated healthy controls. SNP analysis suggested a significant difference in -86C/T allele (P=0.025) and genotype (P=0.03) frequencies between BD and control groups, although significance was lost after correction for multiple testing. Besides, the nucleotide change (T) in rs6494223 had a protective effect against BD [odds ratio (OR)=0.70 (0.57-0.87); P=0.001]. Genotype frequencies also showed significant association (P=0.001) [CT genotype OR=0.71 (0.5-0.96); TT genotype OR=0.47 (0.29-0.77)]. Haplotypic analysis revealed a positive association of the gene with BD (global-stat=24.18, P value=0.007) with a maximum effect in the region that covered introns 3 and 4. In contrast, no evidence of risk variants was found in the analysis of the SCH sample. Our data support the non-duplicated region of CHRNA7 gene as a susceptibility region for BD but not for SCH. Further genotyping of this region may help to delimit the causal polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 59 | Curr. Pharm. Des. 2010 -1 16: 538-54 |
| PMID | 19909231 |
| Title | Targeting alpha7 nicotinic acetylcholine receptors in the treatment of schizophrenia. |
| Abstract | The most abundant homomeric nicotinic acetylcholine receptors (nAChRs) in the mammalian brain are the pentameric alpha7 nAChRs which consist of five alpha7 subunits, and each subunit provides an orthosteric low affinity binding site for its endogenous ligand, acetylcholine. Distribution and high level expression of alpha7 nAChRs within the limbic circuitry, including the hippocampus and prefrontal cortical areas are in line with their involvement in various cognitive functions. Activation of alpha7 nAChRs generates a conformational change of sub-unit proteins, making the channel permeable to cations, in particular calcium, leading to change in neuronal activity and excitability, and via increased intracellular calcium, modulating transmitter release and neuronal network activity. Since genetic linkage studies implicated the alpha7 nAChRs subunit gene CHRNA7 in schizophrenia, there is a considerable interest for developing drug therapies targeting alpha7 nAChRs. In this review recent development of selective agonists and positive allosteric modulators of alpha7 nAChRs are discussed. In addition to summarizing medicinal chemistry efforts, both cellular and neuronal network pharmacology of alpha7 nAChRs are covered. The association between CHRNA7 gene and impaired P50 auditory gating has provided an attractive endophenotype, and its use as a potential translational biomarker for alpha7 nAChRs drug discovery is discussed. Preliminary clinical findings on alpha7 nAChRs agonists are also summarized. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 60 | Am. J. Med. Genet. A 2011 Apr 155A: 805-10 |
| PMID | 21594999 |
| Title | Pharmaco-genetically guided treatment of recurrent rage outbursts in an adult male with 15q13.3 deletion syndrome. |
| Abstract | 15q13.3 deletion syndrome (15q13.3DS) is a common recurrent genomic disorder associated with epilepsy, intellectual impairment, aggressive behavior, schizophrenia, and autism. A 39-year-old male presented with 15q13.3DS, epilepsy, intellectual impairment, psychosis, and recurrent episodes of aggressive rage. We hypothesized that the patient's aggressive behavior reflected deficits in ?7 nicotinic cholinergic receptor (NChR)-mediated neurotransmission, arising from haploinsufficiency of the structural gene CHRNA7 due to the deletion. Treatment with the NChR allosteric modulator and acetylcholinesterase (AChE) inhibitor, galantamine, led to a dramatic decline in the frequency and intensity of rage outbursts, suggesting that enhancement of ?7 NChR function can ameliorate 15q13.3DS-associated rage outbursts. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 61 | Physiol. Behav. 2011 Aug 104: 334-9 |
| PMID | 21382392 |
| Title | Strain dependent effects of prenatal stress on gene expression in the rat hippocampus. |
| Abstract | Multiple animal models have been developed to recapitulate phenotypes of the human disease, schizophrenia. A model that simulates many of the cognitive and sensory deficits of the disorder is the use of random variable prenatal stress (PS) in the rat. These deficits suggest a molecular origin in the hippocampus, a brain region that plays a role in the regulation of stress. To study both hippocampal gene expression changes in offspring of prenatally stressed dams and to address genetic variability, we used a random array of prenatal stressors in three different rat strains with diverse responses to stress: Fischer, Sprague-Dawley, and Lewis rats. Candidate genes involved in stress, schizophrenia, cognition, neurotrophic effects, and immunity were selected for assessment by real-time quantitative PCR under resting conditions and following a brief exposure to restraint stress. PS resulted in significant differences in gene expression in the offspring that were strain dependent. mRNA expression for the N-methyl-D-aspartate receptor subtype 2B (Grin2b) was increased, and tumor necrosis factor-alpha (Tnf?) transcript was decreased in PS Sprague-Dawley and Lewis rats, but not in the Fischer rats. Expression of brain-derived neurotrophic factor (Bdnf) mRNA in the hippocampus was increased after an acute stress in all controls of each strain, yet a decrease was seen after acute stress in the PS Sprague-Dawley and Lewis rats. Expression of the glucocorticoid receptor (Nr3c1) was decreased in the Fischer strain when compared to Lewis or Sprague-Dawley rats, though the Fischer rats had markedly higher ?7 nicotinic receptor (CHRNA7) expression. The expression differences seen in these animals may be important elements of the phenotypic differences seen due to PS and genetic background. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 62 | J. Biol. Chem. 2011 Dec 286: 42123-32 |
| PMID | 21979958 |
| Title | Transcriptional repression of the ?7 nicotinic acetylcholine receptor subunit gene (CHRNA7) by activating protein-2? (AP-2?). |
| Abstract | The CHRNA7 gene, which encodes the ?7 nicotinic acetylcholine receptor (?7*nAChR), has been implicated as a candidate gene in schizophrenia. Expression of the ?7*nAChR mRNA and protein are reduced in multiple regions of post-mortem brain from patients diagnosed with schizophrenia. Transcriptional regulation may therefore be an important mechanism for the regulation of this gene. A 230-bp proximal promoter fragment, necessary for transcription in cultured neuroblastoma cells, was used to study a putative AP-2? binding site. Mutation of the site indicates that AP-2? plays a negative role in regulating CHRNA7 transcription. This was confirmed through knockdown and overexpression of AP-2?. Electrophoretic mobility shift assays (EMSAs) identified positive DNA-protein interaction at this same site, and supershift assays indicate that the complex includes AP-2?. The interaction was confirmed in cells using chromatin immunoprecipitation (ChIP). DNA methylation was discovered as an anomalous mechanism for CHRNA7 regulation in one cell line. These studies suggest a role for AP-2? regulation of CHRNA7 mRNA expression in multiple tissues during development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 63 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2011 Dec 156B: 808-16 |
| PMID | 21812102 |
| Title | Genomic architecture of aggression: rare copy number variants in intermittent explosive disorder. |
| Abstract | Copy number variants (CNVs) are known to be associated with complex neuropsychiatric disorders (e.g., schizophrenia and autism) but have not been explored in the isolated features of aggressive behaviors such as intermittent explosive disorder (IED). IED is characterized by recurrent episodes of aggression in which individuals act impulsively and grossly out of proportion from the involved stressors. Previous studies have identified genetic variants in the serotonergic pathway that play a role in susceptibility to this behavior, but additional contributors have not been identified. Therefore, to further delineate possible genetic influences, we investigated CNVs in individuals diagnosed with IED and/or personality disorder (PD). We carried out array comparative genomic hybridization on 113 samples of individuals with isolated features of IED (n?=?90) or PD (n?=?23). We detected a recurrent 1.35-Mbp deletion on chromosome 1q21.1 in one IED subject and a novel ?350-kbp deletion on chromosome 16q22.3q23.1 in another IED subject. While five recent reports have suggested the involvement of an ?1.6-Mbp 15q13.3 deletion in individuals with behavioral problems, particularly aggression, we report an absence of such events in our study of individuals specifically selected for aggression. We did, however, detect a smaller ?430-kbp 15q13.3 duplication containing CHRNA7 in one individual with PD. While these results suggest a possible role for rare CNVs in identifying genes underlying IED or PD, further studies on a large number of well-characterized individuals are necessary. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 64 | Biochem. Pharmacol. 2011 Oct 82: 904-14 |
| PMID | 21718690 |
| Title | The chimeric gene CHRFAM7A, a partial duplication of the CHRNA7 gene, is a dominant negative regulator of ?7*nAChR function. |
| Abstract | The human ?7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is a candidate gene for schizophrenia and an important drug target for cognitive deficits in the disorder. Activation of the ?7*nAChR, results in opening of the channel and entry of mono- and divalent cations, including Ca(2+), that presynaptically participates to neurotransmitter release and postsynaptically to down-stream changes in gene expression. schizophrenic patients have low levels of ?7*nAChR, as measured by binding of the ligand [(125)I]-?-bungarotoxin (I-BTX). The structure of the gene, CHRNA7, is complex. During evolution, CHRNA7 was partially duplicated as a chimeric gene (CHRFAM7A), which is expressed in the human brain and elsewhere in the body. The association between a 2bp deletion in CHRFAM7A and schizophrenia suggested that this duplicate gene might contribute to cognitive impairment. To examine the putative contribution of CHRFAM7A on receptor function, co-expression of ?7 and the duplicate genes was carried out in cell lines and Xenopus oocytes. Expression of the duplicate alone yielded protein expression but no functional receptor and co-expression with ?7 caused a significant reduction of the amplitude of the ACh-evoked currents. Reduced current amplitude was not correlated with a reduction of I-BTX binding, suggesting the presence of non-functional (ACh-silent) receptors. This hypothesis is supported by a larger increase of the ACh-evoked current by the allosteric modulator 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596) in cells expressing the duplicate than in the control. These results suggest that CHRFAM7A acts as a dominant negative modulator of CHRNA7 function and is critical for receptor regulation in humans. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 65 | Biol. Psychiatry 2011 Jan 69: 7-11 |
| PMID | 20728875 |
| Title | Effects of an alpha 7-nicotinic agonist on default network activity in schizophrenia. |
