| 1 | Hum. Mol. Genet. 2006 Nov 15: 3329-42 |
|---|---|
| PMID | 17030554 |
| Title | Haplotypes spanning SPEC2, PDZ-GEF2 and ACSL6 genes are associated with schizophrenia. |
| Abstract | Chromosome 5q22-33 is a region where studies have repeatedly found evidence for linkage to schizophrenia. In this report, we took a stepwise approach to systematically map this region in the Irish Study of High Density schizophrenia Families (ISHDSF, 267 families, 1337 subjects) sample. We typed 289 SNPs in the critical interval of 8 million basepairs and found a 758 kb interval coding for the SPEC2/PDZ-GEF2/ACSL6 genes to be associated with the disease. Using sex and genotype-conditioned transmission disequilibrium test analyses, we found that 19 of the 24 typed markers were associated with the disease and the associations were sex-specific. We replicated these findings with an Irish case-control sample (657 cases and 414 controls), an Irish parent-proband trio sample (187 families, 564 subjects), a German nuclear family sample (211 families, 751 subjects) and a Pittsburgh nuclear family sample (247 families, 729 subjects). In all four samples, we replicated the sex-specific associations at the levels of both individual markers and haplotypes using sex- and genotype-conditioned analyses. Three risk haplotypes were identified in the five samples, and each haplotype was found in at least two samples. Consistent with the discovery of multiple estrogen-response elements in this region, our data showed that the impact of these haplotypes on risk for schizophrenia differed in males and females. From these data, we concluded that haplotypes underlying the SPEC2/PDZ-GEF2/ACSL6 region are associated with schizophrenia. However, due to the extended high LD in this region, we were unable to distinguish whether the association signals came from one or more of these genes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Genes Brain Behav. 2007 Apr 6: 229-39 |
| PMID | 16827919 |
| Title | DNA pooling: a comprehensive, multi-stage association analysis of ACSL6 and SIRT5 polymorphisms in schizophrenia. |
| Abstract | Many candidate gene association studies have evaluated incomplete, unrepresentative sets of single nucleotide polymorphisms (SNPs), producing non-significant results that are difficult to interpret. Using a rapid, efficient strategy designed to investigate all common SNPs, we tested associations between schizophrenia and two positional candidate genes: ACSL6 (Acyl-Coenzyme A synthetase long-chain family member 6) and SIRT5 (silent mating type information regulation 2 homologue 5). We initially evaluated the utility of DNA sequencing traces to estimate SNP allele frequencies in pooled DNA samples. The mean variances for the DNA sequencing estimates were acceptable and were comparable to other published methods (mean variance: 0.0008, range 0-0.0119). Using pooled DNA samples from cases with schizophrenia/schizoaffective disorder (Diagnostic and Statistical Manual of Mental Disorders edition IV criteria) and controls (n=200, each group), we next sequenced all exons, introns and flanking upstream/downstream sequences for ACSL6 and SIRT5. Among 69 identified SNPs, case-control allele frequency comparisons revealed nine suggestive associations (P<0.2). Each of these SNPs was next genotyped in the individual samples composing the pools. A suggestive association with rs 11743803 at ACSL6 remained (allele-wise P=0.02), with diminished evidence in an extended sample (448 cases, 554 controls, P=0.062). In conclusion, we propose a multi-stage method for comprehensive, rapid, efficient and economical genetic association analysis that enables simultaneous SNP detection and allele frequency estimation in large samples. This strategy may be particularly useful for research groups lacking access to high throughput genotyping facilities. Our analyses did not yield convincing evidence for associations of schizophrenia with ACSL6 or SIRT5. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Schizophr. Res. 2008 Dec 106: 200-7 |
| PMID | 18799291 |
| Title | Is the histidine triad nucleotide-binding protein 1 (HINT1) gene a candidate for schizophrenia? |
| Abstract | : The histidine triad nucleotide-binding protein 1, HINT1, hydrolyzes adenosine 5'-monophosphoramidate substrates such as AMP-morpholidate. The human HINT1 gene is located on chromosome 5q31.2, a region implicated in linkage studies of schizophrenia. HINT1 had been shown to have different expression in postmortem brains between schizophrenia patients and unaffected controls. It was also found to be associated with the dysregulation of postsynaptic dopamine transmission, thus suggesting a potential role in several neuropsychiatric diseases. : In this work, we studied 8 SNPs around the HINT1 gene region using the Irish study of high density schizophrenia families (ISHDSF, 1350 subjects and 273 pedigrees) and the Irish case control study of schizophrenia (ICCSS, 655 affected subjects and 626 controls). The expression level of HINT1 was compared between the postmortem brain cDNAs from schizophrenic patients and unaffected controls provided by the Stanley Medical Research Institute. : We found nominally significant differences in allele frequencies in several SNPs for both ISHDSF and