| Abstract | 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXB-A) is a partial agonist at ?7 nicotinic acetylcholine receptors that has been evaluated clinically for treatment of schizophrenia. This study examined the effects of DMXB-A on default network activity as a biomarker for drug effects on pathologic brain function associated with schizophrenia. Placebo and two doses of DMXB-A were administered in a random, double-blind crossover design during a Phase 2 study of DMXB-A. Functional magnetic resonance imaging was performed on 16 nonsmoking patients with schizophrenia while they performed a simple eye movement task. Independent component analysis was used to identify the default network component. Default network changes were evaluated in the context of a polymorphism in CHRNA7, the ?7-nicotinic acetylcholine receptor subunit gene, which was previously found to be associated with schizophrenia. Compared with placebo, both 150 and 75 mg twice daily DMXB-A altered default network activity, including a reduction in posterior cingulate, inferior parietal cortex, and medial frontal gyrus activity and an increase in precuneus activity. The most robust difference, posterior cingulate activity reduction, was affected by CHRNA7 genotype. The observed DMXB-A-related changes are consistent with improved default network function in schizophrenia. Pharmacogenetic analysis indicates mediation of the effect through the ?7-nicotinic receptor. These results further implicate nicotinic cholinergic dysfunction in the disease and suggest that default network activity may be a useful indicator of biological effects of novel therapeutic agents. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 66 | Biochem. Pharmacol. 2011 Oct 82: 904-14 |
| PMID | 21718690 |
| Title | The chimeric gene CHRFAM7A, a partial duplication of the CHRNA7 gene, is a dominant negative regulator of ?7*nAChR function. |
| Abstract | The human ?7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is a candidate gene for schizophrenia and an important drug target for cognitive deficits in the disorder. Activation of the ?7*nAChR, results in opening of the channel and entry of mono- and divalent cations, including Ca(2+), that presynaptically participates to neurotransmitter release and postsynaptically to down-stream changes in gene expression. schizophrenic patients have low levels of ?7*nAChR, as measured by binding of the ligand [(125)I]-?-bungarotoxin (I-BTX). The structure of the gene, CHRNA7, is complex. During evolution, CHRNA7 was partially duplicated as a chimeric gene (CHRFAM7A), which is expressed in the human brain and elsewhere in the body. The association between a 2bp deletion in CHRFAM7A and schizophrenia suggested that this duplicate gene might contribute to cognitive impairment. To examine the putative contribution of CHRFAM7A on receptor function, co-expression of ?7 and the duplicate genes was carried out in cell lines and Xenopus oocytes. Expression of the duplicate alone yielded protein expression but no functional receptor and co-expression with ?7 caused a significant reduction of the amplitude of the ACh-evoked currents. Reduced current amplitude was not correlated with a reduction of I-BTX binding, suggesting the presence of non-functional (ACh-silent) receptors. This hypothesis is supported by a larger increase of the ACh-evoked current by the allosteric modulator 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596) in cells expressing the duplicate than in the control. These results suggest that CHRFAM7A acts as a dominant negative modulator of CHRNA7 function and is critical for receptor regulation in humans. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 67 | Neuroscience 2012 Apr 207: 274-82 |
| PMID | 22314319 |
| Title | Reduced Chrna7 expression in mice is associated with decreases in hippocampal markers of inhibitory function: implications for neuropsychiatric diseases. |
| Abstract | The ?7* nicotinic acetylcholine receptor encoded by CHRNA7 (human)/CHRNA7 (mice) regulates the release of both the inhibitory neurotransmitter GABA and the excitatory neurotransmitter glutamate in the hippocampal formation. A heterozygous (Het) deletion at 15q13.3 containing CHRNA7 is associated with increased risk for schizophrenia, autism, and epilepsy. Each of these diseases are characterized by abnormalities in excitatory and inhibitory hippocampal circuit function. Reduced CHRNA7 expression results in decreased hippocampal ?7* receptor density, abnormal hippocampal auditory sensory processing, and increased hippocampal CA3 pyramidal neuron activity in C3H mice Het for a null mutation in CHRNA7. These abnormalities demonstrate that decreased CHRNA7 expression alters hippocampal inhibitory circuit function. The current study examined the specific impact of reduced CHRNA7 expression on hippocampal inhibitory circuits by measuring the levels of GABA, GABA(A) receptors, the GABA synthetic enzyme l-glutamic acid decarboxylase-65 (GAD-65), and the vesicular GABA transporter 1 (GAT-1) in wild-type (CHRNA7 +/+) and Het (CHRNA7 +/-) C3H ?7 mice of both genders. GAD-65 levels were significantly decreased in male and female Het C3H ?7 mice, whereas GABA(A) receptors were significantly reduced only in male Het C3H ?7 mice. No changes in GABA and GAT-1 levels were detected. These data suggest that reduced CHRNA7 expression may contribute to the abnormalities in hippocampal inhibitory circuits observed in schizophrenia, autism, and/or epilepsy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 68 | Psychiatr. Genet. 2012 Feb 22: 1-14 |
| PMID | 21970977 |
| Title | Multiple genes in the 15q13-q14 chromosomal region are associated with schizophrenia. |
| Abstract | The chromosomal region, 15q13-q14, including the ?7 nicotinic acetylcholine receptor gene, CHRNA7, is a replicated region for schizophrenia. This study fine-mapped genes at 15q13-q14 to determine whether the association is unique to CHRNA7. Family-based and case-control association studies were performed on Caucasian-non-Hispanic and African-American individuals from 120 families as well as 468 individual patients with schizophrenia and 144 well-characterized controls. Single-nucleotide polymorphism (SNP) markers were genotyped, and association analyses carried out for the outcomes of schizophrenia, smoking, and smoking in schizophrenia. Three genes were associated with schizophrenia in both ethnic populations: TRPM1, KLF13, and RYR3. Two SNPs in CHRNA7 were associated with schizophrenia in African-Americans, and a second SNP in CHRNA7 was significant for an association with smoking and smoking in schizophrenia in Caucasians. Results of these studies support association of the 15q13-q14 region with schizophrenia. The broad positive association suggests that more than one 15q gene may be contributing to the disorder, either in combination or through a regulatory mechanism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 69 | Am J Psychiatry 2012 Feb 169: 195-204 |
| PMID | 22420048 |
| Title | Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3. |
| Abstract | Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology. The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium. The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5?3.6), this locus could be an important contributor to ADHD etiology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 70 | World J Psychiatry 2013 Sep 3: 57-61 |
| PMID | 24255876 |
| Title | New findings in the genetics of schizophrenia. |
| Abstract | New findings in schizophrenia genetics are based on genome-wide association studies (GWAS), research into DNA copy number variations (CNVs), and endophenotypes. More than 70 genes have recently been suspected to be involved in the genetic background of schizophrenia based on the GWAS´s results. They are typically related to neurodevelopment/neuroplasticity, immunology and neuroendocrinology. Nevertheless, for many detected genes their possible relationship to schizophrenia etiopathogenesis is still unknown. The CNVs at genome loci 1q21.1 (candidate gene e.g., PRKAB2), 2p16.3 (candidate gene e.g., NRXN1), 3q29 (candidate genes e.g., BDH1, DLG1, PAK2 or TFRC), 15q11.2 (candidate gene e.g., CYFIP1), 15q13.3 (candidate gene e.g., CHRNA7), 16p13.1 (candidate genes e.g.,NTAN1 or NDE1) and 22q11.2 (candidate genes e.g., COMT, GSTT2 or PRODH) were associated with schizophrenia most frequently. Genetic research of schizophrenia endophenotypes, usually neurophysiological, neuromotoric, neurocognitive, neuroanatomical, neurological or personality-related, will help us to discover the role of relevant genes in the pathogenesis of schizophrenia. It is also necessary to integrate knowledge from other research platforms in schizophrenia, like epigenetics, studies of gene-environment interactions, transcriptomics, proteomics, metabolomics, neuroimaging and psychopathology. A better knowledge of the genetic background of schizophrenia can lead to changes in the treatment, prevention and genetic counselling. It may also reduce stigma in this severe mental disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 71 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2013 Dec 162B: 825-31 |
| PMID | 23894120 |
| Title | Microduplication of 15q13.3 and Xq21.31 in a family with Tourette syndrome and comorbidities. |
| Abstract | Tourette syndrome (TS) is a childhood onset neurodevelopmental disorder. Although it is widely accepted that genetic factors play a significant role in TS pathogenesis the etiology of this disorder is largely unknown. Identification of rare copy number variations (CNVs) as susceptibility factors in several neuropsychiatric disorders such as attention deficit-hyperactivity disorder (ADHD), autism and schizophrenia, suggests involvement of these rare structural changes also in TS etiology. In a male patient with TS, ADHD, and OCD (obsessive compulsive disorder) we identified two microduplications (at 15q13.3 and Xq21.31) inherited from a mother with subclinical ADHD. The 15q duplication included the CHRNA7 gene; while two genes, PABPC5 and PCDH11X, were within the Xq duplication. The Xq21.31 duplication was present in three brothers with TS including the proband, but not in an unaffected brother, whereas the 15q duplication was present only in the proband and his mother. The structural variations observed in this family may contribute to the observed symptoms, but further studies are necessary to investigate the possible involvement of the described variations in the TS etiology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 72 | Psychiatry Res 2013 Feb 205: 276-8 |
| PMID | 22981153 |
| Title | No effect of polymorphisms in the non-duplicated region of the CHRNA7 gene on sensory gating P50 ratios in patients with schizophrenia and bipolar disorder. |
| Abstract | Previous research has reported that bipolar disorder and schizophrenic patients evidence sensory gating deficits. The use of intermediate phenotypes may facilitate genetic studies. Four single nucleotide polymorphisms (SNPs) located on the non-duplicated region of the alpha-7 nicotinic receptor gene (CHRNA7) were genotyped in 95 healthy subjects, 127 bipolar disorder and 153 schizophrenic patients. We evaluated the association of these polymorphisms with P50 evoked potential measures. Our results do not support a role for the candidate gene in this neurophysiological disturbance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 73 | Neuropharmacology 2013 Jan 64: 197-204 |
| PMID | 22766391 |
| Title | Allosteric alpha-7 nicotinic receptor modulation and P50 sensory gating in schizophrenia: a proof-of-mechanism study. |
| Abstract | In this multicenter, double-blind, placebo-controlled, randomized, four way cross-over proof-of-mechanism study, we tested the effect of the positive allosteric ?7 nicotinic acetylcholine receptor (nAChR) modulator JNJ-39393406 in a key translational assay (sensory P50 gating) in 39 regularly smoking male patients with schizophrenia. All patients were clinically stable and JNJ-39393406 was administered as an adjunct treatment to antipsychotics. No indication was found that JNJ-39393406 has the potential to reverse basic deficits of information processing in schizophrenia (sensory P50 gating) or has a significant effect on other tested electrophysiological markers (MMN, P300 and quantitative resting EEG). Sensitivity analyses including severity of disease, baseline P50 gating, medication and gene variants of the CHRNA7 gene did not reveal any subgroups with consistent significant effects. It is discussed that potential positive effects in subgroups not present or not large enough in the current study or upon chronic dosing are possible, but unlikely to be developed. This article is part of a Special Issue entitled 'Cognitive Enhancers'. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 74 | Front Psychiatry 2013 -1 4: 133 |
| PMID | 24155726 |
| Title | Association of the Nicotinic Receptor ?7 Subunit Gene (CHRNA7) with Schizophrenia and Visual Backward Masking. |
| Abstract | The nicotinic system is involved in the pathophysiology of schizophrenia. However, very little is known about its genetic basis and how it relates to clinical symptoms and potentially pharmacological intervention. Here, we investigated five single nucleotide polymorphisms (SNPs) [rs3826029] [rs2337506] [rs982574] [rs904952] [rs2337980] of the cholinergic nicotinic receptor gene, alpha 7 subunit (CHRNA7) and their association to schizophrenia. We found an association with rs904952 (p?=?0.009) in a German sample of 224 schizophrenic patients and 224 healthy control subjects. The same trend was shown in an independent Georgian sample of 50 schizophrenic patients, 57 first order unaffected relatives, and 51 healthy controls. In addition, visual backward masking (VBM), a sensitive test for early visual information processing, was assessed in the Georgian sample. In line with prior studies, VBM performance deficits were much more pronounced in schizophrenic patients and their unaffected relatives compared to healthy controls (schizophrenic patients: 156?ms; unaffected relatives: 60?ms; healthy controls: 33?ms). VBM was strongly correlated with SNP rs904952 (H[2]?=?7.3, p?=?0.026). Our results further support the notion that changes in the nicotinic system are involved in schizophrenia and open the avenue for pharmacological intervention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 75 | Front Psychol 2013 -1 4: 254 |
| PMID | 23717290 |
| Title | Schizophrenia and visual backward masking: a general deficit of target enhancement. |
| Abstract | The obvious symptoms of schizophrenia are of cognitive and psychopathological nature. However, schizophrenia affects also visual processing which becomes particularly evident when stimuli are presented for short durations and are followed by a masking stimulus. Visual deficits are of great interest because they might be related to the genetic variations underlying the disease (endophenotype concept). Visual masking deficits are usually attributed to specific dysfunctions of the visual system such as a hypo- or hyper-active magnocellular system. Here, we propose that visual deficits are a manifestation of a general deficit related to the enhancement of weak neural signals as occurring in all other sorts of information processing. We summarize previous findings with the shine-through masking paradigm where a shortly presented vernier target is followed by a masking grating. The mask deteriorates visual processing of schizophrenic patients by almost an order of magnitude compared to healthy controls. We propose that these deficits are caused by dysfunctions of attention and the cholinergic system leading to weak neural activity corresponding to the vernier. High density electrophysiological recordings (EEG) show that indeed neural activity is strongly reduced in schizophrenic patients which we attribute to the lack of vernier enhancement. When only the masking grating is presented, EEG responses are roughly comparable between patients and control. Our hypothesis is supported by findings relating visual masking to genetic deviants of the nicotinic ?7 receptor (CHRNA7). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 76 | Biochem. Pharmacol. 2013 Jun 85: 1713-20 |
| PMID | 23628449 |
| Title | Importance of the nicotinic acetylcholine receptor system in the prefrontal cortex. |
| Abstract | The prefrontal cortex (PFC) is responsible for integrating cortical and subcortical inputs to execute essential cognitive functions such as attention, working memory planning and decision-making. The importance of this brain region in regulating complex cognitive processes is underscored by a decline in PFC-mediated ability observed in aging and disease. The cholinergic system plays a vital role in cognitive function and treatments (e.g., cholinesterase inhibitors) to improve cholinergic neurotransmission provide the standard-of-care for diseases such as Alzheimer's. Nicotinic receptors (nAChRs) are a primary site of action for acetylcholine (ACh), and the resulting pro-cognitive effects observed by stimulating nAChRs with nicotine has long been appreciated by tobacco users, prompting investigation of therapeutic development for diseases (e.g., schizophrenia, Alzheimer or attention-deficit-hyperactivity disorder) by targeting the neuronal nAChR system. Noteworthy, improvements in attention, working memory and executive processes mediated by the PFC have been reported following nicotinic agonist exposure. Relevance of these ligand gated channels in higher brain function is further supported by the association of cognitive deficits reported in humans with mutations in CHRNB2 or CHRNA7 the genes encoding for the nicotinic receptor ?2 and ?7 subunits, respectively. In this work we review, in light of the latest findings, how nicotinic agonists may be acting in the PFC to influence cognitive function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 77 | Psychiatry Res 2013 Oct 209: 431-8 |
| PMID | 23598060 |
| Title | Association study of polymorphisms in the alpha 7 nicotinic acetylcholine receptor subunit and catechol-o-methyl transferase genes with sensory gating in first-episode schizophrenia. |
| Abstract | The purpose of the current study was to explore the association of auditory P50 sensory gating (P50) and prepulse inhibition (PPI) of schizophrenia with polymorphisms in the CHRNA7 and COMT genes. One hundred and fourty patients with schizophrenia participated in this study. They were administered the tests P50 and PPI. Moreover, three single nucleotide polymorphisms (SNPs) (rs2337980, rs1909884 and rs883473) in CHRNA7 and three SNPs (rs4680, rs737865 and rs165599) in COMT were selected to be genotyped by polyacrylamide gel microarray techniques. P50 index showed significant reduction in S2 amplitude between wild-type and mutation groups in the COMT rs4680. S1 amplitude of mutation group in the COMT rs737865 was also lower compared to wild-type group. PPI index revealed a shorter pulse latency of mutation group in the rs4680. The suppression ratio of mutation group was lower in COMT rs165599. Negative findings were shown between comparisons in all the CHRNA7 SNPs. We find that P50 and PPI may be influenced by COMT rs4680 polymorphisms in schizophrenia; more excitingly, we find that P50 might be influenced by COMT rs737865 polymorphisms and PPI may be influenced by COMT rs165599 polymorphisms in schizophrenia, and their mutations are associated with the reduction of the risk of P50 or PPI defects in schizophrenia. Futher studies with a larger number of subjects are needed to verify the present findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 78 | Am J Psychiatry 2013 Mar 170: 290-8 |
| PMID | 23318559 |
| Title | Perinatal choline effects on neonatal pathophysiology related to later schizophrenia risk. |
| Abstract | Deficient cerebral inhibition is a pathophysiological brain deficit related to poor sensory gating and attention in schizophrenia and other disorders. Cerebral inhibition develops perinatally, influenced by genetic and in utero factors. Amniotic choline activates fetal ?7-nicotinic acetylcholine receptors and facilitates development of cerebral inhibition. Increasing this activation may protect infants from future illness by promoting normal brain development. The authors investigated the effects of perinatal choline supplementation on the development of cerebral inhibition in human infants. A randomized placebo-controlled clinical trial of dietary phosphatidylcholine supplementation was conducted with 100 healthy pregnant women, starting in the second trimester. Supplementation to twice normal dietary levels for mother or newborn continued through the third postnatal month. All women received dietary advice regardless of treatment. Infants' electrophysiological recordings of inhibition of the P50 component of the cerebral evoked response to paired sounds were analyzed. The criterion for inhibition was suppression of the amplitude of the second P50 response by at least half, compared with the first response. No adverse effects of choline were observed in maternal health and delivery, birth, or infant development. At the fifth postnatal week, the P50 response was suppressed in more choline-treated infants (76%) compared with placebo-treated infants (43%) (effect size=0.7). There was no difference at the 13th week. A CHRNA7 genotype associated with schizophrenia was correlated with diminished P50 inhibition in the placebo-treated infants, but not in the choline-treated infants. Neonatal developmental delay in inhibition is associated with attentional problems as the child matures. Perinatal choline activates timely development of cerebral inhibition, even in the presence of gene mutations that otherwise delay it. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 79 | Psychiatry Res 2013 Feb 205: 276-8 |
| PMID | 22981153 |
| Title | No effect of polymorphisms in the non-duplicated region of the CHRNA7 gene on sensory gating P50 ratios in patients with schizophrenia and bipolar disorder. |
| Abstract | Previous research has reported that bipolar disorder and schizophrenic patients evidence sensory gating deficits. The use of intermediate phenotypes may facilitate genetic studies. Four single nucleotide polymorphisms (SNPs) located on the non-duplicated region of the alpha-7 nicotinic receptor gene (CHRNA7) were genotyped in 95 healthy subjects, 127 bipolar disorder and 153 schizophrenic patients. We evaluated the association of these polymorphisms with P50 evoked potential measures. Our results do not support a role for the candidate gene in this neurophysiological disturbance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 80 | Front Psychiatry 2013 -1 4: 133 |
| PMID | 24155726 |
| Title | Association of the Nicotinic Receptor ?7 Subunit Gene (CHRNA7) with Schizophrenia and Visual Backward Masking. |
| Abstract | The nicotinic system is involved in the pathophysiology of schizophrenia. However, very little is known about its genetic basis and how it relates to clinical symptoms and potentially pharmacological intervention. Here, we investigated five single nucleotide polymorphisms (SNPs) [rs3826029] [rs2337506] [rs982574] [rs904952] [rs2337980] of the cholinergic nicotinic receptor gene, alpha 7 subunit (CHRNA7) and their association to schizophrenia. We found an association with rs904952 (p?=?0.009) in a German sample of 224 schizophrenic patients and 224 healthy control subjects. The same trend was shown in an independent Georgian sample of 50 schizophrenic patients, 57 first order unaffected relatives, and 51 healthy controls. In addition, visual backward masking (VBM), a sensitive test for early visual information processing, was assessed in the Georgian sample. In line with prior studies, VBM performance deficits were much more pronounced in schizophrenic patients and their unaffected relatives compared to healthy controls (schizophrenic patients: 156?ms; unaffected relatives: 60?ms; healthy controls: 33?ms). VBM was strongly correlated with SNP rs904952 (H[2]?=?7.3, p?=?0.026). Our results further support the notion that changes in the nicotinic system are involved in schizophrenia and open the avenue for pharmacological intervention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 81 | Front Psychol 2013 -1 4: 254 |
| PMID | 23717290 |
| Title | Schizophrenia and visual backward masking: a general deficit of target enhancement. |