ICCSS samples in sex-stratified analyses. However, the sex effect differed between the two samples. In expression studies, no significant difference in expression was observed between patients and controls. However, significant interactions amongst sex, diagnosis and rs3864283 genotypes were observed. : Data from both association and expression studies suggested that variants at HINT1 may be associated with schizophrenia and the associations may be sex-specific. However, the markers showing associations were in high LD to the SPEC2/PDZ-GEF2/ACSL6 locus reported previously in the same samples. This made it difficult to separate the association signals amongst these genes. Other independent studies may be necessary to distinguish these candidate genes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Schizophr. Res. 2008 Dec 106: 200-7 |
| PMID | 18799291 |
| Title | Is the histidine triad nucleotide-binding protein 1 (HINT1) gene a candidate for schizophrenia? |
| Abstract | : The histidine triad nucleotide-binding protein 1, HINT1, hydrolyzes adenosine 5'-monophosphoramidate substrates such as AMP-morpholidate. The human HINT1 gene is located on chromosome 5q31.2, a region implicated in linkage studies of schizophrenia. HINT1 had been shown to have different expression in postmortem brains between schizophrenia patients and unaffected controls. It was also found to be associated with the dysregulation of postsynaptic dopamine transmission, thus suggesting a potential role in several neuropsychiatric diseases. : In this work, we studied 8 SNPs around the HINT1 gene region using the Irish study of high density schizophrenia families (ISHDSF, 1350 subjects and 273 pedigrees) and the Irish case control study of schizophrenia (ICCSS, 655 affected subjects and 626 controls). The expression level of HINT1 was compared between the postmortem brain cDNAs from schizophrenic patients and unaffected controls provided by the Stanley Medical Research Institute. : We found nominally significant differences in allele frequencies in several SNPs for both ISHDSF and ICCSS samples in sex-stratified analyses. However, the sex effect differed between the two samples. In expression studies, no significant difference in expression was observed between patients and controls. However, significant interactions amongst sex, diagnosis and rs3864283 genotypes were observed. : Data from both association and expression studies suggested that variants at HINT1 may be associated with schizophrenia and the associations may be sex-specific. However, the markers showing associations were in high LD to the SPEC2/PDZ-GEF2/ACSL6 locus reported previously in the same samples. This made it difficult to separate the association signals amongst these genes. Other independent studies may be necessary to distinguish these candidate genes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | J. Med. Genet. 2008 Dec 45: 818-26 |
| PMID | 18718982 |
| Title | Association of haplotypes spanning PDZ-GEF2, LOC728637 and ACSL6 with schizophrenia in Han Chinese. |
| Abstract | schizophrenia is a complex genetic disorder caused by multiple genetic and environmental factors. Several lines of linkage and association studies have repeatedly suggested that the chromosome 5q22-33 region is implicated in the aetiology of schizophrenia. However, most of the previous studies on the linkage of 5q22-33 with schizophrenia were from European populations, and it was not well characterised in other populations. We analysed eight single nucleotide polymorphisms (SNPs) located in the 5q23.3 region in a cohort of 506 schizophrenia patients and 672 control subjects from south western China. Single marker association, haplotypic association, sex-specific association and molecular evolutionary analysis were performed. Single marker analysis indicated that SNP5 (rs1355095) in LOC728637 is associated with schizophrenia. When males and females were analysed separately, SNP4 (rs31251) in PDZ-GEF2 is associated with schizophrenia in females. Further analysis using haplotypes demonstrated that a haplotype block spanning PDZ-GEF2, LOC728637 and ACSL6 is highly associated with schizophrenia and several haplotypes in this haploblock have about twofold to 10-fold increase in the affected subjects. In addition, molecular evolutionary analysis suggests that PDZ-GEF2 has undergone adaptive evolution due to Darwinian positive selection in the human lineage. Our data provide evidence of the association of 5q22-33 with schizophrenia in Han Chinese. This chromosomal region is likely responsible for genetic susceptibility to schizophrenia, supporting previous data from European patients. In addition, our evolutionary analysis is consistent with the hypothesis that genes contributing to schizophrenia are likely under positive selection during human evolution. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | PLoS ONE 2011 -1 6: e20589 |
| PMID | 21655227 |
| Title | Identification of novel schizophrenia loci by homozygosity mapping using DNA microarray analysis. |