| Abstract | The obvious symptoms of schizophrenia are of cognitive and psychopathological nature. However, schizophrenia affects also visual processing which becomes particularly evident when stimuli are presented for short durations and are followed by a masking stimulus. Visual deficits are of great interest because they might be related to the genetic variations underlying the disease (endophenotype concept). Visual masking deficits are usually attributed to specific dysfunctions of the visual system such as a hypo- or hyper-active magnocellular system. Here, we propose that visual deficits are a manifestation of a general deficit related to the enhancement of weak neural signals as occurring in all other sorts of information processing. We summarize previous findings with the shine-through masking paradigm where a shortly presented vernier target is followed by a masking grating. The mask deteriorates visual processing of schizophrenic patients by almost an order of magnitude compared to healthy controls. We propose that these deficits are caused by dysfunctions of attention and the cholinergic system leading to weak neural activity corresponding to the vernier. High density electrophysiological recordings (EEG) show that indeed neural activity is strongly reduced in schizophrenic patients which we attribute to the lack of vernier enhancement. When only the masking grating is presented, EEG responses are roughly comparable between patients and control. Our hypothesis is supported by findings relating visual masking to genetic deviants of the nicotinic ?7 receptor (CHRNA7). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 82 | Schizophr Bull 2014 Nov 40: 1285-99 |
| PMID | 24664977 |
| Title | Systematic prioritization and integrative analysis of copy number variations in schizophrenia reveal key schizophrenia susceptibility genes. |
| Abstract | schizophrenia is a common mental disorder with high heritability and strong genetic heterogeneity. Common disease-common variants hypothesis predicts that schizophrenia is attributable in part to common genetic variants. However, recent studies have clearly demonstrated that copy number variations (CNVs) also play pivotal roles in schizophrenia susceptibility and explain a proportion of missing heritability. Though numerous CNVs have been identified, many of the regions affected by CNVs show poor overlapping among different studies, and it is not known whether the genes disrupted by CNVs contribute to the risk of schizophrenia. By using cumulative scoring, we systematically prioritized the genes affected by CNVs in schizophrenia. We identified 8 top genes that are frequently disrupted by CNVs, including NRXN1, CHRNA7, BCL9, CYFIP1, GJA8, NDE1, SNAP29, and GJA5. Integration of genes affected by CNVs with known schizophrenia susceptibility genes (from previous genetic linkage and association studies) reveals that many genes disrupted by CNVs are also associated with schizophrenia. Further protein-protein interaction (PPI) analysis indicates that protein products of genes affected by CNVs frequently interact with known schizophrenia-associated proteins. Finally, systematic integration of CNVs prioritization data with genetic association and PPI data identifies key schizophrenia candidate genes. Our results provide a global overview of genes impacted by CNVs in schizophrenia and reveal a densely interconnected molecular network of de novo CNVs in schizophrenia. Though the prioritized top genes represent promising schizophrenia risk genes, further work with different prioritization methods and independent samples is needed to confirm these findings. Nevertheless, the identified key candidate genes may have important roles in the pathogenesis of schizophrenia, and further functional characterization of these genes may provide pivotal targets for future therapeutics and diagnostics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 83 | Sci Rep 2014 -1 4: 7316 |
| PMID | 25471068 |
| Title | Small effects of smoking on visual spatiotemporal processing. |
| Abstract | Nicotine is an important stimulant that is involved in modulating many neuronal processes, including those related to vision. Nicotine is also thought to play a key role in schizophrenia: A genetic variation of the cholinergic nicotine receptor gene, alpha-7 subunit (CHRNA7) has been shown to be associated with stronger backward masking deficits in schizophrenic patients. In this study, we tested visual backward masking in healthy smokers and non-smokers to further understand the effects of nicotine on spatiotemporal vision. In the first study, we tested 48 participants, a group of non-smokers (n = 12) and three groups of regular smokers that were either nicotine deprived (n = 12), non-deprived (n = 12) or deprived but were allowed to smoke a cigarette directly before the start of the experiment (n = 12). Performance was similar across groups, except for some small negative effects in nicotine-deprived participants. In the second study, we compared backward masking performance between regular smokers and non-smokers for older (n = 37, 13 smokers) and younger (n = 67, 21 smokers) adults. Older adults performed generally worse than younger adults but there were no significant differences in performance between smokers and non-smokers. Taken together, these findings indicate that nicotine has no long-term negative effects on visual spatiotemporal processing as determined by visual backward masking. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 84 | Genet. Med. 2014 Sep 16: 649-56 |
| PMID | 24556925 |
| Title | Nicotinic acetylcholine receptors in human genetic disease. |
| Abstract | Nicotinic acetylcholine receptors represent a family of ligand-gated ion channels that are widely expressed in the central and peripheral nervous systems. To date, 16 genes encoding subunits of mammalian nicotinic acetylcholine receptors have been identified. The various subunits form homomeric or heteromeric receptor proteins, allowing for a complex and adaptable system of nicotinic neurotransmission. Mutations of nicotinic receptor genes can cause Mendelian disorders, most importantly congenital myasthenic syndromes, multiple pterygium syndromes, and nocturnal frontal lobe epilepsies. Haploinsufficiency of CHRNA7 predisposes to neuropsychiatric phenotypes in 15q13.3 deletion syndrome. The role of various nicotinic receptor genes is also discussed for complex disorders such as addiction, schizophrenia, Alzheimer disease, and Parkinson disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 85 | Annu. Rev. Med. 2014 -1 65: 245-61 |
| PMID | 24111888 |
| Title | ?7-nicotinic acetylcholine receptor agonists for cognitive enhancement in schizophrenia. |
| Abstract | ?7-Nicotinic acetylcholine receptors have emerged as a potential therapeutic target for the treatment of neurocognitive dysfunctions in schizophrenia that are often resistant to existing antipsychotic drugs. Molecular evidence for involvement in schizophrenia of CHRNA7, the gene for the receptor subunit, in the neurobiology of deficits in attention is a critical rationale for the clinical study of ?7-nicotinic receptor agonists to improve neurocognition. Initial clinical trials show enhancement of inhibitory neuron function related to sensory gating and increased attention and working memory, as well as improvement in negative symptoms such as anhedonia and alogia. Further development of this therapeutic strategy requires assessment of interactions with patients' heavy cigarette smoking and the relationship of this mechanism to the therapeutic effects of clozapine and olanzapine, both highly effective therapeutics with significant side effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 86 | Biomed Rep 2014 Sep 2: 729-736 |
| PMID | 25054019 |
| Title | Meta-analyses of 10 polymorphisms associated with the risk of schizophrenia. |
| Abstract | schizophrenia (SCZ) is a severe complex psychiatric disorder that generates problems for the associated family and society and causes disability with regards to work for patients. The aim of the present study was to assess the contribution of 10 genetic polymorphisms to SCZ susceptibility. Meta-analyses were conducted using the data without a limitation for time or language. A total of 27 studies with 7 genes and 10 polymorphisms were selected for the meta-analyses. Two polymorphisms were found to be significantly associated with SCZ. SNAP25 rs3746544 was shown to increase the SCZ risk by 18% [P=0.01; odds ratio (OR), 1.18; 95% confidence interval (CI), 1.05-1.34] and GRIK3 rs6691840 was found to increase the risk by 30% (P=0.008; OR, 1.30; 95% CI, 1.07-1.58). Significant results were found under the dominant (P=0.001; OR, 1.36; 95% CI, 1.13-1.65) and additive (P=0.02; OR, 1.45; 95% CI, 1.06-1.98) model for the SNAP25 rs3746544 polymorphism and under the additive model for the GRIK3 rs6691840 polymorphism (P=0.03; OR, 1.73; 95% CI, 1.04-2.85). There were no significant results observed for the other eight polymorphisms, which were CCKAR rs1800857, CHRNA7 rs904952, CHRNA7 rs6494223, CHRNA7 rs2337506, DBH Ins>Del, FEZ1 rs559668, FEZ1 rs597570 and GCLM rs2301022. In conclusion, the present meta-analyses indicated that the SNAP25 rs3746544 and GRIK3 rs6691840 polymorphisms were risk factors of SCZ, which may provide valuable information for the clinical diagnosis of SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 87 | J. Biol. Chem. 2014 Sep 289: 26451-63 |
| PMID | 25056953 |
| Title | The duplicated ?7 subunits assemble and form functional nicotinic receptors with the full-length ?7. |
| Abstract | The ?7 nicotinic acetylcholine receptor gene (CHRNA7) is linked to schizophrenia. A partial duplication of CHRNA7 (CHRFAM7A) is found in humans on 15q13-14. Exon 6 of CHRFAM7A harbors a 2-bp deletion polymorphism, CHRFAM7A?2bp, which is also associated with schizophrenia. To understand the effects of the duplicated subunits on ?7 receptors, we fused ?7, dup?7, and dup??7 subunits with various fluorescent proteins. The duplicated subunits co-localized with full-length ?7 subunits in mouse neuroblastoma cells (Neuro2a) as well as rat hippocampal neurons. We investigated the interaction between the duplicated subunits and full-length ?7 by measuring Förster resonance energy transfer using donor recovery after photobleaching and fluorescence lifetime imaging microscopy. The results revealed that the duplicated proteins co-assemble with ?7. In electrophysiological studies, Leu at the 9'-position in the M2 membrane-spanning segment was replaced with Cys in dup?7 or dup??7, and constructs were co-transfected with full-length ?7 in Neuro2a cells. Exposure to ethylammonium methanethiosulfonate inhibited acetylcholine-induced currents, showing that the assembled functional nicotinic acetylcholine receptors (nAChRs) included the duplicated subunit. Incorporation of dup?7 and dup??7 subunits modestly changes the sensitivity of receptors to choline and varenicline. Thus, the duplicated proteins are assembled and transported to the cell membrane together with full-length ?7 subunits and alter the function of the nAChRs. The characterization of dup?7 and dup??7 as well as their influence on ?7 nAChRs may help explain the pathophysiology of schizophrenia and may suggest therapeutic strategies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 88 | Mol. Cell. Neurosci. 2014 Jul 61: 163-75 |
| PMID | 24983521 |
| Title | Cortical parvalbumin GABAergic deficits with ?7 nicotinic acetylcholine receptor deletion: implications for schizophrenia. |
| Abstract | Dysfunction of cortical parvalbumin (PV)-containing GABAergic interneurons has been implicated in cognitive deficits of schizophrenia. In humans microdeletion of the CHRNA7 (?7 nicotinic acetylcholine receptor, nAChR) gene is associated with cortical dysfunction in a broad spectrum of neurodevelopmental and neuropsychiatric disorders including schizophrenia while in mice similar deletion causes analogous abnormalities including impaired attention, working-memory and learning. However, the pathophysiological roles of ?7 nAChRs in cortical PV GABAergic development remain largely uncharacterized. In both in vivo and in vitro models, we identify here that deletion of the ?7 nAChR gene in mice impairs cortical PV GABAergic development and recapitulates many of the characteristic neurochemical deficits in PV-positive GABAergic interneurons found in schizophrenia. ?7 nAChR null mice had decreased cortical levels of GABAergic markers including PV, glutamic acid decarboxylase 65/67 (GAD65/67) and the ?1 subunit of GABAA receptors, particularly reductions of PV and GAD67 levels in cortical PV-positive interneurons during late postnatal life and adulthood. Cortical GABAergic synaptic deficits were identified in the prefrontal cortex of ?7 nAChR null mice and ?7 nAChR null cortical cultures. Similar disruptions in development of PV-positive GABAergic interneurons and perisomatic synapses were found in cortical cultures lacking ?7 nAChRs. Moreover, NMDA receptor expression was reduced in GABAergic interneurons, implicating NMDA receptor hypofunction in GABAergic deficits in ?7 nAChR null mice. Our findings thus demonstrate impaired cortical PV GABAergic development and multiple characteristic neurochemical deficits reminiscent of schizophrenia in cortical PV-positive interneurons in ?7 nAChR gene deletion models. This implicates crucial roles of ?7 nAChRs in cortical PV GABAergic development and dysfunction in schizophrenia and other neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 89 | Neuroscience 2014 Jul 273: 52-64 |
| PMID | 24836856 |
| Title | Reduced CHRNA7 expression in C3H mice is associated with increases in hippocampal parvalbumin and glutamate decarboxylase-67 (GAD67) as well as altered levels of GABA(A) receptor subunits. |
| Abstract | Decreased expression of CHRNA7, the gene encoding the ?7(?) subtype of nicotinic receptor, may contribute to the cognitive dysfunction observed in schizophrenia by disrupting the inhibitory/excitatory balance in the hippocampus. C3H mice with reduced CHRNA7 expression have significant reductions in hippocampal ?7(?) receptor density, deficits in hippocampal auditory gating, increased hippocampal activity as well as significant decreases in hippocampal glutamate decarboxylase-65 (GAD65) and ?-aminobutyric acid-A (GABAA) receptor levels. The current study investigated whether altered CHRNA7 expression is associated with changes in the levels of parvalbumin, GAD67 and/or GABAA receptor subunits in the hippocampus from male and female C3H CHRNA7 wildtype, C3H CHRNA7 heterozygous and C3H CHRNA7 knockout (KO) mice using quantitative Western immunoblotting. Reduced CHRNA7 expression was associated with significant increases in hippocampal parvalbumin and GAD67 and with complex alterations in GABAA receptor subunits. A decrease in ?3 subunit protein was seen in both female C3H CHRNA7 Het and KO mice while a decrease in ?4 subunit protein was also detected in C3H CHRNA7 KO mice with no sex difference. In contrast, an increase in ? subunit protein was observed in C3H CHRNA7 Het mice while a decrease in this subunit was observed in C3H CHRNA7 KO mice, with ? subunit protein levels being greater in males than in females. Finally, an increase in ?2 subunit protein was found in C3H CHRNA7 KO mice with the levels of this subunit again being greater in males than in females. The increases in hippocampal parvalbumin and GAD67 observed in C3H CHRNA7 mice are contrary to reports of reductions in these proteins in the postmortem hippocampus from schizophrenic individuals. We hypothesize that the disparate results may occur because of the influence of factors other than CHRNA7 that have been found to be abnormal in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 90 | Brain Res. 2014 Mar 1552: 26-33 |
| PMID | 24462939 |
| Title | Long-term improvements in sensory inhibition with gestational choline supplementation linked to ?7 nicotinic receptors through studies in Chrna7 null mutation mice. |
| Abstract | Perinatal choline supplementation has produced several benefits in rodent models, from improved learning and memory to protection from the behavioral effects of fetal alcohol exposure. We have shown that supplemented choline through gestation and lactation produces long-term improvement in deficient sensory inhibition in DBA/2 mice which models a similar deficit in schizophrenia patients. The present study extends that research by feeding normal or supplemented choline diets to DBA/2 mice carrying the null mutation for the ?7 nicotinic receptor gene (CHRNA7). DBA/2 mice heterozygotic for CHRNA7 were bred together. Dams were placed on supplemented (5 gm/kg diet) or normal (1.1 gm/kg diet) choline at mating and remained on the specific diet until offspring weaning. Thereafter, offspring were fed standard rodent chow. Adult offspring were assessed for sensory inhibition. Brains were obtained to ascertain hippocampal ?7 nicotinic receptor levels. Choline-supplemented mice heterozygotic or null-mutant for CHRNA7 failed to show improvement in sensory inhibition. Only wildtype choline-supplemented mice showed improvement with the effect solely through a decrease in test amplitude. This supports the hypothesis that gestational-choline supplementation is acting through the ?7 nicotinic receptor to improve sensory inhibition. Although there was a significant gene-dose-related change in hippocampal ?7 receptor numbers, binding studies did not reveal any choline-dose-related change in binding in any hippocampal region, the interaction being driven by a significant genotype main effect (wildtype>heterozygote>null mutant). These data parallel a human study wherein the offspring of pregnant women receiving choline supplementation during gestation, showed better sensory inhibition than offspring of women on placebo. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 91 | Neurobiol. Dis. 2014 Mar 63: 129-40 |
| PMID | 24326163 |
| Title | Cortical synaptic NMDA receptor deficits in ?7 nicotinic acetylcholine receptor gene deletion models: implications for neuropsychiatric diseases. |
| Abstract | Microdeletion of the human CHRNA7 gene (?7 nicotinic acetylcholine receptor, nAChR) as well as dysfunction in N-methyl-d-aspartate receptors (NMDARs) have been associated with cortical dysfunction in a broad spectrum of neurodevelopmental and neuropsychiatric disorders including schizophrenia. However, the pathophysiological roles of synaptic vs. extrasynaptic NMDARs and their interactions with ?7 nAChRs in cortical dysfunction remain largely uncharacterized. Using a combination of in vivo and in vitro models, we demonstrate that ?7 nAChR gene deletion leads to specific loss of synaptic NMDARs and their coagonist, d-serine, as well as glutamatergic synaptic deficits in mouse cortex. ?7 nAChR null mice had decreased cortical NMDAR expression and glutamatergic synapse formation during postnatal development. Similar reductions in NMDAR expression and glutamatergic synapse formation were revealed in cortical cultures lacking ?7 nAChRs. Interestingly, synaptic, but not extrasynaptic, NMDAR currents were specifically diminished in cultured cortical pyramidal neurons as well as in acute prefrontal cortical slices of ?7 nAChR null mice. Moreover, d-serine responsive synaptic NMDAR-mediated currents and levels of the d-serine synthetic enzyme serine racemase were both reduced in ?7 nAChR null cortical pyramidal neurons. Our findings thus identify specific loss of synaptic NMDARs and their coagonist, d-serine, as well as glutamatergic synaptic deficits in ?7 nAChR gene deletion models of cortical dysfunction, thereby implicating ?7 nAChR-mediated control of synaptic NMDARs and serine racemase/d-serine pathways in cortical dysfunction underlying many neuropsychiatric and neurodevelopmental disorders, particularly those associated with deletion of human CHRNA7. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 92 | Biol. Psychiatry 2014 Jul 76: 128-37 |
| PMID | 24090792 |
| Title | A mouse model that recapitulates cardinal features of the 15q13.3 microdeletion syndrome including schizophrenia- and epilepsy-related alterations. |
| Abstract | Genome-wide scans have uncovered rare copy number variants conferring high risk of psychiatric disorders. The 15q13.3 microdeletion is associated with a considerably increased risk of idiopathic generalized epilepsy, intellectual disability, and schizophrenia. A 15q13.3 microdeletion mouse model (Df[h15q13]/+) was generated by hemizygous deletion of the orthologous region and characterized with focus on schizophrenia- and epilepsy-relevant parameters. Df(h15q13)/+ mice showed marked changes in neuronal excitability in acute seizure assays, with increased propensity to develop myoclonic and absence-like seizures but decreased propensity for clonic and tonic seizures. Furthermore, they had impaired long-term spatial reference memory and a decreased theta frequency in hippocampus and prefrontal cortex. Electroencephalogram characterization revealed auditory processing deficits similar to those observed in schizophrenia. Gamma band power was increased during active state, but evoked gamma power following auditory stimulus (40 Hz) was dramatically reduced, mirroring observations in patients with schizophrenia. In addition, Df(h15q13)/+ mice showed schizophrenia-like decreases in amplitudes of auditory evoked potentials. Although displaying a grossly normal behavior, Df(h15q13)/+ mice are more aggressive following exposure to mild stressors, similar to what is described in human deletion carriers. Furthermore, Df(h15q13)/+ mice have increased body weight, and a similar increase in body weight was subsequently found in a sample of human subjects with 15q13.3 deletion. The Df(h15q13)/+ mouse shows similarities to several alterations related to the 15q13.3 microdeletion syndrome, epilepsy, and schizophrenia, offering a novel tool for addressing the underlying biology of these diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 93 | Sci Rep 2014 -1 4: 7316 |
| PMID | 25471068 |
| Title | Small effects of smoking on visual spatiotemporal processing. |
| Abstract | Nicotine is an important stimulant that is involved in modulating many neuronal processes, including those related to vision. Nicotine is also thought to play a key role in schizophrenia: A genetic variation of the cholinergic nicotine receptor gene, alpha-7 subunit (CHRNA7) has been shown to be associated with stronger backward masking deficits in schizophrenic patients. In this study, we tested visual backward masking in healthy smokers and non-smokers to further understand the effects of nicotine on spatiotemporal vision. In the first study, we tested 48 participants, a group of non-smokers (n = 12) and three groups of regular smokers that were either nicotine deprived (n = 12), non-deprived (n = 12) or deprived but were allowed to smoke a cigarette directly before the start of the experiment (n = 12). Performance was similar across groups, except for some small negative effects in nicotine-deprived participants. In the second study, we compared backward masking performance between regular smokers and non-smokers for older (n = 37, 13 smokers) and younger (n = 67, 21 smokers) adults. Older adults performed generally worse than younger adults but there were no significant differences in performance between smokers and non-smokers. Taken together, these findings indicate that nicotine has no long-term negative effects on visual spatiotemporal processing as determined by visual backward masking. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 94 | Neuroscience 2014 Jul 273: 52-64 |
| PMID | 24836856 |
| Title | Reduced CHRNA7 expression in C3H mice is associated with increases in hippocampal parvalbumin and glutamate decarboxylase-67 (GAD67) as well as altered levels of GABA(A) receptor subunits. |