| Abstract | The recent development of high-resolution DNA microarrays, in which hundreds of thousands of single nucleotide polymorphisms (SNPs) are genotyped, enables the rapid identification of susceptibility genes for complex diseases. Clusters of these SNPs may show runs of homozygosity (ROHs) that can be analyzed for association with disease. An analysis of patients whose parents were first cousins enables the search for autozygous segments in their offspring. Here, using the Affymetrix® Genome-Wide Human SNP Array 5.0 to determine ROHs, we genotyped 9 individuals with schizophrenia (SCZ) whose parents were first cousins. We identified overlapping ROHs on chromosomes 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 16, 17, 19, 20, and 21 in at least 3 individuals. Only the locus on chromosome 5 has been reported previously. The ROHs on chromosome 5q23.3-q31.1 include the candidate genes histidine triad nucleotide binding protein 1 (HINT1) and acyl-CoA synthetase long-chain family member 6 (ACSL6). Other overlapping ROHs may contain novel rare recessive variants that affect SCZ specifically in our samples, given the highly heterozygous nature of SCZ. Analysis of patients whose parents are first cousins may provide new insights for the genetic analysis of psychiatric diseases. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | PLoS ONE 2011 -1 6: e28790 |
| PMID | 22205969 |
| Title | ACSL6 is associated with the number of cigarettes smoked and its expression is altered by chronic nicotine exposure. |
| Abstract | Individuals with schizophrenia tend to be heavy smokers and are at high risk for tobacco dependence. However, the nature of the comorbidity is not entirely clear. We previously reported evidence for association of schizophrenia with SNPs and SNP haplotypes in a region of chromosome 5q containing the SPEC2, PDZ-GEF2 and ACSL6 genes. In this current study, analysis of the control subjects of the Molecular Genetics of schizophrenia (MGS) sample showed similar pattern of association with number of cigarettes smoked per day (numCIG) for the same region. To further test if this locus is associated with tobacco smoking as measured by numCIG and FTND, we conducted replication and meta-analysis in 12 independent samples (n>16,000) for two markers in ACSL6 reported in our previous schizophrenia study. In the meta-analysis of the replication samples, we found that rs667437 and rs477084 were significantly associated with numCIG (p?=?0.00038 and 0.00136 respectively) but not with FTND scores. We then used in vitro and in vivo techniques to test if nicotine exposure influences the expression of ACSL6 in brain. Primary cortical culture studies showed that chronic (5-day) exposure to nicotine stimulated ACSL6 mRNA expression. Fourteen days of nicotine administration via osmotic mini pump also increased ACSL6 protein levels in the prefrontal cortex and hippocampus of mice. These increases were suppressed by injection of the nicotinic receptor antagonist mecamylamine, suggesting that elevated expression of ACSL6 requires nicotinic receptor activation. These findings suggest that variations in the ACSL6 gene may contribute to the quantity of cigarettes smoked. The independent associations of this locus with schizophrenia and with numCIG in non-schizophrenic subjects suggest that this locus may be a common liability to both conditions. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | PLoS ONE 2011 -1 6: e28790 |
| PMID | 22205969 |
| Title | ACSL6 is associated with the number of cigarettes smoked and its expression is altered by chronic nicotine exposure. |
| Abstract | Individuals with schizophrenia tend to be heavy smokers and are at high risk for tobacco dependence. However, the nature of the comorbidity is not entirely clear. We previously reported evidence for association of schizophrenia with SNPs and SNP haplotypes in a region of chromosome 5q containing the SPEC2, PDZ-GEF2 and ACSL6 genes. In this current study, analysis of the control subjects of the Molecular Genetics of schizophrenia (MGS) sample showed similar pattern of association with number of cigarettes smoked per day (numCIG) for the same region. To further test if this locus is associated with tobacco smoking as measured by numCIG and FTND, we conducted replication and meta-analysis in 12 independent samples (n>16,000) for two markers in ACSL6 reported in our previous schizophrenia study. In the meta-analysis of the replication samples, we found that rs667437 and rs477084 were significantly associated with numCIG (p?=?0.00038 and 0.00136 respectively) but not with FTND scores. We then used in vitro and in vivo techniques to test if nicotine exposure influences the expression of ACSL6 in brain. Primary cortical culture studies showed that chronic (5-day) exposure to nicotine stimulated ACSL6 mRNA expression. Fourteen days of nicotine administration via osmotic mini pump also increased ACSL6 protein levels in the prefrontal cortex and hippocampus of mice. These increases were suppressed by injection of the nicotinic receptor antagonist mecamylamine, suggesting that elevated expression of ACSL6 requires nicotinic receptor activation. These findings suggest that variations in the ACSL6 gene may contribute to the quantity of cigarettes smoked. The independent associations of this locus with schizophrenia and with numCIG in non-schizophrenic subjects suggest that this locus may be a common liability to both conditions. |
| SCZ Keywords | schizophrenia, schizophrenic |