| Abstract | Decreased expression of CHRNA7, the gene encoding the ?7(?) subtype of nicotinic receptor, may contribute to the cognitive dysfunction observed in schizophrenia by disrupting the inhibitory/excitatory balance in the hippocampus. C3H mice with reduced CHRNA7 expression have significant reductions in hippocampal ?7(?) receptor density, deficits in hippocampal auditory gating, increased hippocampal activity as well as significant decreases in hippocampal glutamate decarboxylase-65 (GAD65) and ?-aminobutyric acid-A (GABAA) receptor levels. The current study investigated whether altered CHRNA7 expression is associated with changes in the levels of parvalbumin, GAD67 and/or GABAA receptor subunits in the hippocampus from male and female C3H CHRNA7 wildtype, C3H CHRNA7 heterozygous and C3H CHRNA7 knockout (KO) mice using quantitative Western immunoblotting. Reduced CHRNA7 expression was associated with significant increases in hippocampal parvalbumin and GAD67 and with complex alterations in GABAA receptor subunits. A decrease in ?3 subunit protein was seen in both female C3H CHRNA7 Het and KO mice while a decrease in ?4 subunit protein was also detected in C3H CHRNA7 KO mice with no sex difference. In contrast, an increase in ? subunit protein was observed in C3H CHRNA7 Het mice while a decrease in this subunit was observed in C3H CHRNA7 KO mice, with ? subunit protein levels being greater in males than in females. Finally, an increase in ?2 subunit protein was found in C3H CHRNA7 KO mice with the levels of this subunit again being greater in males than in females. The increases in hippocampal parvalbumin and GAD67 observed in C3H CHRNA7 mice are contrary to reports of reductions in these proteins in the postmortem hippocampus from schizophrenic individuals. We hypothesize that the disparate results may occur because of the influence of factors other than CHRNA7 that have been found to be abnormal in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 95 | Epilepsy Res. 2015 Nov 117: 70-3 |
| PMID | 26421493 |
| Title | Evaluation of multiple putative risk alleles within the 15q13.3 region for genetic generalized epilepsy. |
| Abstract | The chromosome 15q13.3 region has been implicated in epilepsy, intellectual disability and neuropsychiatric disorders, especially schizophrenia. Deficiency of the acetylcholine receptor gene CHRNA7 and the partial duplication, CHRFAM7A, may contribute to these phenotypes and we sought to comprehensively analyze these genes in genetic generalized epilepsy. We analyzed using DHPLC, Sanger sequencing and long range PCR, 174 probands with genetic generalized epilepsy with or without intellectual disability or psychosis, including 8 with the recurrent 15q13.3 microdeletion. We searched CHRNA7 and CHRFAM7A for single sequence variants, small copy number variants, and the common 2-bp deletion in CHRFAM7A. We identified two novel and one reported missense variants. The common 2-bp deletion was not enriched in patients compared to controls. Our data suggest that missense mutations in CHRNA7 contribute to complex inheritance in genetic generalized epilepsy in a similar fashion to the 15q13.3 microdeletion. They do not support a pathogenic role for the common 2-bp CHRFAM7A deletion. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 96 | Biochem. Pharmacol. 2015 Oct 97: 352-62 |
| PMID | 26095975 |
| Title | The human clinical phenotypes of altered CHRNA7 copy number. |
| Abstract | Copy number variants (CNVs) have been implicated in multiple neuropsychiatric conditions, including autism spectrum disorder (ASD), schizophrenia, and intellectual disability (ID). Chromosome 15q13 is a hotspot for such CNVs due to the presence of low copy repeat (LCR) elements, which facilitate non-allelic homologous recombination (NAHR). Several of these CNVs have been overrepresented in individuals with neuropsychiatric disorders; yet variable expressivity and incomplete penetrance are commonly seen. Dosage sensitivity of the CHRNA7 gene, which encodes for the ?7 nicotinic acetylcholine receptor in the human brain, has been proposed to have a major contribution to the observed cognitive and behavioral phenotypes, as it represents the smallest region of overlap to all the 15q13.3 deletions and duplications. Individuals with zero to four copies of CHRNA7 have been reported in the literature, and represent a range of clinical severity, with deletions causing generally more severe and more highly penetrant phenotypes. Potential mechanisms to account for the variable expressivity within each group of 15q13.3 CNVs will be discussed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 97 | PLoS ONE 2015 -1 10: e0125116 |
| PMID | 25906356 |
| Title | Pharmacological Characterisation of Nicotinic Acetylcholine Receptors Expressed in Human iPSC-Derived Neurons. |
| Abstract | Neurons derived from human induced pluripotent stem cells (iPSCs) represent a potentially valuable tool for the characterisation of neuronal receptors and ion channels. Previous studies on iPSC-derived neuronal cells have reported the functional characterisation of a variety of receptors and ion channels, including glutamate receptors, ?-aminobutyric acid (GABA) receptors and several voltage-gated ion channels. In the present study we have examined the expression and functional properties of nicotinic acetylcholine receptors (nAChRs) in human iPSC-derived neurons. Gene expression analysis indicated the presence of transcripts encoding several nAChR subunits, with highest levels detected for ?3-?7, ?1, ?2 and ?4 subunits (encoded by CHRNA3-CHRNA7, CHRNB1, CHRNB2 and CHRNB4 genes). In addition, similarly high transcript levels were detected for the truncated dup?7 subunit transcript, encoded by the partially duplicated gene CHRFAM7A, which has been associated with psychiatric disorders such as schizophrenia. The functional properties of these nAChRs have been examined by calcium fluorescence and by patch-clamp recordings. The data obtained suggest that the majority of functional nAChRs expressed in these cells have pharmacological properties typical of ?7 receptors. Large responses were induced by a selective ?7 agonist (compound B), in the presence of the ?7-selective positive allosteric modulator (PAM) PNU-120596, which were blocked by the ?7-selective antagonist methyllycaconitine (MLA). In addition, a small proportion of the neurons express nAChRs with properties typical of heteromeric (non-?7 containing) nAChR subtypes. These cells therefore represent a great tool to advance our understanding of the properties of native human nAChRs, ?7 in particular. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 98 | Neuromolecular Med. 2015 Dec 17: 423-30 |
| PMID | 26376812 |
| Title | Association Study of CHRNA7 Promoter Variants with Sensory and Sensorimotor Gating in Schizophrenia Patients and Healthy Controls: A Danish Case-Control Study. |
| Abstract | schizophrenia is a severe psychiatric disorder with a core component of impaired cognitive function still remaining as one of the greatest challenges in the pharmacological treatment of the disorder. The CHRNA7 gene, encoding the subunit of the human ?7 nicotinic acetylcholine receptor (?7nAChR), is suggested as a susceptibility factor for schizophrenia. CHRNA7 has also been genetically linked to the P50 auditory evoked potential deficit, a candidate endophenotype of schizophrenia, but not to prepulse inhibition of the startle reflex (PPI). In this study, 95 antipsychotic-naïve schizophrenic patients and 450 unaffected controls were screened for CHRNA7 promoter variants to investigate the association with schizophrenia, P50 suppression and PPI. We found that the promoter variant -194C (rs28531779) was significantly associated with schizophrenia, but did not find any association of this variant with P50 suppression or PPI. In addition, individuals with CHRNA7 promoter variants had elevated startle magnitude in pulse-alone trials compared to individuals without a variant. The present findings provide further support for a role of the ?7nAChR in schizophrenia and show a genetic link between CHRNA7 and startle magnitude, indicating that cholinergic neurotransmission involving the ?7nAChR could be involved in sensory registration processes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 99 | Am J Psychiatry 2015 Nov 172: 1122-30 |
| PMID | 26206074 |
| Title | CHRNA7 and CHRFAM7A mRNAs: co-localized and their expression levels altered in the postmortem dorsolateral prefrontal cortex in major psychiatric disorders. |
| Abstract | CHRNA7, coding ?-7 nicotinic acetylcholine receptor (?7 nAChR), is involved in cognition through interneuron modulation of dopamine and glutamate signaling. CHRNA7 and its partially duplicated chimeric gene CHRFAM7A have been implicated in schizophrenia through linkage and association studies. Expression of CHRNA7 and CHRFAM7A mRNA was measured in the postmortem prefrontal cortex in more than 700 subjects, including patients with schizophrenia, bipolar disorder, major depression, and normal comparison subjects. The effects of antipsychotics and nicotine, as well as associations of CHRNA7 SNPs with gene expression, were explored. Fluorescent in-situ hybridization was used to examine coexpression of both transcripts in the human cortex. CHRFAM7A expression and CHRFAM7A/CHRNA7 ratios were higher in fetal compared with postnatal life, whereas CHRNA7 expression was relatively stable. CHRFAM7A expression was significantly elevated in all diagnostic groups, while CHRNA7 expression was reduced in the schizophrenia group and increased in the major depression group compared with the comparison group. CHRFAM7A/CHRNA7 ratios were significantly increased in the schizophrenia and bipolar disorder groups compared with the comparison group. There was no effect of nicotine or antipsychotics and no association of SNPs in CHRNA7 with expression. CHRNA7 and CHRFAM7A mRNAs were expressed in the same neuronal nuclei of the human neocortex. These data show preferential fetal CHRFAM7A expression in the human prefrontal cortex and suggest abnormalities in the CHRFAM7A/CHRNA7 ratios in schizophrenia and bipolar disorder, due mainly to overexpression of CHRFAM7A. Given that these transcripts are coexpressed in a subset of human cortical neurons and can interact to alter function of nAChRs, these results support the concept of aberrant function of nAChRs in mental illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 100 | Brain Res. 2015 Jun 1611: 8-17 |
| PMID | 25744161 |
| Title | Maximizing the effect of an ?7 nicotinic receptor PAM in a mouse model of schizophrenia-like sensory inhibition deficits. |
| Abstract | Positive allosteric modulators (PAMs) for the ?7 nicotinic receptor hold promise for the treatment of sensory inhibition deficits observed in schizophrenia patients. Studies of these compounds in the DBA/2 mouse, which models the schizophrenia-related deficit in sensory inhibition, have shown PAMs to be effective in improving the deficit. However, the first published clinical trial of a PAM for both sensory inhibition deficits and related cognitive difficulties failed, casting a shadow on this therapeutic approach. The present study used both DBA/2 mice, and C3H CHRNA7 heterozygote mice to assess the ability of the ?7 PAM, PNU-120596, to improve sensory inhibition. Both of these strains of mice have reduced hippocampal ?7 nicotinic receptor numbers and deficient sensory inhibition similar to schizophrenia patients. Low doses of PNU-120596 (1 or 3.33mg/kg) were effective in the DBA/2 mouse but not the C3H CHRNA7 heterozygote mouse. Moderate doses of the selective ?7 nicotinic receptor agonist, choline chloride (10 or 33mg/kg), were also ineffective in improving sensory inhibition in the C3H CHRNA7 heterozygote mouse. However, combining the lowest doses of both PNU-120596 and choline chloride in this mouse model did improve sensory inhibition. We propose here that the difference in efficacy of PNU-120596 between the 2 mouse strains is driven by differences in hippocampal ?7 nicotinic receptor numbers, such that C3H CHRNA7 heterozygote mice require additional direct stimulation of the ?7 receptors. These data may have implications for further clinical testing of putative ?7 nicotinic receptor PAMs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 101 | Neuropharmacology 2015 Sep 96: 274-88 |
| PMID | 25701707 |
| Title | The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function. |
| Abstract | The human ?7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is ubiquitously expressed in both the central nervous system and in the periphery. CHRNA7 is genetically linked to multiple disorders with cognitive deficits, including schizophrenia, bipolar disorder, ADHD, epilepsy, Alzheimer's disease, and Rett syndrome. The regulation of CHRNA7 is complex; more than a dozen mechanisms are known, one of which is a partial duplication of the parent gene. Exons 5-10 of CHRNA7 on chromosome 15 were duplicated and inserted 1.6 Mb upstream of CHRNA7, interrupting an earlier partial duplication of two other genes. The chimeric CHRFAM7A gene product, dup?7, assembles with ?7 subunits, resulting in a dominant negative regulation of function. The duplication is human specific, occurring neither in primates nor in rodents. The duplicated ?7 sequence in exons 5-10 of CHRFAM7A is almost identical to CHRNA7, and thus is not completely queried in high throughput genetic studies (GWAS). Further, pre-clinical animal models of the ?7nAChR utilized in drug development research do not have CHRFAM7A (dup?7) and cannot fully model human drug responses. The wide expression of CHRNA7, its multiple functions and modes of regulation present challenges for study of this gene in disease. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 102 | Brain Behav. Immun. 2015 May 46: 192-202 |
| PMID | 25683697 |
| Title | The interaction between maternal immune activation and alpha 7 nicotinic acetylcholine receptor in regulating behaviors in the offspring. |
| Abstract | Mutation of human chromosome 15q13.3 increases the risk for autism and schizophrenia. One of the noteworthy genes in 15q13.3 is CHRNA7, which encodes the nicotinic acetylcholine receptor alpha 7 subunit (?7nAChR) associated with schizophrenia in clinical studies and rodent models. This study investigates the role of ?7nAChR in maternal immune activation (MIA) mice model, a murine model of environmental risk factor for autism and schizophrenia. We provided choline, a selective ?7nAChR agonist among its several developmental roles, in the diet of C57BL/6N wild-type dams throughout the gestation and lactation period and induced MIA at mid-gestation. The adult offspring behavior and gene expression profile in the maternal-placental-fetal axis at mid-gestation were investigated. We found that choline supplementation prevented several MIA-induced behavioral abnormalities in the wild-type offspring. Pro-inflammatory cytokine interleukin-6 (Il6) and CHRNA7 gene expression in the wild-type fetal brain were elevated by poly(I:C) injection and were suppressed by gestational choline supplementation. We further investigated the gene expression level of Il6 in CHRNA7 mutant mice. We found that the basal level of Il6 was higher in CHRNA7 mutant fetal brain, which suggests that ?7nAChR may serve an anti-inflammatory role in the fetal brain during development. Lastly, we induced MIA in CHRNA7(+/-) offspring. The CHRNA7(+/-) offspring were more vulnerable to MIA, with increased behavioral abnormalities. Our study shows that ?7nAChR modulates inflammatory response affecting the fetal brain and demonstrates its effects on offspring behavior development after MIA. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 103 | FASEB J. 2015 Jun 29: 2292-302 |
| PMID | 25681457 |
| Title | CHRFAM7A: a human-specific ?7-nicotinic acetylcholine receptor gene shows differential responsiveness of human intestinal epithelial cells to LPS. |
| Abstract | The human genome contains a unique, distinct, and human-specific ?7-nicotinic acetylcholine receptor (?7nAChR) gene [CHRNA7 (gene-encoding ?7-nicotinic acetylcholine receptor)] called CHRFAM7A (gene-encoding dup-?7-nicotinic acetylcholine receptor) on a locus of chromosome 15 associated with mental illness, including schizophrenia. Located 5' upstream from the "wild-type" CHRNA7 gene that is found in other vertebrates, we demonstrate CHRFAM7A expression in a broad range of epithelial cells and sequenced the CHRFAM7A transcript found in normal human fetal small intestine epithelial (FHs) cells to prove its identity. We then compared its expression to CHRNA7 in 11 gut epithelial cell lines, showed that there is a differential response to LPS when compared to CHRNA7, and characterized the CHRFAM7A promoter. We report that both CHRFAM7A and CHRNA7 gene expression are widely distributed in human epithelial cell lines but that the levels of CHRFAM7A gene expression vary up to 5000-fold between different gut epithelial cells. A 3-hour treatment of epithelial cells with 100 ng/ml LPS increased CHRFAM7A gene expression by almost 1000-fold but had little effect on CHRNA7 gene expression. Mapping the regulatory elements responsible for CHRFAM7A gene expression identifies a 1 kb sequence in the UTR of the CHRFAM7A gene that is modulated by LPS. Taken together, these data establish the presence, identity, and differential regulation of the human-specific CHRFAM7A gene in human gut epithelial cells. In light of the fact that CHRFAM7A expression is reported to modulate ligand binding to, and alter the activity of, the wild-type ?7nAChR ligand-gated pentameric ion channel, the findings point to the existence of a species-specific ?7nAChR response that might regulate gut epithelial function in a human-specific fashion. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 104 | Neuromolecular Med. 2015 Dec 17: 423-30 |
| PMID | 26376812 |
| Title | Association Study of CHRNA7 Promoter Variants with Sensory and Sensorimotor Gating in Schizophrenia Patients and Healthy Controls: A Danish Case-Control Study. |
| Abstract | schizophrenia is a severe psychiatric disorder with a core component of impaired cognitive function still remaining as one of the greatest challenges in the pharmacological treatment of the disorder. The CHRNA7 gene, encoding the subunit of the human ?7 nicotinic acetylcholine receptor (?7nAChR), is suggested as a susceptibility factor for schizophrenia. CHRNA7 has also been genetically linked to the P50 auditory evoked potential deficit, a candidate endophenotype of schizophrenia, but not to prepulse inhibition of the startle reflex (PPI). In this study, 95 antipsychotic-naïve schizophrenic patients and 450 unaffected controls were screened for CHRNA7 promoter variants to investigate the association with schizophrenia, P50 suppression and PPI. We found that the promoter variant -194C (rs28531779) was significantly associated with schizophrenia, but did not find any association of this variant with P50 suppression or PPI. In addition, individuals with CHRNA7 promoter variants had elevated startle magnitude in pulse-alone trials compared to individuals without a variant. The present findings provide further support for a role of the ?7nAChR in schizophrenia and show a genetic link between CHRNA7 and startle magnitude, indicating that cholinergic neurotransmission involving the ?7nAChR could be involved in sensory registration processes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 105 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2016 Mar -1: -1 |
| PMID | 26968334 |
| Title | 15q13.3 duplication in two patients with childhood-onset schizophrenia. |
| Abstract | We report two cases of paternally inherited 15q13.3 duplications in carriers diagnosed with childhood-onset schizophrenia (COS), a rare neurodevelopmental disorder of proposed polygenic origin with onset in children before age 13. This study documents that the 15q13.3 deletion and duplication exhibit pathogenicity for COS, with both copy number variants (CNVs) sharing a disrupted CHRNA7 gene. CHRNA7 encodes the neuronal alpha7 nicotinic acetylcholine receptor (?7nAChR) and is a candidate gene that has been suggested as a pathophysiological process mediating adult-onset schizophrenia (AOS) and other neurodevelopmental disorders. These results support the incomplete penetrance and variable expressivity of this CNV and represent the first report of 15q13.3 duplication carriers exhibiting COS. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 106 | Neurosci. Lett. 2016 May -1: -1 |
| PMID | 27233215 |
| Title | Genetic knockout of the ?7 nicotinic acetylcholine receptor gene alters hippocampal long-term potentiation in a background strain-dependent manner. |
| Abstract | Reduced ?7 nicotinic acetylcholine receptor (nAChR) function is linked to impaired hippocampal-dependent sensory processing and learning and memory in schizophrenia. While knockout of the CHRNA7 gene encoding the ?7nAChR on a C57/Bl6 background results in changes in cognitive measures, prior studies found little impact on hippocampal synaptic plasticity in these mice. However, schizophrenia is a multi-genic disorder where complex interactions between specific genetic mutations and overall genetic background may play a prominent role in determining phenotypic penetrance. Thus, we compared the consequences of knocking out the ?7nAChR on synaptic plasticity in C57/Bl6 and C3H mice, which differ in their basal ?7nAChR expression levels. Homozygous ?7 deletion in C3H mice, which normally express higher ?7nAChR levels, resulted in impaired long-term potentiation (LTP) at hippocampal CA1 synapses, while C3H ?7 heterozygous mice maintained robust LTP. In contrast, homozygous ?7 deletion in C57 mice, which normally express lower ?7nAChR levels, did not alter LTP, as had been previously reported for this strain. Thus, the threshold of CHRNA7 expression required for LTP may be different in the two strains. Measurements of auditory gating, a hippocampal-dependent behavioral paradigm used to identify schizophrenia-associated sensory processing deficits, was abnormal in C3H ?7 knockout mice confirming that auditory gating also requires ?7nAChR expression. Our studies highlight the importance of genetic background on the regulation of synaptic plasticity and could be relevant for understanding genetic and cognitive heterogeneity in human studies of ?7nAChR dysfunction in mental disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 107 | Neurosci. Lett. 2016 Jun 623: 36-41 |
| PMID | 27109789 |
| Title | Cholinergic modulation of auditory P3 event-related potentials as indexed by CHRNA4 and CHRNA7 genotype variation in healthy volunteers. |
| Abstract | schizophrenia (SZ) is a psychiatric disorder characterized by cognitive dysfunction within the realm of attentional processing. Reduced P3a and P3b event-related potentials (ERPs), indexing involuntary and voluntary attentional processing respectively, have been consistently observed in SZ patients who also express prominent cholinergic deficiencies. The involvement of the brain's cholinergic system in attention has been examined for several decades; however, further inquiry is required to further comprehend how abnormalities in this system affect neighbouring neurotransmitter systems and contribute to neurocognitive deficits. The objective of this pilot study was to examine the moderating role of the CHRNA4 (rs1044396), CHRNA7 (rs3087454), and SLC5A7 (rs1013940) genes on ERP indices of attentional processing in healthy volunteers (N=99; Caucasians and non-Caucasians) stratified by genotype and assessed using the auditory P300 "oddball" paradigm. Results indicated significantly greater P3a and P3b-indexed attentional processing for CT (vs. CC) CHRNA4 carriers and greater P3b for AA (vs. CC) CHRNA7 carriers. SLC5A7 allelic variants did not show significant differences in P3a and P3b processing. These findings expand our knowledge on the moderating effect of cholinergic genes on attention and could help inform targeted drug developments aimed at restoring attention deficits in SZ patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 108 | Schizophr Res Cogn 2016 Jun 4: 4-9 |
| PMID | 27069875 |
| Title | Kynurenine pathway and cognitive impairments in schizophrenia: Pharmacogenetics of galantamine and memantine. |
| Abstract | The Measurement and Treatment Research to Improve Cognition in schizophrenia (MATRICS) project designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia, identified three drug mechanisms of particular interest: dopaminergic, cholinergic, and glutamatergic. Galantamine is an acetylcholinesterase inhibitor and a positive allosteric modulator of the ?7 nicotinic receptors. Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist. There is evidence to suggest that the combination of galantamine and memantine may be effective in the treatment of cognitive impairments in schizophrenia. There is a growing body of evidence that excess kynurenic acid (KYNA) is associated with cognitive impairments in schizophrenia. The ?-7 nicotinic and the NMDA receptors may counteract the effects of kynurenic acid (KYNA) resulting in cognitive enhancement. Galantamine and memantine through its ?-7 nicotinic and NMDA receptors respectively may counteract the effects of KYNA thereby improving cognitive impairments. The Single Nucleotide Polymorphisms in the Cholinergic Receptor, Nicotinic, Alpha 7 gene (CHRNA7), Glutamate (NMDA) Receptor, Metabotropic 1 (GRM1) gene, Dystrobrevin Binding Protein 1 (DTNBP1) and kynurenine 3-monooxygenase (KMO) gene may predict treatment response to galantamine and memantine combination for cognitive impairments in schizophrenia in the kynurenine pathway. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 109 | Eur Neuropsychopharmacol 2016 Mar -1: -1 |
| PMID | 27061851 |
| Title | An acetylcholine alpha7 positive allosteric modulator rescues a schizophrenia-associated brain endophenotype in the 15q13.3 microdeletion, encompassing CHRNA7. |
| Abstract | The 15q13.3 microdeletion copy number variation is strongly associated with schizophrenia and epilepsy. The CHRNA7 gene, encoding nicotinic acetylcholine alpha 7 receptors (nAChA7Rs), is hypothesized to be one of the main genes in this deletion causing the neuropsychiatric phenotype. Here we used a recently developed 15q13.3 microdeletion mouse model to explore whether an established schizophrenia-associated connectivity phenotype is replicated in a murine model, and whether positive modulation of nAChA7 receptor might pharmacologically normalize the connectivity patterns. Resting-state fMRI data were acquired from male mice carrying a hemizygous 15q13.3 microdeletion (N=9) and from wild-type mice (N=9). To study the connectivity profile of 15q13.3 mice and test the effect of nAChA7 positive allosteric modulation, the 15q13.3 mice underwent two imaging sessions, one week apart, receiving a single intraperitoneal injection of either 15mg/kg Lu AF58801 or saline. The control group comprised wild-type mice treated with saline. We performed seed-based functional connectivity analysis to delineate aberrant connectivity patterns associated with the deletion (15q13.3 mice (saline treatment) versus wild-type mice (saline treatment)) and their modulation by Lu AF58801 (15q13.3 mice (Lu AF58801 treatment) versus 15q13.3 mice (saline treatment)). Compared to wild-type mice, 15q13.3 mice evidenced a predominant hyperconnectivity pattern. The main effect of Lu AF58801 was a normalization of elevated functional connectivity between prefrontal and frontal, hippocampal, striatal, thalamic and auditory regions. The strongest effects were observed in brain regions expressing nAChA7Rs, namely hippocampus, cerebral cortex and thalamus. These effects may underlie the antiepileptic, pro-cognitive and auditory gating deficit-reversal effects of nAChA7R stimulation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 110 | Psychopharmacology (Berl.) 2016 Jun 233: 2151-63 |
| PMID | 26983414 |
| Title | A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment. |
| Abstract | A microdeletion at locus 15q13.3 is associated with high incidence rates of psychopathology, including schizophrenia. A mouse model of the 15q13.3 microdeletion syndrome has been generated (Df[h15q13]/+) with translational utility for modelling schizophrenia-like pathology. Among other deficits, schizophrenia is characterised by dysfunctions in prefrontal cortical (PFC) inhibitory circuitry and attention. The objective of this study is to assess PFC-dependent functioning in the Df(h15q13)/+ mouse using electrophysiological, pharmacological, and behavioural assays. Experiments 1-2 investigated baseline firing and auditory-evoked responses of PFC interneurons and pyramidal neurons. Experiment 3 measured pyramidal firing in response to intra-PFC GABAA receptor antagonism. Experiments 4-6 assessed PFC-dependent attentional functioning through the touchscreen 5-choice serial reaction time task (5-CSRTT). Experiments 7-12 assessed reversal learning, paired-associate learning, extinction learning, progressive ratio, trial-unique non-match to sample, and object recognition. In experiments 1-3, the Df(h15q13)/+ mouse showed reduced baseline firing rate of fast-spiking interneurons and in the ability of the GABAA receptor antagonist gabazine to increase the firing rate of pyramidal neurons. In assays of auditory-evoked responses, PFC interneurons in the Df(h15q13)/+ mouse had reduced detection amplitudes and increased detection latencies, while pyramidal neurons showed increased detection latencies. In experiments 4-6, the Df(h15q13)/+ mouse showed a stimulus duration-dependent decrease in percent accuracy in the 5-CSRTT. The impairment was insensitive to treatment with the partial ?7nAChR agonist EVP-6124. The Df(h15q13)/+ mouse showed no cognitive impairments in experiments 7-12. The Df(h15q13)/+ mouse has multiple dysfunctions converging on disrupted PFC processing as measured by several independent assays of inhibitory transmission and attentional function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 111 | Oncol. Rep. 2016 Feb 35: 999-1005 |
| PMID | 26719016 |
| Title | CHRNA7 inhibits cell invasion and metastasis of LoVo human colorectal cancer cells through PI3K/Akt signaling. |
| Abstract | The ?7 neuronal nicotinic receptor gene (CHRNA7) is widely expressed in both the brain and periphery whereas its encoding protein of ?7 neuronal acetylcholine receptor (?7nAChR) belongs to the nicotinic acetylcholine receptor family. Considerable evidence suggests that ?7nAChR plays an important role in chronic inflammatory and neuropathic pain signaling and thus has been proposed as a potential target for treating cognitive deficits in patients with schizophrenia, attention deficit hyperactivity disorder (ADHD) and Alzheimer's disease. The aim of the present study was to determine the role of endogenous ?7nAChR signaling in human colorectal cancer growth and metastasis. pLVX?CHRNA7 encoding the full length of CHRNA7 was constructed and transfected into LoVo human colorectal cancer cells. Cell proliferation was measured by Cell Counting Kit?8 (CCK?8), and cell migration and invasion were detected by Transwell chamber assays. Expression and activity of metastasis?related metalloproteinases (MMPs) were analyzed by western blotting and gelatin zymography, respectively. Activation of metastasis-related signaling molecules was detected by western blotting. LY294002 was used to specifically block the phosphatidylinositol 3?kinase/v?akt murine thymoma viral oncogene homologue (PI3K/Akt) pathway. We showed that concomitantly with an increase in ?7nAChR expression after transfection, LoVo cells presented reduced abilities for migration and invasion, which was accompanied by reduced expression levels of MMP?1 and MMP?9 as well as activation of the PI3K/Akt signaling pathway. The application of LY294002 restored the migration and invasion abilities of the LoVo cells bearing CHRNA7. Collectively, we conclude that overexpression of CHRNA7 negatively controls colorectal cancer LoVo cell invasion and metastasis via PI3K/Akt pathway activation and may serve as either a diagnostic marker or a therapeutic target for colorectal cancer metastasis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 112 | Am J Psychiatry 2016 May 173: 509-16 |
| PMID | 26651393 |
| Title | Perinatal Phosphatidylcholine Supplementation and Early Childhood Behavior Problems: Evidence for CHRNA7 Moderation. |
| Abstract | ?7-Nicotinic receptors are involved in the final maturation of GABA inhibitory synapses before birth. Choline at levels found in the amniotic fluid is an agonist at ?7-nicotinic receptors. The authors conducted a double-blind placebo-controlled trial to assess whether high-dose oral phosphatidylcholine supplementation during pregnancy to increase maternal amniotic fluid choline levels would enhance fetal development of cerebral inhibition and, as a result, decrease childhood behavior problems associated with later mental illness. The authors previously reported that newborns in the phosphatidylcholine treatment group have increased suppression of the cerebral evoked response to repeated auditory stimuli. In this follow-up, they report parental assessments of the children's behavior at 40 months of age, using the Child Behavior Checklist. At 40 months, parent ratings of children in the phosphatidylcholine group (N=23) indicated fewer attention problems and less social withdrawal compared with the placebo group (N=26). The improvement is comparable in magnitude to similar deficits at this age associated with later schizophrenia. The children's behavior is moderated by CHRNA7 variants associated with later mental illness and is related to their enhanced cerebral inhibition as newborns. CHRNA7, the ?7-nicotinic acetylcholine receptor gene, has been associated with schizophrenia, autism, and attention deficit hyperactivity disorder. Maternal phosphatidylcholine treatment may, by increasing activation of the ?7-nicotinic acetylcholine receptor, alter the development of behavior problems in early childhood that can presage later mental illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 113 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2016 Jan 64: 109-17 |
| PMID | 26257138 |
| Title | The 15q13.3 deletion syndrome: Deficient ?(7)-containing nicotinic acetylcholine receptor-mediated neurotransmission in the pathogenesis of neurodevelopmental disorders. |
| Abstract | Array comparative genomic hybridization (array CGH) has led to the identification of microdeletions of the proximal region of chromosome 15q between breakpoints (BP) 3 or BP4 and BP5 encompassing CHRNA7, the gene encoding the ?7-nicotinic acetylcholine receptor (?7nAChR) subunit. Phenotypic manifestations of persons with these microdeletions are variable and some heterozygous carriers are seemingly unaffected, consistent with their variable expressivity and incomplete penetrance. Nonetheless, the 15q13.3 deletion syndrome is associated with several neuropsychiatric disorders, including idiopathic generalized epilepsy, intellectual disability, autism spectrum disorders (ASDs) and schizophrenia. Haploinsufficient expression of CHRNA7 in this syndrome has highlighted important roles the ?7nAChR plays in the developing brain and normal processes of attention, cognition, memory and behavior throughout life. Importantly, the existence of the 15q13.3 deletion syndrome contributes to an emerging literature supporting clinical trials therapeutically targeting the ?7nAChR in disorders such as ASDs and schizophrenia, including the larger population of patients with no evidence of haploinsufficient expression of CHRNA7. Translational clinical trials will be facilitated by the existence of positive allosteric modulators (PAMs) of the ?7nAChR that act at sites on the receptor distinct from the orthosteric site that binds acetylcholine and choline, the receptor's endogenous ligands. PAMs lack intrinsic efficacy by themselves, but act where and when the endogenous ligands are released in response to relevant social and cognitive provocations to increase the likelihood they will result in ?7nAChR ion channel activation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |