| 1 | Nippon Rinsho 2009 Jun 67: 1085-9 |
|---|---|
| PMID | 19507497 |
| Title | [Genome wide studies of mental disorders]. |
| Abstract | In these two years, genome wide association studies of SNPs and CNVs in large samples of patients with bipolar disorder or schizophrenia were published. In bipolar disorder, association with SNPs of ANK3 and CACNA1C was found by the combined analysis of three sample sets, which was consistent across three sample sets. In schizophrenia, two deletions, 1q21.1 and 15q13.3, were found to increase the risk of schizophrenia with odds ratios larger than 10. These two deletions are regarderd as the causes of genome diseases that accompany facial dysmorphism and developmental disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 2 | Hum. Genet. 2009 Jul 126: 3-12 |
| PMID | 19521722 |
| Title | Genetics of psychosis; insights from views across the genome. |
| Abstract | The major psychotic illnesses, schizophrenia and bipolar disorder (BD), are among the most heritable common disorders, but finding specific susceptibility genes for them has not been straightforward. The reasons are widely assumed to include lack of valid phenotypic definition, absence of good theories of pathophysiology for candidate gene studies, and the involvement of many genes, each making small contributions to population risk. Within the last year or so, a number of genome wide association (GWAS) of schizophrenia and BD have been published. These have produced stronger evidence for association to specific risk loci than have earlier studies, specifically for the zinc finger binding protein 804A (ZNF804A) locus in schizophrenia and for the calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) and ankyrin 3, node of Ranvier (ANK3) loci in bipolar disorder. The ZNF804A and CACNA1C loci appear to influence risk for both disorders, a finding that supports the hypothesis that schizophrenia and BD are not aetiologically distinct. In the case of schizophrenia, a number of rare copy number variants have also been detected that have fairly large effect sizes on disease risk, and that additionally influence risk of autism, mental retardation, and other neurodevelopmental disorders. The existing findings point to some likely pathophysiological mechanisms but also challenge current concepts of disease classification. They also provide grounds for optimism that larger studies will reveal more about the origins of these disorders, although currently, very little of the genetic risk of either disorder is explained. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 3 | Neuroscience 2009 Nov 164: 331-43 |
| PMID | 19358880 |
| Title | The genetics of bipolar disorder. |
| Abstract | Bipolar disorder is a mood disorder characterized by impairing episodes of mania and depression. Twin studies have established that bipolar disorder is among the most heritable of medical disorders and efforts to identify specific susceptibility genes have intensified over the past two decades. The search for genes influencing bipolar disorder has been complicated by a paucity of animal models, limited understanding of pathogenesis, and the genetic and phenotypic complexity of the syndrome. Linkage studies have implicated several chromosomal regions as harboring relevant genes, but results have been inconsistent. It is now widely accepted that the genetic liability to bipolar disorder reflects the action of many genes of individually small effect, a scenario for which linkage studies are poorly suited. Thus, association studies, which are more powerful for the detection of modest effect loci, have become the focus of gene-finding research. A large number of candidate genes, including biological candidates derived from hypotheses about the pathogenesis of the disorder and positional candidates derived from linkage and cytogenetic studies, have been evaluated. Several of these genes have been associated with the disorder in independent studies (including BDNF, DAOA, DISC1, GRIK4, SLC6A4, and TPH2), but none has been established. The clinical heterogeneity of bipolar disorder and its phenotypic and genetic overlap with other disorders (especially schizophrenia, schizoaffective disorder, and major depressive disorder) have raised questions about the optimal phenotype definition for genetic studies. Nevertheless, genomewide association analysis, which has successfully identified susceptibility genes for a variety of complex disorders, has begun to implicate specific genes for bipolar disorder (DGKH, CACNA1C, ANK3). The polygenicity of the disorder means that very large samples will be needed to detect the modest effect loci that likely contribute to bipolar disorder. Detailed genetic dissection of the disorder may provide novel targets (both pharmacologic and psychosocial) for intervention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 4 | Schizophr Bull 2009 May 35: 482-90 |
| PMID | 19329560 |
| Title | Psychosis genetics: modeling the relationship between schizophrenia, bipolar disorder, and mixed (or "schizoaffective") psychoses. |
| Abstract | As a result of improving technologies and greatly increased sample sizes, the last 2 years has seen unprecedented advances in identification of specific genetic risk factors for psychiatric phenotypes. Strong genetic associations have been reported at common polymorphisms within ANK3 and CACNA1C in bipolar disorder and ZNF804A in schizophrenia and a relatively specific association between common variation in GABA(A) receptor genes and cases with features of both bipolar disorder and schizophrenia. Further, the occurrence of rare copy number variants (CNVs) has been shown to be increased in schizophrenia compared with controls. These emerging data provide a powerful resource for exploring the relationship between psychiatric phenotypes and can, and should, be used to inform conceptualization, classification, and diagnosis in psychiatry. It is already clear that, in general, genetic associations are not specific to one of the traditional diagnostic categories. For example, variation at ZNF804A is associated with risk of both bipolar disorder and schizophrenia, and some rare CNVs are associated with risk of autism and epilepsy as well as schizophrenia. These data are not consistent with a simple dichotomous model of functional psychosis and indicate the urgent need for moves toward approaches that (a) better represent the range of phenotypic variation seen in the clinical population and (b) reflect the underlying biological variation that gives rise to the phenotypes. We consider the implications for models of psychosis and the importance of recognizing and studying illness that has prominent affective and psychotic features. We conclude that if psychiatry is to translate the opportunities offered by new research methodologies, we must finally abandon a 19th-century dichotomy and move to a classificatory approach that is worthy of the 21st century. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 5 | Mol. Psychiatry 2009 Mar 14: 252-60 |
| PMID | 19065143 |
| Title | Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk. |
| Abstract | Genome-wide association (GWAS) analyses have identified susceptibility loci for many diseases, but most risk for any complex disorder remains unattributed. There is therefore scope for complementary approaches to these data sets. Gene-wide approaches potentially offer additional insights. They might identify association to genes through multiple signals. Also, by providing support for genes rather than single nucleotide polymorphisms (SNPs), they offer an additional opportunity to compare the results across data sets. We have undertaken gene-wide analysis of two GWAS data sets: schizophrenia and bipolar disorder. We performed two forms of analysis, one based on the smallest P-value per gene, the other on a truncated product of P method. For each data set and at a range of statistical thresholds, we observed significantly more SNPs within genes (P(min) for excess<0.001) showing evidence for association than expected whereas this was not true for extragenic SNPs (P(min) for excess>0.1). At a range of thresholds of significance, we also observed substantially more associated genes than expected (P(min) for excess in schizophrenia=1.8 x 10(-8), in bipolar=2.4 x 10(-6)). Moreover, an excess of genes showed evidence for association across disorders. Among those genes surpassing thresholds highly enriched for true association, we observed evidence for association to genes reported in other GWAS data sets (CACNA1C) or to closely related family members of those genes including CSF2RB, CACNA1B and DGKI. Our analyses show that association signals are enriched in and around genes, large numbers of genes contribute to both disorders and gene-wide analyses offer useful complementary approaches to more standard methods. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 6 | Mol. Psychiatry 2010 Feb 15: 119-21 |
| PMID | 20098439 |
| Title | CACNA1C (rs1006737) is associated with schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 7 | Arch. Gen. Psychiatry 2010 Sep 67: 939-45 |
| PMID | 20819988 |
| Title | Genetic variation in CACNA1C affects brain circuitries related to mental illness. |
| Abstract | The CACNA1C gene (alpha-1C subunit of the L-type voltage-gated calcium channel) has been identified as a risk gene for bipolar disorder and schizophrenia, but the mechanism of association has not been explored. To identify the neural system mechanism that explains the genetic association between the CACNA1C gene and psychiatric illness using neuroimaging and human brain expression. We used blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to measure brain activation in circuitries related to bipolar disorder and schizophrenia by comparing CACNA1C genotype groups among healthy subjects. We tested the effect of genotype on messenger RNA (mRNA) levels of CACNA1C in postmortem human brain. A case-control analysis was used to determine the association of CACNA1C genotype with schizophrenia. National Institutes of Health Clinical Center. Healthy men and women of white race/ethnicity participated in the fMRI study. Postmortem samples from normal human brains were used for the brain expression study. Patients with schizophrenia and healthy subjects were used in the case-control analysis. BOLD fMRI, mRNA levels in postmortem brain samples, and genetic association with schizophrenia. The risk-associated single-nucleotide polymorphism (SNP rs1006737) in CACNA1C predicted increased hippocampal activity during emotional processing (P = .001 uncorrected, P((false recovery rate [FDR])) = .05, z = 3.20) and increased prefrontal activity during executive cognition (P = 2.8e-05 uncorrected, P(FDR) = .01, z = 4.03). The risk-associated SNP also predicted increased expression of CACNA1C mRNA in human brain (P = .002). CACNA1C was associated with schizophrenia in our case-control sample (odds ratio, 1.77; P = .03). The risk-associated SNP in CACNA1C maps to circuitries implicated in genetic risk for bipolar disorder and schizophrenia. Its effects in human brain expression implicate a molecular and neural system mechanism for the clinical genetic association. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 8 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Dec 34: 1375-80 |
| PMID | 20600464 |
| Title | Genetic findings in schizophrenia patients related to alterations in the intracellular Ca-homeostasis. |
| Abstract | There is a relatively high genetic heritability of schizophrenia as shown by family, twin and adoption studies. A large number of hypotheses on the causes of schizophrenia occurred over time. In this review we focus on genetic findings related to potential alterations of intracellular Ca-homeostasis in association with schizophrenia. First, we provide evidence for the NMDA/glutamatergic theory of schizophrenia including calcium processes. We mainly focus on genes including: DAO (D-amino acid oxidase), DAOA (D-amino acid oxidase activator), DTNBP1 (Dysbindin 1, dystrobrevin-binding protein 1), NRG1 (Neuregulin 1), ERBB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4, avian), NOS1 (nitric oxide synthase 1, neuronal) and NRGN (Neurogranin). Furthermore, a gene coding for a calcium channel subunit (CACNA1C: calcium channel, voltage-dependent, L type, alpha 1C subunit) is discussed in the light of schizophrenia whereas genetic findings related to alterations in the intracellular Ca-homeostasis associated specifically with dopaminergic and serotonergic neurotransmission in schizophrenia are not herein closer reviewed. Taken together there is converging evidence for the contribution of genes potentially related to alterations in intracellular Ca-homeostasis to the risk of schizophrenia. Replications and functional studies will hopefully provide further insight into these genetic variants and the underlying processes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 9 | Neuroimage 2010 Jan 49: 1831-6 |
| PMID | 19781653 |
| Title | Effect of CACNA1C rs1006737 on neural correlates of verbal fluency in healthy individuals. |
| Abstract | Recent genetic studies found the A allele of the variant rs1006737 in the alpha 1C subunit of the L-type voltage-gated calcium channel (CACNA1C) gene to be overrepresented in patients suffering from bipolar disorder, schizophrenia or major depression. While the functions underlying the pathophysiology of these psychiatric disorders are yet unknown, impaired performance in verbal fluency tasks is an often replicated finding. We investigated the influence of the rs1006737 single nucleotide polymorphism (SNP) on verbal fluency and its neural correlates. Brain activation was measured with functional magnetic resonance imaging (fMRI) during a semantic verbal fluency task in 63 healthy male individuals. They additionally performed more demanding verbal fluency tasks outside the scanner. All subjects were genotyped for CACNA1C rs1006737. For the behavioral measures outside the scanner, rs1006737genotype had an effect on semantic but not on lexical verbal fluency with decreased performance in risk-allele carriers. In the fMRI experiment, while there were no differences in behavioural performance, increased activation in the left inferior frontal gyrus as well as the left precuneus was found in risk-allele carriers in the semantic verbal fluency task. The rs1006737 variant does influence language production on a semantic level in conjunction with the underlying neural systems. These findings are in line with results of studies in bipolar disorder, schizophrenia and major depression and may explain some of the cognitive and brain activation variation found in these disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 10 | Mol. Psychiatry 2010 Oct 15: 1016-22 |
| PMID | 19621016 |
| Title | The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. |
| Abstract | Molecular genetic analysis offers opportunities to advance our understanding of the nosological relationship between psychiatric diagnostic categories in general, and the mood and psychotic disorders in particular. Strong evidence (P=7.0 × 10(-7)) of association at the polymorphism rs1006737 (within CACNA1C, the gene encoding the ?-1C subunit of the L-type voltage-gated calcium channel) with the risk of bipolar disorder (BD) has recently been reported in a meta-analysis of three genome-wide association studies of BD, including our BD sample (N=1868) studied within the Wellcome Trust Case Control Consortium. Here, we have used our UK case samples of recurrent major depression (N=1196) and schizophrenia (N=479) and UK non-psychiatric comparison groups (N=15316) to examine the spectrum of phenotypic effect of the bipolar risk allele at rs1006737. We found that the risk allele conferred increased risk for schizophrenia (P=0.034) and recurrent major depression (P=0.013) with similar effect sizes to those previously observed in BD (allelic odds ratio ?1.15). Our findings are evidence of some degree of overlap in the biological underpinnings of susceptibility to mental illness across the clinical spectrum of mood and psychotic disorders, and show that at least some loci can have a relatively general effect on susceptibility to diagnostic categories, as currently defined. Our findings will contribute to a better understanding of the pathogenesis of major psychiatric illness, and such knowledge should be useful in providing an etiological rationale for shaping psychiatric nosology, which is currently reliant entirely on descriptive clinical data. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 11 | Nat. Genet. 2011 Oct 43: 969-76 |
| PMID | 21926974 |
| Title | Genome-wide association study identifies five new schizophrenia loci. |
| Abstract | We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9)). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 12 | World J. Biol. Psychiatry 2011 Aug 12: 392-7 |
| PMID | 21767209 |
| Title | ANK3, CACNA1C and ZNF804A gene variants in bipolar disorders and psychosis subphenotype. |
| Abstract | OBJECTIVES. The ANK3, CACNA1C and ZNF804A genes have been implicated in both bipolar disorders (BPD) and schizophrenia (SCZ). It has been suggested that BPD with psychosis may be a clinical manifestation of genes overlapping between BPD and SCZ. We therefore tested the association of these genes with BPD in a large family-based sample, and then dissected the phenotype into psychosis present or absent subgroups. METHODS. We genotyped four high interest single nucleotide polymorphisms from ANK3 (rs10994336, rs9804190), CACNA1C (rs1006737), and ZNF804A (rs1344706). Family based association testing (FBAT) was performed on 312 families, and within psychotic (N = 158) and non-psychotic BPD (N = 119) subgroups. RESULTS. In the whole sample, we found a nominal association in ZNF804A (rs1344706, P = 0.046), and a trend in CACNA1C (rs1006737, P = 0.077). In the psychotic BPD subgroup, as hypothesized, stronger signals were observed in ZNF804A (P = 0.019) and CACNA1C (P = 0.017). We found no association in the ANK3 markers, but the rs10994336 variant was nominally associated with non-psychotic BPD (P = 0.046). Exploratory analysis revealed the rs1344706 variant was also implicated in suicide-attempt behaviour (P = 0.038). CONCLUSIONS. These tentative results are consistent with the hypothesis that the subphenotype of BPD with psychosis may represent a clinical manifestation of shared genetic liability between BPD and SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 13 | Bipolar Disord 2011 May 13: 250-9 |
| PMID | 21676128 |
| Title | The CACNA1C and ANK3 risk alleles impact on affective personality traits and startle reactivity but not on cognition or gating in healthy males. |
| Abstract | The rs10994336 ANK3 and rs1006737 CACNA1C genetic variants have recently been identified as the most consistent, genome-wide significant risk factors for bipolar disorder, while the CACNA1C variant has also been associated with schizophrenia and major depression. The aim of this study was to examine the phenotypic consequences of the risk CACNA1C and ANK3 alleles in a large homogeneous cohort of healthy young males. We recruited 703 randomly selected, healthy army conscripts (mean age 22.1 ± 3.0 years) from the first wave of the Learning on Genetics of schizophrenia project in Heraklion, Crete. Of those recruited, 530 subjects entered and completed the study. Subjects were assessed for prepulse inhibition (PPI), startle reactivity, neuropsychology, and personality. ? UNPHASED analysis revealed that the rs1006737 A-allele was associated with lower extraversion and higher harm avoidance, trait anxiety, and paranoid ideation, while the rs10994336 T-allele was associated with lower novelty seeking and behavioral activation scores (p < 0.01). Both alleles were associated with high startle reactivity (p < 0.05). There were no significant associations with any cognitive task performance or PPI. The CACNA1C genotype was associated with proneness to anxiety and negative mood, while the ANK3 genotype was associated with proneness to anhedonia. Both risk genotypes were associated with high startle reactivity, suggesting a role of these polymorphisms in threat/stress signal processing, probably in the hippocampus and/or amygdala. None of the risk genotypes affected sensorimotor gating or behavioral performance in an extensive battery of executive function tests in this cohort of healthy males. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 14 | Hum. Mol. Genet. 2011 Jan 20: 387-91 |
| PMID | 21037240 |
| Title | Most genome-wide significant susceptibility loci for schizophrenia and bipolar disorder reported to date cross-traditional diagnostic boundaries. |
| Abstract | Recent findings from genetic epidemiology and from genome-wide association studies point strongly to a partial overlap in the genes that contribute susceptibility to schizophrenia and bipolar disorder (BD). Previous data have also directly implicated one of the best supported schizophrenia-associated loci, zinc finger binding protein 804A (ZNF804A), as showing trans-disorder effects, and the same is true for one of the best supported bipolar loci, calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) which has also been associated with schizophrenia. We have undertaken a cross-phenotype study based upon the remaining variants that show genome-wide evidence for association in large schizophrenia and BD meta-analyses. These comprise in schizophrenia, SNPs in or in the vicinity of transcription factor 4 (TCF4), neurogranin (NRGN) and an extended region covering the MHC locus on chromosome 6. For BD, the strongly supported variants are in the vicinity of ankyrin 3, node of Ranvier (ANK3) and polybromo-1 (PBRM1). Using data sets entirely independent of their original discoveries, we observed strong evidence that the PBRM1 locus is also associated with schizophrenia (P = 0.00015) and nominally significant evidence (P < 0.05) that the NRGN and the extended MHC region are associated with BD. Moreover, considering this highly restricted set of loci as a group, the evidence for trans-disorder effects is compelling (P = 4.7 × 10(-5)). Including earlier reported data for trans-disorder effects for ZNF804A and CACNA1C, six out of eight of the most robustly associated loci for either disorder show trans-disorder effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 15 | Psychiatr. Genet. 2011 Feb 21: 1-4 |
| PMID | 21057379 |
| Title | Case-case genome-wide association analysis shows markers differentially associated with schizophrenia and bipolar disorder and implicates calcium channel genes. |
| Abstract | There are theoretical reasons why comparing marker allele frequencies between cases of different diseases, rather than with controls, may offer benefits. The samples may be better matched, especially for background risk factors common to both diseases. Genetic loci may also be detected which influence which of the two diseases occurs if common risk factors are present. We used samples of UK bipolar and schizophrenic cases that had earlier been subject to genome-wide association studies and compared marker allele frequencies between the two samples. When these differed for a marker, we compared the case sample allele frequencies with those of a control sample. Eight markers were significant at P value of less than 10(-5). Of these, the most interesting finding was for rs17645023, which was significant at P value of less than 10(-6) and which lies 36 kb from CACNG5. Control allele frequencies for this marker were intermediate between those for bipolar and schizophrenic cases. The application of this approach suggests that it does have some merits. The finding for CACNG5, taken together with the earlier implication of CACNA1C and CACNA1B, strongly suggests a key role for voltage-dependent calcium channel genes in the susceptibility to bipolar disorder and/or schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 16 | Nat. Genet. 2011 Oct 43: 977-83 |
| PMID | 21926972 |
| Title | Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. |
| Abstract | We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10(-7)). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 17 | Psychiatr. Genet. 2011 Feb 21: 1-4 |
| PMID | 21057379 |
| Title | Case-case genome-wide association analysis shows markers differentially associated with schizophrenia and bipolar disorder and implicates calcium channel genes. |
| Abstract | There are theoretical reasons why comparing marker allele frequencies between cases of different diseases, rather than with controls, may offer benefits. The samples may be better matched, especially for background risk factors common to both diseases. Genetic loci may also be detected which influence which of the two diseases occurs if common risk factors are present. We used samples of UK bipolar and schizophrenic cases that had earlier been subject to genome-wide association studies and compared marker allele frequencies between the two samples. When these differed for a marker, we compared the case sample allele frequencies with those of a control sample. Eight markers were significant at P value of less than 10(-5). Of these, the most interesting finding was for rs17645023, which was significant at P value of less than 10(-6) and which lies 36 kb from CACNG5. Control allele frequencies for this marker were intermediate between those for bipolar and schizophrenic cases. The application of this approach suggests that it does have some merits. The finding for CACNG5, taken together with the earlier implication of CACNA1C and CACNA1B, strongly suggests a key role for voltage-dependent calcium channel genes in the susceptibility to bipolar disorder and/or schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 18 | Psychol Med 2011 Jul 41: 1551-61 |
| PMID | 21078228 |
| Title | Effects of a CACNA1C genotype on attention networks in healthy individuals. |
| Abstract | Recent genetic studies found the A allele of the variant rs1006737 in the alpha 1C subunit of the L-type voltage-gated calcium channel (CACNA1C) gene to be over-represented in patients with psychosis, including schizophrenia, bipolar disorder and major depressive disorder. In these disorders, attention deficits are among the main cognitive symptoms and have been related to altered neural activity in cerebral attention networks. The particular effect of CACNA1C on neural function, such as attention networks, remains to be elucidated. The current event-related functional magnetic resonance imaging (fMRI) study investigated the effect of the CACNA1C gene on brain activity in 80 subjects while performing a scanner-adapted version of the Attention Network Test (ANT). Three domains of attention were probed simultaneously: alerting, orienting and executive control of attention. Risk allele carriers showed impaired performance in alerting and orienting in addition to reduced neural activity in the right inferior parietal lobule [Brodmann area (BA) 40] during orienting and in the medial frontal gyrus (BA 8) during executive control of attention. These areas belong to networks that have been related to impaired orienting and executive control mechanisms in neuropsychiatric disorders. Our results suggest that CACNA1C plays a role in the development of specific attention deficits in psychiatric disorders by modulation of neural attention networks. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 19 | Mol. Psychiatry 2012 Jan 17: 36-48 |
| PMID | 21042317 |
| Title | Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned. |
| Abstract | Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1?M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 20 | Neurosci Biobehav Rev 2012 Jan 36: 556-71 |
| PMID | 21946175 |
| Title | Genome wide association studies (GWAS) and copy number variation (CNV) studies of the major psychoses: what have we learnt? |
| Abstract | schizophrenia (SZ) and bipolar disorder (BPD) have high heritabilities and are clinically and genetically complex. Genome wide association studies (GWAS) and studies of copy number variations (CNV) in SZ and BPD have allowed probing of their underlying genetic risks. In this systematic review, we assess extant genetic signals from published GWAS and CNV studies of SZ and BPD up till March 2011. Risk genes associated with SZ at genome wide significance level (p value<7.2 × 10(-8)) include zinc finger binding protein 804A (ZNF804A), major histocompatibility (MHC) region on chromosome 6, neurogranin (NRGN) and transcription factor 4 (TCF4). Risk genes associated with BPD include ankyrin 3, node of Ranvier (ANK3), calcium channel, voltage dependent, L type, alpha 1C subunit (CACNA1C), diacylglycerol kinase eta (DGKH), gene locus on chromosome 16p12, and polybromo-1 (PBRM1) and very recently neurocan gene (NCAN). Possible common genes underlying psychosis include ZNF804A, CACNA1C, NRGN and PBRM1. The CNV studies suggest that whilst CNVs are found in both SZ and BPD, the large deletions and duplications are more likely found in SZ rather than BPD. The validation of any genetic signal is likely confounded by genetic and phenotypic heterogeneities which are influenced by epistatic, epigenetic and gene-environment interactions. There is a pressing need to better integrate the multiple research platforms including systems biology computational models, genomics, cross disorder phenotyping studies, transcriptomics, proteomics, metabolomics, neuroimaging and clinical correlations in order to get us closer to a more enlightened understanding of the genetic and biological basis underlying these potentially crippling conditions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 21 | Sci Rep 2012 -1 2: 634 |
| PMID | 22957138 |
| Title | Effects of the CACNA1C risk allele on neurocognition in patients with schizophrenia and healthy individuals. |
| Abstract | Recent genetic association studies have identified the A-allele of rs1006737 within CACNA1C as a risk factor for schizophrenia as well as mood disorders. Some evidence suggests that this polymorphism plays a role in cognitive function both in schizophrenia patients and healthy individuals; however, the precise nature of this association remains unclear. Here we investigated the possible association of this polymorphism with a wide range of neurocognitive functions in schizophrenia patients and in healthy subjects. schizophrenia patients exhibited significantly poorer performance on all the cognitive domains as compared to healthy controls. In patients, A-allele carriers demonstrated significantly worse logical memory performance than the G-allele homozygotes. In controls, no significant association was observed between the genotype and any of the cognitive domains examined. These results add to the literature suggesting that rs1006737 may be associated with schizophrenia through its detrimental effect on endophenotypic traits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 22 | Schizophr. Res. 2012 Oct 141: 60-4 |
| PMID | 22883350 |
| Title | Experimental validation of candidate schizophrenia gene ZNF804A as target for hsa-miR-137. |
| Abstract | MicroRNAs (miRNAs) are small non-coding RNAs that mainly function as negative regulators of gene expression (Lai, 2002) and have been shown to be involved in schizophrenia etiology through genetic and expression studies (Burmistrova et al., 2007; Hansen et al., 2007a; Perkins et al., 2007; Beveridge et al., 2010; Kim et al., 2010). In a mega analysis of genome-wide association study (GWAS) of schizophrenia (SZ) and bipolar disorders (BP), a polymorphism (rs1625579) located in the primary transcript of a miRNA gene, hsa-miR-137, was reported to be strongly associated with SZ. Four SZ loci (CACNA1C, TCF4, CSMD1, C10orf26) achieving genome-wide significance in the same study were predicted and later experimentally validated (Kwon et al., 2011) as hsa-miR-137 targets. Here, using in silico, cellular and luciferase based approaches we also provide evidence that another well replicated candidate schizophrenia gene, ZNF804A, is also target for hsa-miR-137. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 23 | Neuropsychopharmacology 2012 Feb 37: 677-84 |
| PMID | 22012475 |
| Title | The effects of CACNA1C gene polymorphism on spatial working memory in both healthy controls and patients with schizophrenia or bipolar disorder. |
| Abstract | CACNA1C gene polymorphism (rs1006737) is a susceptibility factor for both schizophrenia (SCZ) and bipolar disorder (BP). However, its role in working memory, a cognitive function that is impaired in both diseases, is not clear. Using three samples, including healthy controls, patients with SCZ, and patients currently in manic episodes of BP, this study tested the association between the SNP rs1006737 and spatial working memory as measured by an N-back task and a dot pattern expectancy (DPX) task. Among SCZ patients and healthy controls, the clinical risk allele was associated with impaired working memory, but the association was either in opposite direction or non-significant in patients with BP. These results indicated that rs1006737 may have differential effects on working memory in different disease populations and pointed to the necessity for more studies in different patient populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 24 | Prog. Neurobiol. 2012 Oct 99: 1-14 |
| PMID | 22705413 |
| Title | CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease. |
| Abstract | One of the most consistent genetic findings to have emerged from bipolar disorder genome wide association studies (GWAS) is with CACNA1C, a gene that codes for the ?(1C) subunit of the Ca(v)1.2 voltage-dependent L-type calcium channel (LTCC). Genetic variation in CACNA1C have also been associated with depression, schizophrenia, autism spectrum disorders, as well as changes in brain function and structure in control subjects who have no diagnosable psychiatric illness. These data are consistent with a continuum of shared neurobiological vulnerability between diverse-Diagnostic and Statistical Manual (DSM) defined-neuropsychiatric diseases. While involved in numerous cellular functions, Ca(v)1.2 is most frequently implicated in coupling of cell membrane depolarization to transient increase of the membrane permeability for calcium, leading to activation and, potentially, changes in intracellular signaling pathway activity, gene transcription, and synaptic plasticity. Ca(v)1.2 is involved in the proper function of numerous neurological circuits including those involving the hippocampus, amygdala, and mesolimbic reward system, which are strongly implicated in psychiatric disease pathophysiology. A number of behavioral effects of LTCC inhibitors have been described including antidepressant-like behavioral actions in rodent models. Clinical studies suggest possible treatment effects in a subset of patients with mood disorders. We review the genetic structure and variation of CACNA1C, discussing relevant human genetic and clinical findings, as well as the biological actions of Ca(v)1.2 that are most relevant to psychiatric illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 25 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Jun 159B: 465-75 |
| PMID | 22488967 |
| Title | Identification of a CACNA2D4 deletion in late onset bipolar disorder patients and implications for the involvement of voltage-dependent calcium channels in psychiatric disorders. |
| Abstract | The GWAS-based association of CACNA1C with bipolar disorder (BPD) is one of the strongest genetic findings to date. CACNA1C belongs to the family of CACN genes encoding voltage-dependent calcium channels (VDCCs). VDCCs are involved in brain circuits and cognitive processes implicated in BPD and schizophrenia (SZ). Recently, it was shown that rare copy number variations (CNVs) are found at an increased frequency in SZ and to a lesser extent also in BPD, suggesting the involvement of CNVs in the causation of these diseases. We hypothesize that CNVs in CACN genes can influence the susceptibility to BPD, SZ, and/or schizoaffective disorder (SZA). A search for CNVs in eight CACN genes in a patient-control sample of European decent was performed. A total of 709 BP patients, 645 SZ patients, 189 SZA patients, and 1,470 control individuals were screened using the Multiplex Amplicon Quantification (MAQ) method. We found a rare, partial deletion of 35.7 kb in CACNA2D4 in two unrelated late onset bipolar I patients and in one control individual. All three deletions shared the same breakpoints removing exons 17-26 of CACNA2D4, comprising part of the CACHE domain. Based on the data we cannot claim causality to BPD of the identified CACNA2D4 deletion but nevertheless this deletion can be important in unraveling the underlying processes leading to psychiatric diseases in general and BPD in particular. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 26 | Mol. Psychiatry 2013 Jan 18: 11-2 |
| PMID | 22182936 |
| Title | Validation of schizophrenia-associated genes CSMD1, C10orf26, CACNA1C and TCF4 as miR-137 targets. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 27 | Psychiatry Res 2013 Mar 206: 122-3 |
| PMID | 22985546 |
| Title | CACNA1C as a risk factor for schizotypal personality disorder and schizotypy in healthy individuals. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 28 | Psychiatry Res 2013 Mar 206: 122-3 |
| PMID | 22985546 |
| Title | CACNA1C as a risk factor for schizotypal personality disorder and schizotypy in healthy individuals. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 29 | Neuropsychiatr Dis Treat 2013 -1 9: 1573-82 |
| PMID | 24143106 |
| Title | Evidence for single nucleotide polymorphisms and their association with bipolar disorder. |
| Abstract | Bipolar disorder (BD) is a complex disorder with a number of susceptibility genes and environmental risk factors involved in its pathogenesis. In recent years, huge progress has been made in molecular techniques for genetic studies, which have enabled identification of numerous genomic regions and genetic variants implicated in BD across populations. Despite the abundance of genetic findings, the results have often been inconsistent and not replicated for many candidate genes/single nucleotide polymorphisms (SNPs). Therefore, the aim of the review presented here is to summarize the most important data reported so far in candidate gene and genome-wide association studies. Taking into account the abundance of association data, this review focuses on the most extensively studied genes and polymorphisms reported so far for BD to present the most promising genomic regions/SNPs involved in BD. The review of association data reveals evidence for several genes (SLC6A4/5-HTT [serotonin transporter gene], BDNF [brain-derived neurotrophic factor], DAOA [D-amino acid oxidase activator], DTNBP1 [dysbindin], NRG1 [neuregulin 1], DISC1 [disrupted in schizophrenia 1]) to be crucial candidates in BD, whereas numerous genome-wide association studies conducted in BD indicate polymorphisms in two genes (CACNA1C [calcium channel, voltage-dependent, L type, alpha 1C subunit], ANK3 [ankyrin 3]) replicated for association with BD in most of these studies. Nevertheless, further studies focusing on interactions between multiple candidate genes/SNPs, as well as systems biology and pathway analyses are necessary to integrate and improve the way we analyze the currently available association data. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 30 | J Affect Disord 2013 Oct 151: 291-7 |
| PMID | 23820096 |
| Title | No evidence for association between bipolar disorder risk gene variants and brain structural phenotypes. |
| Abstract | While recent genome-wide association studies have identified several new bipolar disorder (BD) risk variants, structural imaging studies have reported enlarged ventricles and volumetric reductions among the most consistent findings. We investigated whether these genetic risk variants could explain some of the structural brain abnormalities in BD. In a sample of 517 individuals (N=121 BD cases, 116 SZ cases, 61 other psychosis cases and 219 healthy controls), we tested the potential association between nine SNPs in the genes CACNA1C, ANK3, ODZ4 and SYNE1 and eight brain structural measures found to be altered in BD, and if these were specifically affecting the BD sample. We also assessed the polygenic effect of all these 9 SNPs on the brain phenotypes. Our most significant result was an association between the risk allele A in CACNA1C SNP rs4775913 and decreased cerebellar volume (pnom.=0.0075) in the total sample, which did not remain significant after multiple testing correction (pthreshold<0.0064). There was no evidence for diagnostic specificity for this association in the BD group. Further, no polygenic effect of these 9 SNPs was observed. Low statistical power might increase our type II error rate. The present findings indicate that these risk SNPs do not explain a large proportion of the structural brain alterations in BD. Thus, these genes which are all related to neuronal functions must be involved in other pathophysiological aspects of BD development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 31 | J. Mol. Neurosci. 2013 Oct 51: 474-7 |
| PMID | 23900723 |
| Title | Does the bipolar disorder-associated CACNA1C gene confer susceptibility to schizophrenia in Han Chinese? |
| Abstract | The gene coding for the calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) has been reported to be associated with bipolar disorder (BD) in our previous study. Broad evidence suggests some degree of shared genetic susceptibility between BD and schizophrenia. In this study, we aimed to determine whether the BD-associated gene CACNA1C confers susceptibility to schizophrenia. The association was assessed using a cross section study of 696 schizophrenia patients and 1,114 matched control subjects of Han Chinese origin. Between-group comparisons of genotypic or allelic frequencies showed no statistically significant differences. CACNA1C is unlikely to play a major role in the pathophysiology of schizophrenia in Han Chinese. Further large-scale replication studies using a haplotype-tagging single-nucleotide polymorphism selection approach are required to obtain more conclusive results of any potential association. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 32 | Lancet 2013 May 381: 1654-62 |
| PMID | 23663951 |
| Title | Genetics of bipolar disorder. |
| Abstract | Studies of families and twins show the importance of genetic factors affecting susceptibility to bipolar disorder and suggest substantial genetic and phenotypic complexity. Robust and replicable genome-wide significant associations have recently been reported in genome-wide association studies at several common polymorphisms, including variants within the genes CACNA1C, ODZ4, and NCAN. Strong evidence exists for a polygenic contribution to risk (ie, many risk alleles of small effect). A notable finding is the overlap of susceptibility between bipolar disorder and schizophrenia for several individual risk alleles and for the polygenic risk. By contrast, genomic structural variation seems to play a smaller part in bipolar disorder than it does in schizophrenia. Together, these genetic findings suggest directions for future studies to delineate the aetiology and pathogenesis of bipolar disorder, indicate the need to re-evaluate our diagnostic classifications, and might eventually pave the way for major improvements in clinical management. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 33 | Acta Psychiatr Scand 2013 Nov 128: 362-9 |
| PMID | 23406546 |
| Title | The CACNA1C risk allele selectively impacts on executive function in bipolar type I disorder. |
| Abstract | Calcium channels are important for converting electrical activity into biochemical events. A single nucleotide polymorphism (SNP) (rs1006737) in the CACNA1C gene has been strongly associated with increased risk for Bipolar disorder (BD) in genome-wide association studies. Recently, this same SNP has been reported to influence executive function in schizophrenia and controls, but it remains unclear whether this SNP affects behaviour, especially cognition in subjects with BD. A total of 109 BD type I subjects and 96 controls were genotyped for CACNA1C rs1006737 and assessed with an executive function tests battery [Wechsler Adult Intelligence Scale III (WAIS-III) Letter-Number Sequence subtest (WAIS-LNS), digit span (WAISDS), trail making test (TMT), and WCST (Wisconsin Card Sorting Test)]. In patients with BD, the CACNA1C genotype Met/Met was associated with worse performance on all four executive function tests compared to Val/Val. No influence of CACNA1C was observed in the cognitive performance of healthy controls. Our data indicate for the first time that the CACNA1C risk allele is likely associated with executive dysfunction as a trait in BD, as this association was found regardless the presence of mood symptoms. Larger studies should evaluate the potential influence of CACNA1C on other cognitive domains in BD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 34 | Int. J. Dev. Neurosci. 2013 Apr 31: 89-95 |
| PMID | 23183239 |
| Title | Neuronal cell-type specific DNA methylation patterns of the Cacna1c gene. |
| Abstract | Gene expression of the alpha-1 subunit of the L-type voltage-gated calcium channel, CACNA1C, is known to be complexly regulated. Because CACNA1C is not only a crucial gene in normal brain function but also a promising candidate risk gene for psychiatric disorders such as bipolar disorder and schizophrenia, elucidating the molecular basis of transcriptional regulatory mechanism will be critically important. Here we examined DNA methylation status of CpG islands and a CpG island shore on mouse CACNA1C in neuronal and non-neuronal nuclei, which were separated with a fluorescent activated cell sorting technique. We found that neurons and non-neurons showed differential DNA methylation profile on a CpG island shore. This difference was evolutionarily conserved in human neuronal and non-neuronal nuclei in the prefrontal cortex, suggesting that DNA methylation status on the CpG island shore of CACNA1C may have an important role in transcript regulation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 35 | J Psychiatr Res 2013 Sep 47: 1215-21 |
| PMID | 23786914 |
| Title | Analysis of miR-137 expression and rs1625579 in dorsolateral prefrontal cortex. |
| Abstract | MicroRNAs (miRNAs) are small non-coding RNAs that act as potent regulators of gene expression. A recent GWAS reported the rs1625579 SNP, located downstream of miR-137, as the strongest new association with schizophrenia [Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA, et al. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011;43:969-76.]. Prior to this GWAS finding, a schizophrenia imaging-genetic study found miR-137 target genes significantly enriched for association with activation in the dorsolateral prefrontal cortex (DLPFC) [Potkin SG, Macciardi F, Guffanti G, Fallon JH, Wang Q, Turner JA, et al. Identifying gene regulatory networks in schizophrenia. Neuroimage 2010;53:839-47.]. We investigated the expression levels of miR-137 and three candidate target genes (ZNF804A, CACNA1C, TCF4) in the DLPFC of postmortem brain tissue from 2 independent cohorts: (1) 26 subjects (10 control (CTR), 7 schizophrenia (SZ), 9 bipolar disorder (BD)) collected at the UCI brain bank; and (2) 99 subjects (33 CTR, 35 SZ, 31 BD) obtained from the Stanley Medical Research Institute (SMRI). MiR-137 expression in the DLPFC did not differ between diagnoses. We also explored the relationship between rs1625579 genotypes and miR-137 expression. Significantly lower miR-137 expression levels were observed in the homozygous TT subjects compared to TG and GG subjects in the control group (30% decrease, p-value = 0.03). Moreover, reduced miR-137 levels in TT subjects corresponded to increased levels of the miR-137 target gene TCF4. The miR-137 expression pattern in 9 brain regions was significant for regional effect (ANOVA p-value = 1.83E-12), with amygdala and hippocampus having the highest miR-137 expression level. In conclusion, decreased miR-137 expression is associated with the SZ risk allele of rs1625579, and potential regulation of TCF4, another SZ candidate gene. This study offers additional support for involvement of miR-137 and downstream targets as mechanisms of risk for psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 36 | Front Genet 2013 -1 4: 58 |
| PMID | 23637704 |
| Title | Potential Impact of miR-137 and Its Targets in Schizophrenia. |
| Abstract | The significant impact of microRNAs (miRNAs) on disease pathology is becoming increasingly evident. These small non-coding RNAs have the ability to post-transcriptionally silence the expression of thousands of genes. Therefore, dysregulation of even a single miRNA could confer a large polygenic effect. schizophrenia is a genetically complex illness thought to involve multiple genes each contributing a small risk. Large genome-wide association studies identified miR-137, a miRNA shown to be involved in neuronal maturation, as one of the top risk genes. To assess the potential mechanism of impact of miR-137 in this disorder and identify its targets, we used a combination of literature searches, ingenuity pathway analysis (IPA), and freely accessible bioinformatics resources. Using TargetScan and the schizophrenia gene resource (SZGR) database, we found that in addition to CSMD1, C10orf26, CACNA1C, TCF4, and ZNF804A, five schizophrenia risk genes whose transcripts are also validated miR-137 targets, there are other schizophrenia-associated genes that may be targets of miR-137, including ERBB4, GABRA1, GRIN2A, GRM5, GSK3B, NRG2, and HTR2C. IPA analyses of all the potential targets identified several nervous system (NS) functions as the top canonical pathways including synaptic long-term potentiation, a process implicated in learning and memory mechanisms and recently shown to be altered in patients with schizophrenia. Among the subset of targets involved in NS development and function, the top scoring pathways were ephrin receptor signaling and axonal guidance, processes that are critical for proper circuitry formation and were shown to be disrupted in schizophrenia. These results suggest that miR-137 may indeed play a substantial role in the genetic etiology of schizophrenia by regulating networks involved in neural development and brain function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 37 | Lancet 2013 Apr 381: 1371-9 |
| PMID | 23453885 |
| Title | Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. |
| Abstract | Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia. We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33,332 cases and 27,888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples. SNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10(-8)) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers. Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause. National Institute of Mental Health. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 38 | PLoS ONE 2013 -1 8: e56970 |
| PMID | 23437284 |
| Title | CACNA1C risk variant and amygdala activity in bipolar disorder, schizophrenia and healthy controls. |
| Abstract | Several genetic studies have implicated the CACNA1C SNP rs1006737 in bipolar disorder (BD) and schizophrenia (SZ) pathology. This polymorphism was recently found associated with increased amygdala activity in healthy controls and patients with BD. We performed a functional Magnetic Resonance Imaging (fMRI) study in a sample of BD and SZ cases and healthy controls to test for altered amygdala activity in carriers of the rs1006737 risk allele (AA/AG), and to investigate if there were differences across the diagnostic groups. Rs1006737 was genotyped in 250 individuals (N?=?66 BD, 61 SZ and 123 healthy controls), all of Northern European origin, who underwent an fMRI negative faces matching task. Statistical tests were performed with a model correcting for sex, age, diagnostic category and medication status in the total sample, and then in each diagnostic group. In the total sample, carriers of the risk allele had increased activation in the left amygdala. Group-wise analyses showed that this effect was significant in the BD group, but not in the other diagnostic groups. However, there was no significant interaction effect for the risk allele between BD and the other groups. These results indicate that CACNA1C SNP rs1006737 affects amygdala activity during emotional processing across all diagnostic groups. The current findings add to the growing body of knowledge of the pleiotropic effect of this polymorphism, and further support that ion channel dysregulation is involved in the underlying mechanisms of BD and SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 39 | Mol. Psychiatry 2013 May 18: 607-13 |
| PMID | 22665259 |
| Title | The psychiatric vulnerability gene CACNA1C and its sex-specific relationship with personality traits, resilience factors and depressive symptoms in the general population. |
| Abstract | Genome-wide association studies have reported an association between the A-allele of rs1006737 within CACNA1C and affective disorders and schizophrenia. The aim of the present study was to investigate the relationship between rs1006737 and established and potential endophenotypes for these disorders in a population-based cohort of 3793 subjects, using an analytical method designed to assess a previously reported sex-specific effect of CACNA1C. The investigated endophenotypes included personality traits and resilience factors. At 10-year follow-up, subjects were screened for depressive symptoms. All subjects were genotyped for rs1006737. The direction of the effect and mode of inheritance of rs1006737 differed between the sexes. In men, the A-allele was associated with higher emotional lability and lower resilience, that is, lower sense of coherence (P=0.021), lower perceived social support (P=0.018), lower dispositional optimism (P=0.032) and more depressive symptoms at follow-up (P=0.007). In women, the A-allele was associated with lower emotional lability and stronger resilience, that is, higher sense of coherence (P=0.00028), higher perceived social support (P=0.010), lower neuroticism (P=0.022) and fewer depressive symptoms at follow-up (P=0.035). After conservative Bonferroni correction for 32 tests, results only remained significant for sense of coherence in women (P=0.009). These results suggest that CACNA1C is involved in the genetic architecture of endophenotypes for affective disorders and schizophrenia, and that it shows a distinct sex-specific effect. Comprehensive phenotype characterization in case-control samples and the general population, as well as an adequate modeling of sex-specific genetic effects, may be warranted to elucidate the pathogenetic mechanisms conferred by robustly identified susceptibility genes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 40 | Mol. Psychiatry 2013 Jun 18: 708-12 |
| PMID | 22614287 |
| Title | Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. |
| Abstract | The schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC) highlighted 81 single-nucleotide polymorphisms (SNPs) with moderate evidence for association to schizophrenia. After follow-up in independent samples, seven loci attained genome-wide significance (GWS), but multi-locus tests suggested some SNPs that did not do so represented true associations. We tested 78 of the 81 SNPs in 2640 individuals with a clinical diagnosis of schizophrenia attending a clozapine clinic (CLOZUK), 2504 cases with a research diagnosis of bipolar disorder, and 2878 controls. In CLOZUK, we obtained significant replication to the PGC-associated allele for no fewer than 37 (47%) of the SNPs, including many prior GWS major histocompatibility complex (MHC) SNPs as well as 3/6 non-MHC SNPs for which we had data that were reported as GWS by the PGC. After combining the new schizophrenia data with those of the PGC, variants at three loci (ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS in schizophrenia attained that level of support. In bipolar disorder, we also obtained significant evidence for association for 21% of the alleles that had been associated with schizophrenia in the PGC. Our study independently confirms association to three loci previously reported to be GWS in schizophrenia, and identifies the first GWS evidence in schizophrenia for a further three loci. Given the number of independent replications and the power of our sample, we estimate 98% (confidence interval (CI) 78-100%) of the original set of 78 SNPs represent true associations. We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 41 | Schizophr Bull 2013 May 39: 518-26 |
| PMID | 22499782 |
| Title | Brain vs behavior: an effect size comparison of neuroimaging and cognitive studies of genetic risk for schizophrenia. |
| Abstract | Genetic variants associated with increased risk for schizophrenia (SZ) are hypothesized to be more penetrant at the level of brain structure and function than at the level of behavior. However, to date the relative sensitivity of imaging vs cognitive measures of these variants has not been quantified. We considered effect sizes associated with cognitive and imaging studies of 9 robust SZ risk genes (DAOA, DISC1, DTNBP1, NRG1, RGS4, NRGN, CACNA1C, TCF4, and ZNF804A) published between January 2005-November 2011. Summary data was used to calculate estimates of effect size for each significant finding. The mean effect size for each study was categorized as small, medium, or large and the relative frequency of each category was compared between modalities and across genes. Random effects meta-analysis was used to consider the impact of experimental methodology on effect size. Imaging studies reported mostly medium or large effects, whereas cognitive investigations commonly reported small effects. Meta-analysis confirmed that imaging studies were associated with larger effects. Effect size estimates were negatively correlated with sample size but did not differ as a function of gene nor imaging modality. These observations support the notion that SZ risk variants show larger effects, and hence greater penetrance, when characterized using indices of brain structure and function than when indexed by cognitive measures. However, it remains to be established whether this holds true for individual risk variants, imaging modalities, or cognitive functions, and how such effects may be mediated by a relationship with sample size and other aspects of experimental variability. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 42 | Eur Arch Psychiatry Clin Neurosci 2014 Mar 264: 91-2 |
| PMID | 24481959 |
| Title | The new risk variant CACNA1C and brain circuits in schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 43 | Front Neurosci 2014 -1 8: 331 |
| PMID | 25414627 |
| Title | Neuroinformatic analyses of common and distinct genetic components associated with major neuropsychiatric disorders. |
| Abstract | Major neuropsychiatric disorders are highly heritable, with mounting evidence suggesting that these disorders share overlapping sets of molecular and cellular underpinnings. In the current article we systematically test the degree of genetic commonality across six major neuropsychiatric disorders-attention deficit hyperactivity disorder (ADHD), anxiety disorders (Anx), autistic spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). We curated a well-vetted list of genes based on large-scale human genetic studies based on the NHGRI catalog of published genome-wide association studies (GWAS). A total of 180 genes were accepted into the analysis on the basis of low but liberal GWAS p-values (<10(-5)). 22% of genes overlapped two or more disorders. The most widely shared subset of genes-common to five of six disorders-included ANK3, AS3MT, CACNA1C, CACNB2, CNNM2, CSMD1, DPCR1, ITIH3, NT5C2, PPP1R11, SYNE1, TCF4, TENM4, TRIM26, and ZNRD1. Using a suite of neuroinformatic resources, we showed that many of the shared genes are implicated in the postsynaptic density (PSD), expressed in immune tissues and co-expressed in developing human brain. Using a translational cross-species approach, we detected two distinct genetic components that were both shared by each of the six disorders; the 1st component is involved in CNS development, neural projections and synaptic transmission, while the 2nd is implicated in various cytoplasmic organelles and cellular processes. Combined, these genetic components account for 20-30% of the genetic load. The remaining risk is conferred by distinct, disorder-specific variants. Our systematic comparative analysis of shared and unique genetic factors highlights key gene sets and molecular processes that may ultimately translate into improved diagnosis and treatment of these debilitating disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 44 | Curr Psychiatry Rep 2014 Nov 16: 493 |
| PMID | 25194313 |
| Title | New developments in the genetics of bipolar disorder. |
| Abstract | The last several years have been breakthrough ones in bipolar disorder (BPD) genetics, as the field has identified robust risk variants for the first time. Leading the way have been genome-wide association studies (GWAS) that have assessed common genetic markers across very large groups of patients and controls. These have resulted in findings in genes including ANK3, CACNA1C, SYNE1, ODZ4, and TRANK1. Additional studies have begun to examine the biology of these genes and how risk variants influence aspects of brain and behavior that underlie BPD. For example, carriers of the CACNA1C risk variant have been found to exhibit hippocampal and anterior cingulate dysfunction during episodic memory recall. This work has shed additional light on the relationship of bipolar susceptibility variants to other disorders, particularly schizophrenia. Even larger BPD GWAS are expected with samples now amassed of 21,035 cases and 28,758 controls. Studies have examined the pharmacogenomics of BPD with studies of lithium response, yielding high profile results that remain to be confirmed. The next frontier in the field is the identification of rare bipolar susceptibility variants through large-scale DNA sequencing. While only a couple of papers have been published to date, many studies are underway. The Bipolar Sequencing Consortium has been formed to bring together all of the groups working in this area, and to perform meta-analyses of the data generated. The consortium, with 13 member groups, now has exome data on ~3,500 cases and ~5,000 controls, and on ~162 families. The focus will likely shift within several years from exome data to whole genome data as costs of obtaining such data continue to drop. Gene-mapping studies are now providing clear results that provide insights into the pathophysiology of the disorder. Sequencing studies should extend this process further. Findings could eventually set the stage for rational therapeutic development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 45 | J Affect Disord 2014 Jul 163: 110-4 |
| PMID | 24461634 |
| Title | Association analysis between suicidal behaviour and candidate genes of bipolar disorder and schizophrenia. |
| Abstract | The present study investigated associations between the strongest joint genetic risk variants for bipolar disorder (BD) and schizophrenia (SCZ) and a history of suicide attempt in patients with BD, SCZ and related psychiatric disorders. A history of suicide attempt was assessed in a sample of 1009 patients with BD, SCZ and related psychosis spectrum disorders, and associations with the joint genetic risk variants for BD and SCZ (rs2239547 (ITIH3/4-region), rs10994359 (ANK3) and rs4765905 (CACNA1C)) were investigated. Previously reported susceptibility loci for suicide attempt in BD were also investigated. Associations were tested by logistic regression with Bonferroni correction for multiple testing. The risk allele in rs2239547 (ITIH3/4-region) was significantly associated with a history of suicide attempt (p=0.01) after multiple testing correction (p threshold<0.017). The previous suicide attempt susceptibility loci were only nominally associated, but had the same direction of risk in the replication sample (sign test, p=0.02). Relatively small sample size and retrospective clinical assessment. We detected a novel association between suicide attempt and the ITIH3/4-region in a combined group of patients with BD, SCZ and related psychosis spectrum disorders. This may be useful in understanding molecular mechanisms of suicidal behaviour in severe mental disorders, although replication is warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 46 | Cell Rep 2014 Nov 9: 1417-29 |
| PMID | 25453756 |
| Title | A role for noncoding variation in schizophrenia. |
| Abstract | A large portion of common variant loci associated with genetic risk for schizophrenia reside within noncoding sequence of unknown function. Here, we demonstrate promoter and enhancer enrichment in schizophrenia variants associated with expression quantitative trait loci (eQTL). The enrichment is greater when functional annotations derived from the human brain are used relative to peripheral tissues. Regulatory trait concordance analysis ranked genes within schizophrenia genome-wide significant loci for a potential functional role, based on colocalization of a risk SNP, eQTL, and regulatory element sequence. We identified potential physical interactions of noncontiguous proximal and distal regulatory elements. This was verified in prefrontal cortex and -induced pluripotent stem cell-derived neurons for the L-type calcium channel (CACNA1C) risk locus. Our findings point to a functional link between schizophrenia-associated noncoding SNPs and 3D genome architecture associated with chromosomal loopings and transcriptional regulation in the brain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 47 | Transl Psychiatry 2014 -1 4: e461 |
| PMID | 25290268 |
| Title | CACNA1C risk variant affects reward responsiveness in healthy individuals. |
| Abstract | The variant at rs1006737 in the L-type voltage-gated calcium channel (alpha 1c subunit) CACNA1C gene is reliably associated with both bipolar disorder and schizophrenia. We investigated whether this risk variant affects reward responsiveness because reward processing is one of the central cognitive-motivational domains implicated in both disorders. In a sample of 164 young, healthy individuals, we show a dose-dependent response, where the rs1006737 risk genotype was associated with blunted reward responsiveness, whereas discriminability did not significantly differ between genotype groups. This finding suggests that the CACNA1C risk locus may have a role in neural pathways that facilitate value representation for rewarding stimuli. Impaired reward processing may be a transdiagnostic phenotype of variation in CACNA1C that could contribute to anhedonia and other clinical features common to both affective and psychotic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 48 | Br J Psychiatry 2014 Jan 204: 36-9 |
| PMID | 24262814 |
| Title | CACNA1C, schizophrenia and major depressive disorder in the Han Chinese population. |
| Abstract | Common psychiatric disorders are highly heritable, indicating that genetic factors play an important role in their aetiology. The CACNA1C gene, which codes for subunit alpha-1C of the Cav1.2 voltage-dependent L-type calcium channel, has been consistently found to be the shared risk gene for several kinds of mental disorder. To investigate whether CACNA1C is a susceptibility gene for schizophrenia and major depressive disorder in the Han Chinese population. We carried out a case-control study of 1235 patients with schizophrenia, 1045 with major depressive disorder and 1235 healthy controls. A tag single nucleotide polymorphism (SNP) rs1006737 along with another 10 tag SNPs in the CACNA1C gene were genotyped in all samples. We found that rs1006737 was associated with both schizophrenia (P(allele) = 0.0014, P(genotype) = 0.006, odds ratio (OR) = 1.384, 95% CI 1.134-1.690) and major depressive disorder (P(allele) = 0.0007, P(genotype) = 0.003, OR = 1.425, 95% CI 1.160-1.752). Our findings support CACNA1C being a risk gene for both schizophrenia and major depressive disorder in the Han Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 49 | J Clin Psychiatry 2014 Nov 75: e1284-90 |
| PMID | 25470093 |
| Title | CACNA1C genomewide supported psychosis genetic variation affects cortical brain white matter integrity in Chinese patients with schizophrenia. |
| Abstract | Recent genomewide association studies have implicated the calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) genetic variant in schizophrenia, which is associated with functional brain changes and cognitive deficits in healthy individuals. However, the impact of CACNA1C on brain white matter integrity in schizophrenia remains unclear. On the basis of prior evidence of CACNA1C-mediated changes involving cortical brain regions, we hypothesize that CACNA1C risk variant rs1006737 is associated with reductions of white matter integrity in the frontal, parietal, and temporal regions and cingulate gyrus. A total of 160 Chinese participants (96 DSM-IV-diagnosed patients with schizophrenia and 64 healthy controls) were genotyped by using blood samples and underwent structural magnetic resonance imaging and diffusion tensor imaging scans from 2008 to 2012. Two-way analysis of covariance was employed to examine CACNA1C-related genotype effects, diagnosis effects, and genotype × diagnosis interaction effects on fractional anisotropy (FA) of relevant brain regions. Significant diagnosis-genotype interactions were observed (left frontal lobe mean FA: F?,??? = 6.22, P = .014; left parietal lobe mean FA: F?,??? = 7.14, P = .008; left temporal lobe mean FA: F?,??? = 8.37, P = .004). Compared with patients who were A carriers, patients who were G homozygotes had lower mean FA in the left frontal lobe (F?,?? = 2.504, P = .014), left parietal lobe (F?,?? = 2.37, P = .020), and left temporal lobe (F?,?? = 3.01, P = .003), with standardized effect sizes of -1.43, -1.3, and -1.0, respectively. CACNA1C risk variant rs1006737 affects cortical white matter integrity in schizophrenia. Further imaging genetic investigations on the mediating effect of CACNA1C in schizophrenia can uncover brain circuitries involved in schizophrenia and suggest potential novel targets for intervention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 50 | Genome Med 2014 -1 6: 75 |
| PMID | 25360157 |
| Title | Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome. |
| Abstract | Common genetic variation and rare mutations in genes encoding calcium channel subunits have pleiotropic effects on risk for multiple neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. To gain further mechanistic insights by extending previous gene expression data, we constructed co-expression networks in Timothy syndrome (TS), a monogenic condition with high penetrance for ASD, caused by mutations in the L-type calcium channel, Cav1.2. To identify patient-specific alterations in transcriptome organization, we conducted a genome-wide weighted co-expression network analysis (WGCNA) on neural progenitors and neurons from multiple lines of induced pluripotent stem cells (iPSC) derived from normal and TS (G406R in CACNA1C) individuals. We employed transcription factor binding site enrichment analysis to assess whether TS associated co-expression changes reflect calcium-dependent co-regulation. We identified reproducible developmental and activity-dependent gene co-expression modules conserved in patient and control cell lines. By comparing cell lines from case and control subjects, we also identified co-expression modules reflecting distinct aspects of TS, including intellectual disability and ASD-related phenotypes. Moreover, by integrating co-expression with transcription factor binding analysis, we showed the TS-associated transcriptional changes were predicted to be co-regulated by calcium-dependent transcriptional regulators, including NFAT, MEF2, CREB, and FOXO, thus providing a mechanism by which altered Ca(2+) signaling in TS patients leads to the observed molecular dysregulation. We applied WGCNA to construct co-expression networks related to neural development and depolarization in iPSC-derived neural cells from TS and control individuals for the first time. These analyses illustrate how a systems biology approach based on gene networks can yield insights into the molecular mechanisms of neural development and function, and provide clues as to the functional impact of the downstream effects of Ca(2+) signaling dysregulation on transcription. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 51 | Schizophr. Res. 2014 Oct 159: 107-13 |
| PMID | 25124521 |
| Title | Replication of previous genome-wide association studies of psychiatric diseases in a large schizophrenia case-control sample from Spain. |
| Abstract | Genome wide association studies (GWAS) has allowed the discovery of some interesting risk variants for schizophrenia (SCZ). However, this high-throughput approach presents some limitations, being the most important the necessity of highly restrictive statistical corrections as well as the loss of statistical power inherent to the use of a Single Nucleotide Polymorphism (SNP) analysis approach. These problems can be partially solved through the use of a polygenic approach. We performed a genotyping study in SCZ using 86 previously associated SNPs identified by GWAS of SCZ, bipolar disorder (BPD) and autistic spectrum disorder (ASD) patients. The sample consisted of 3063 independent cases with DSM-IV-TR diagnosis of SCZ and 2847 independent controls of European origin from Spain. A polygenic score analysis was also used to test the overall effect on the SCZ status. One SNP, rs12290811, located in the ODZ4 gene reached statistical significance (p=1.7×10(-4), Allelic odds ratio=1.21), a value very near to those reported in previous GWAS of BPD patients. In addition, 4 SNPs were close to the significant threshold: rs3850333, in the NRXN1 gene; rs6932590, at MHC; rs2314398, located in an intergenic region on chromosome 2; and rs1006737, in the CACNA1C gene. We also found that 74% of the studied SNPs showed the same tendency (risk or protection alleles) previously reported in the original GWAS (p<0.001). Our data strengthen the polygenic component of susceptibility to SCZ. Our findings show ODZ4 as a risk gene for SCZ, emphasizing the existence of common vulnerability in psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 52 | Neuroimage 2014 Jul 94: 147-54 |
| PMID | 24642287 |
| Title | Replication of brain function effects of a genome-wide supported psychiatric risk variant in the CACNA1C gene and new multi-locus effects. |
| Abstract | Variation in the CACNA1C gene has consistently been associated with psychosis in genome wide association studies. We have previously shown in a sample of n=110 healthy subjects that carriers of the CACNA1C rs1006737 risk variant exhibit hippocampal and perigenual anterior cingulate dysfunction (pgACC) during episodic memory recall. Here, we aimed to replicate our results, by testing for the effects of the rs1006737 risk variant in a new large cohort of healthy controls. We furthermore sought to refine these results by identifying the impact of a CACNA1C specific, gene-wide risk score in the absence of clinical pathology. An independent sample of 179 healthy subjects genotyped for rs1006737 underwent functional magnetic resonance imaging (fMRI) while performing an associative episodic memory task and underwent psychological testing similar to the discovery sample. The effect of gene-wide risk scores was analyzed in the combined sample of 289 subjects. We replicated our discovery findings of hippocampal and pgACC dysfunction in carriers of the rs1006737 risk variant. Additionally, we observed diminished activation of the dorsolateral prefrontal cortex, in the replication sample. Our replicated results as well as this new effect were also observable in the combined sample. Moreover, the same system-level phenotypes were significantly associated with the individual gene-based genetic risk score. Our findings suggest that altered hippocampal and frontolimbic function is associated with variants in the CACNA1C gene. Since CACNA1C variants have been associated repeatedly with psychosis at a genome-wide level, and preclinical data provide convergent evidence for the relevance of the CACNA1C gene for hippocampal and frontolimbic plasticity and adaptive regulation of stress, our data suggest a potential pathophysiological mechanism conferred by CACNA1C variants that may mediate risk for symptom dimensions shared among bipolar disorder, major depression, and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 53 | Int J Epidemiol 2014 Apr 43: 465-75 |
| PMID | 24618187 |
| Title | Recent challenges to the psychiatric diagnostic nosology: a focus on the genetics and genomics of neurodevelopmental disorders. |
| Abstract | Recent advances in the genetics of neurodevelopmental disorder (NDD) have demonstrated that rare mutations play a role not only in Mendelian syndromes, but in complex, common forms of NDDs as well. Strikingly, both common polymorphisms and rare variations in a single gene or genetic locus have been found to carry risk for conditions previously considered to be clinically and aetiologically distinct. Recent developments in the methods and tools available for studying complex NDDs have led to systematic and reliable genome-wide variant discovery. Both common as well as rare, and structural as well as sequence, genetic variations have been identified as contributing to NDDs. There are multiple examples in which the identical variant had been found to contribute to a wide range of formerly distinct diagnoses, including autism, schizophrenia, epilepsy, intellectual disability and language disorders. These include variations in chromosomal structure at 16p11.2, rare de novo point mutations at the gene SCN2A, and common single nucleotide polymorphisms (SNPs) mapping near loci encoding the genes ITIH3, AS3MT, CACNA1C and CACNB2. These selected examples point to the challenges to current diagnostic approaches. Widely used categorical schema have been adequate to provide an entré into molecular mechanisms of NDDs, but there is a need to develop an alternative, more biologically-relevant nosology. Thus recent advances in gene discovery in the area of NDDs are leading to a re-conceptualization of diagnostic boundaries. Findings suggest that epidemiological samples may provide important new insights into the genetics and diagnosis of NDDs and that other areas of medicine may provide useful models for developing a new diagnostic nosology, one that simultaneously integrates categorical diagnoses, biomarkers and dimensional variables. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 54 | Biol. Psychiatry 2014 Sep 76: 466-75 |
| PMID | 24411473 |
| Title | Hippocampal and frontolimbic function as intermediate phenotype for psychosis: evidence from healthy relatives and a common risk variant in CACNA1C. |
| Abstract | Variation in CACNA1C has consistently been associated with psychiatric disease in genome-wide association studies. We have previously shown that healthy carriers of the CACNA1C rs1006737 risk variant exhibit hippocampal and perigenual anterior cingulate (pgACC) dysfunction during episodic memory recall. To test whether this brain systems-level abnormality is a potential intermediate phenotype for psychiatric disorder, we studied unaffected relatives of patients with bipolar disorder, major depression, and schizophrenia. The study population comprised 188 healthy first-degree relatives of patients with bipolar disorder (n=59), major depression (n=73), and schizophrenia (n=56) and 110 comparison subjects from our discovery study who were genotyped for rs1006737 and underwent functional magnetic resonance imaging while performing an episodic memory task and psychological testing. Group comparisons were analyzed using SPM8 and PASW Statistics 20. Similar to risk allele carriers in the discovery sample, relatives of index patients exhibited hippocampal and pgACC dysfunction as well as increased scores in depression and anxiety measures, correlating negatively with hippocampal activation. Carrying the rs1006737 risk variant resulted in a stronger decrease of hippocampal and pgACC activation in relatives, indicating an additive effect of CACNA1C variation on familial risk. Our findings implicate abnormal perigenual and hippocampal activation as a promising intermediate phenotype for psychiatric disease and suggest a pathophysiologic mechanism conferred by a CACNA1C variant being implicated in risk for symptom dimensions shared among bipolar disorder, major depression, and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 55 | Schizophr. Res. 2014 Jan 152: 105-10 |
| PMID | 24355530 |
| Title | Further evidence for genetic association of CACNA1C and schizophrenia: new risk loci in a Han Chinese population and a meta-analysis. |
| Abstract | CACNA1C (12p13.3) has been implicated as a susceptibility gene for schizophrenia by several replicated genome wide association studies. While these results have been consistent among studies in European populations, the findings in East Asian populations have varied. To test whether CACNA1C is a risk gene for schizophrenia, we conducted a case-control study in 5897 schizophrenic patients and 6323 healthy control subjects selected from Han Chinese population. Our study replicated the positive associations of rs1006737 (P=0.0108, OR=1.16, 95% CI: 1.03-1.29) and rs1024582 (P=0.0062, OR=1.18, 95% CI: 1.05-1.33), and identified a novel risk locus, rs2007044 (P=0.0053, OR=1.08, 95% CI: 1.02-1.14). A meta-analysis of rs1006737 combining our study and previous studies was conducted in a total of 8222 schizophrenia cases and 24,661 healthy controls. In the meta-analysis, the association between rs1006737 and schizophrenia remained significant (OR=1.14, 95% CI: 1.07-1.22, P=0.0001). Stratified analysis showed no heterogeneity between East Asian and European ancestries (?(2)[1]=0.07, P=0.795), and the difference in pooled ORs between ancestries was not significant (Z=0.25, P=0.801). Our results provide further support for associations of rs1006737 and rs1024582 with schizophrenia, identify a new risk locus rs2007044 in a Han Chinese population, and further establish CACNA1C as an important susceptibility gene for the disease across world populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 56 | Schizophr. Res. 2014 Jan 152: 105-10 |
| PMID | 24355530 |
| Title | Further evidence for genetic association of CACNA1C and schizophrenia: new risk loci in a Han Chinese population and a meta-analysis. |
| Abstract | CACNA1C (12p13.3) has been implicated as a susceptibility gene for schizophrenia by several replicated genome wide association studies. While these results have been consistent among studies in European populations, the findings in East Asian populations have varied. To test whether CACNA1C is a risk gene for schizophrenia, we conducted a case-control study in 5897 schizophrenic patients and 6323 healthy control subjects selected from Han Chinese population. Our study replicated the positive associations of rs1006737 (P=0.0108, OR=1.16, 95% CI: 1.03-1.29) and rs1024582 (P=0.0062, OR=1.18, 95% CI: 1.05-1.33), and identified a novel risk locus, rs2007044 (P=0.0053, OR=1.08, 95% CI: 1.02-1.14). A meta-analysis of rs1006737 combining our study and previous studies was conducted in a total of 8222 schizophrenia cases and 24,661 healthy controls. In the meta-analysis, the association between rs1006737 and schizophrenia remained significant (OR=1.14, 95% CI: 1.07-1.22, P=0.0001). Stratified analysis showed no heterogeneity between East Asian and European ancestries (?(2)[1]=0.07, P=0.795), and the difference in pooled ORs between ancestries was not significant (Z=0.25, P=0.801). Our results provide further support for associations of rs1006737 and rs1024582 with schizophrenia, identify a new risk locus rs2007044 in a Han Chinese population, and further establish CACNA1C as an important susceptibility gene for the disease across world populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 57 | Mol. Psychiatry 2014 Sep 19: 1017-24 |
| PMID | 24280982 |
| Title | Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia. |
| Abstract | Bipolar disorder and schizophrenia are two often severe disorders with high heritabilities. Recent studies have demonstrated a large overlap of genetic risk loci between these disorders but diagnostic and molecular distinctions still remain. Here, we perform a combined genome-wide association study (GWAS) of 19?779 bipolar disorder (BP) and schizophrenia (SCZ) cases versus 19?423 controls, in addition to a direct comparison GWAS of 7129 SCZ cases versus 9252 BP cases. In our case-control analysis, we identify five previously identified regions reaching genome-wide significance (CACNA1C, IFI44L, MHC, TRANK1 and MAD1L1) and a novel locus near PIK3C2A. We create a polygenic risk score that is significantly different between BP and SCZ and show a significant correlation between a BP polygenic risk score and the clinical dimension of mania in SCZ patients. Our results indicate that first, combining diseases with similar genetic risk profiles improves power to detect shared risk loci and second, that future direct comparisons of BP and SCZ are likely to identify loci with significant differential effects. Identifying these loci should aid in the fundamental understanding of how these diseases differ biologically. These findings also indicate that combining clinical symptom dimensions and polygenic signatures could provide additional information that may someday be used clinically. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 58 | Schizophr. Res. 2014 Jan 152: 97-104 |
| PMID | 24275578 |
| Title | MIR137 gene and target gene CACNA1C of miR-137 contribute to schizophrenia susceptibility in Han Chinese. |
| Abstract | Recently, evidence has accumulated indicating that the MIR137 gene and the target gene CACNA1C of miR-137 might be two of the most robustly implicated genes in schizophrenia. In this study, we examined 33 single nucleotide polymorphisms (SNPs) located in two genes by performing an association analysis in a cohort of 1430 schizophrenia patients and 1570 healthy Han Chinese control subjects. Single SNP association, sex-specific association and haplotype association analyses were performed. For the rs1625579 marker in MIR137 and the rs1006737 and rs4765905 markers in CACNA1C, significant differences in the allele frequencies were found between the patients and controls (p=0.007949, p=0.013658 and p=0.013999, respectively), and the genotype association analysis for them suggested a similar pattern (p=0.023167, p=0.046623 and p=0.047824, respectively). Further analysis of the haplotype rs1006737-rs4765905-rs882194 in CACNA1C showed significant associations with schizophrenia (corrected global p<0.005), and two haplotypes (ACC and ACT) in the block were significantly increased in the patients. When the samples were analyzed separately by gender, we found no significant sex-specific associations in MIR137 and CACNA1C, which was similar to the results from the relevant haplotype association analysis in the female and male subgroups. We have provided new evidence supporting the association between MIR137 and CACNA1C and schizophrenia in the Han Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 59 | Eur Arch Psychiatry Clin Neurosci 2014 Mar 264: 93-102 |
| PMID | 23880959 |
| Title | CACNA1C genotype explains interindividual differences in amygdala volume among patients with schizophrenia. |
| Abstract | Affective deficits are one common denominator of schizophrenia (SZ), bipolar disorder (BD) and obsessive compulsive disorder (OCD) with the amygdala indicated as one of the major structures involved in emotion regulation. Previous findings of differences in amygdala volume between healthy controls and patients with SZ, BD or OCD diverge with respect to the affected hemisphere, size and direction of the effect. Variability in the CACNA1C gene has been linked to BD, SZ as well as structural and functional variation in the amygdala in healthy people and patients with BD. We were interested to investigate whether amygdala volumes differ between hemispheres, diagnostic or genotype groups, and whether any interactive effects exist. We combined genotyping of SNP rs1006737 in CACNA1C with structural MRI measurements of relative gray matter (GM) amygdala volume in patients with SZ, BD or OCD as well as healthy controls (N Total = 72). The CACNA1C genotype showed a significant effect on relative GM amygdala volume in patients with SZ. There was a significant left versus right relative GM amygdala volume decrease in patients with SZ or BD. The effects of hemisphere and diagnosis (controls vs. patients with SZ) on relative GM amygdala volume were genotype specific. Our data suggest that the CACNA1C genotype may account for some heterogeneity in the effects of hemisphere and diagnosis on amygdala volume when comparing patients with SZ and controls and point to disturbed Ca(2+)-signaling as a plausible mechanism contributing to the pathology in patients with SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 60 | Eur Arch Psychiatry Clin Neurosci 2014 Mar 264: 103-10 |
| PMID | 23860750 |
| Title | A genome-wide supported variant in CACNA1C influences hippocampal activation during episodic memory encoding and retrieval. |
| Abstract | The alpha 1C subunit of the L-type voltage-gated calcium channel (CACNA1C) gene is one of the best replicated susceptibility loci for bipolar disorder, schizophrenia and major depression. It is involved in learning, memory and brain plasticity. Genetic studies using functional magnetic resonance imaging (fMRI) reported evidence of association with the CACNA1C single nucleotide polymorphism rs1006737 with functional correlates of episodic memory encoding and retrieval, especially activations in the hippocampus. These results, however, are inconsistent with regard to the magnitude and directionality of effect. In the present study, brain activation was measured with fMRI during an episodic memory encoding and retrieval task using neutral faces in two independent samples of 94 and 111 healthy subjects, respectively. Within whole brain analyses, a main effect of genotype emerged mainly in the right hippocampus during encoding as well as retrieval within the first sample: Carriers of the minor allele (A) exhibited lower activations compared to G/G allele carriers. This effect could be replicated within the second sample, however, only for the retrieval condition. The results strengthen findings that rs1006737 is associated with neural systems related to memory processes in hippocampal regions which are detectable in healthy subjects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 61 | Hum Brain Mapp 2014 Apr 35: 1190-200 |
| PMID | 23404764 |
| Title | Association of rs1006737 in CACNA1C with alterations in prefrontal activation and fronto-hippocampal connectivity. |
| Abstract | Genome-wide association studies have identified the rs1006737 single nucleotide polymorphism (SNP) in the CACNA1C gene as a susceptibility locus for schizophrenia and bipolar disorder. On the neural systems level this association is explained by altered functioning of the dorsolateral prefrontal cortex (DLPFC) and the hippocampal formation (HF), brain regions also affected by mental illness. In the present study we investigated the association of rs1006737 genotype with prefrontal activation and fronto-hippocampal connectivity. We used functional magnetic resonance imaging to measure neural activation during an n-back working memory task in 94 healthy subjects. All subjects were genotyped for the SNP rs1006737. We tested associations of the rs1006737 genotype with changes in working-memory-related DLPFC activation and functional integration using a seed region functional connectivity approach. Rs1006737 genotype was associated with altered right-hemispheric DLPFC activation. The homozygous A (risk) group showed decreased activation compared to G-allele carriers. Further, the functional connectivity analysis revealed a positive association of fronto-hippocampal connectivity with rs1006737 A alleles. We did not replicate the previous findings of increased right DLPFC activation in CACNA1C rs1006737 A homozygotes. In fact, we found the opposite effect, thus questioning prefrontal inefficiency as rs1006737 genotype-related intermediate phenotype. On the other hand, our results indicate that alterations in the functional coupling between the prefrontal cortex and the medial temporal lobe could represent a neural system phenotype that is mediated by CACNA1C rs1006737 and other genetic susceptibility loci for schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 62 | Cell Tissue Res. 2014 Aug 357: 463-76 |
| PMID | 24996399 |
| Title | The role of L-type voltage-gated calcium channels Cav1.2 and Cav1.3 in normal and pathological brain function. |
| Abstract | The use of specific activators and inhibitors that penetrate the central nervous system has suggested an essential functional role of L-type calcium channels (LTCC) in several important physiological processes of the brain, including the modulation of the mesoaccumbal dopamine signalling pathway, synaptic transmission of auditory stimuli and synaptic plasticity of neutral and aversive learning and memory processes. However, the lack of selectivity of available pharmacological agents towards the most prominent LTCC isoforms in the brain, namely Cav1.2 and Cav1.3, has hampered the elucidation of the precise contribution made by each specific channel isoform within these specific physiological processes. Modern genetic approaches, both in rodents and in human, have recently enhanced our understanding of the selective functional roles of Cav1.2 and Cav1.3 channels. In rodents, the characterisation of global and conditional isoform-specific knockouts suggests a contribution of Cav1.2 channels in spatial memory formation, whereas Cav1.3 channels seem to be involved in the consolidation of fear memories and in neurodegenerative mechanisms associated with the development of Parkinson's disease. With regard to the molecular mechanisms underlying drug addiction, Cav1.3 channels are necessary for the development and Cav1.2 channels for the expression of cocaine and amphetamine behavioural sensitisation. In humans, both the identification of naturally occurring LTCC variants ("channelopathies") and unbiased genome-wide association studies have linked LTCCs to working memory performance in healthy individuals and schizophrenic patients. Individually, CACNA1C polymorphisms and CACNA1D variants have been linked to a variety of psychiatric diseases and to congenital deafness, respectively. However, the contribution of individual LTCCs and their polymorphisms to human brain function and diseases remains unclear, necessitating the use of isoform-specific pharmacological agents. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 63 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2015 Dec 168: 637-48 |
| PMID | 26227746 |
| Title | Genetic analysis of SNPs in CACNA1C and ANK3 gene with schizophrenia: A comprehensive meta-analysis. |
| Abstract | Recently, genome-wide association studies (GWAS), meta-analyses, and replication studies focusing on bipolar disorder (BD) have implicated the ?-1C subunit of the L-type voltage-dependent calcium channel (CACNA1C) and ankyrin 3 (ANK3) genes in BD. Based on the hypothesis that both schizophrenia (SZ) and BD may share some common genetic risk factors, we investigated the association of CACNA1C and ANK3 with SZ using meta-analytic techniques, combining all published data up to April 2015. Nine teams, including four European decent samples and five Asian samples, contributed 14,141 cases and 30,679 controls for the analysis of CACNA1C rs1006737 and SZ. A significant difference was identified between patients and controls for the A-allele of rs1006737 in combined studies (Z?=?6.02, P?=?1.74E-09), in European studies (Z?=?4.08, P?=?4.50E-05), and in Asian studies (Z?=?4.60, P?=?4.22E-06). Meanwhile, for the T-allele of ANK3 rs10761482 (1,794 cases versus 1,395 controls), a significant association was observed in combined samples (Z?=?2.06, P?=?0.04) and in Asian samples (Z?=?3.10, P?=?0.002). In summary, our study provides further evidence for the positive association of CACNA1C and ANK3 with SZ. These results support the hypothesis that both SZ and BD share common genetic risk factors. Further research is needed to examine the functions of CACNA1C and ANK3, and their interacting partners in the molecular, developmental, and pathophysiological processes in SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 64 | Psychol Med 2015 -1 45: 2461-80 |
| PMID | 25858580 |
| Title | What is the impact of genome-wide supported risk variants for schizophrenia and bipolar disorder on brain structure and function? A systematic review. |
| Abstract | The powerful genome-wide association studies (GWAS) revealed common mutations that increase susceptibility for schizophrenia (SZ) and bipolar disorder (BD), but the vast majority were not known to be functional or associated with these illnesses. To help fill this gap, their impact on human brain structure and function has been examined. We systematically discuss this output to facilitate its timely integration in the psychosis research field; and encourage reflection for future research. Irrespective of imaging modality, studies addressing the effect of SZ/BD GWAS risk genes (ANK3, CACNA1C, MHC, TCF4, NRGN, DGKH, PBRM1, NCAN and ZNF804A) were included. Most GWAS risk variations were reported to affect neuroimaging phenotypes implicated in SZ/BD: white-matter integrity (ANK3 and ZNF804A), volume (CACNA1C and ZNF804A) and density (ZNF804A); grey-matter (CACNA1C, NRGN, TCF4 and ZNF804A) and ventricular (TCF4) volume; cortical folding (NCAN) and thickness (ZNF804A); regional activation during executive tasks (ANK3, CACNA1C, DGKH, NRGN and ZNF804A) and functional connectivity during executive tasks (CACNA1C and ZNF804A), facial affect recognition (CACNA1C and ZNF804A) and theory-of-mind (ZNF804A); but inconsistencies and non-replications also exist. Further efforts such as standardizing reporting and exploring complementary designs, are warranted to test the reproducibility of these early findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 65 | Sci Rep 2015 -1 5: 12935 |
| PMID | 26255836 |
| Title | Evaluation of genetic susceptibility of common variants in CACNA1D with schizophrenia in Han Chinese. |
| Abstract | The heritability of schizophrenia (SCZ) has been estimated to be as high as 80%, suggesting that genetic factors may play an important role in the etiology of SCZ. Cav1.2 encoded by CACNA1C and Cav1.3 encoded by CACNA1D are dominant calcium channel-forming subunits of L-type Voltage-dependent Ca(2+) channels, expressed in many types of neurons. The CACNA1C has been consistently found to be a risk gene for SCZ, but it is unknown for CACNA1D. To investigate the association of CACNA1D with SCZ, we designed a two-stage case-control study, including a testing set with 1117 cases and 1815 controls and a validation set with 1430 cases and 4295 controls in Han Chinese. A total of selected 97 tag single nucleotide polymorphisms (SNPs) in CACNA1D were genotyped, and single-SNP association, imputation analysis and gender-specific association analyses were performed in the two independent datasets. None was found to associate with SCZ. Further genotype and haplotype association analyses indicated a similar pattern in the two-stage study. Our findings suggested CACNA1D might not be a risk gene for SCZ in Han Chinese population, which add to the current state of knowledge regarding the susceptibility of CACNA1D to SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 66 | Mol. Psychiatry 2015 Feb 20: 162-9 |
| PMID | 25403839 |
| Title | Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons. |
| Abstract | Psychiatric disorders have clear heritable risk. Several large-scale genome-wide association studies have revealed a strong association between susceptibility for psychiatric disorders, including bipolar disease, schizophrenia and major depression, and a haplotype located in an intronic region of the L-type voltage-gated calcium channel (VGCC) subunit gene CACNA1C (peak associated SNP rs1006737), making it one of the most replicable and consistent associations in psychiatric genetics. In the current study, we used induced human neurons to reveal a functional phenotype associated with this psychiatric risk variant. We generated induced human neurons, or iN cells, from more than 20 individuals harboring homozygous risk genotypes, heterozygous or homozygous non-risk genotypes at the rs1006737 locus. Using these iNs, we performed electrophysiology and quantitative PCR experiments that demonstrated increased L-type VGCC current density as well as increased mRNA expression of CACNA1C in iNs homozygous for the risk genotype, compared with non-risk genotypes. These studies demonstrate that the risk genotype at rs1006737 is associated with significant functional alterations in human iNs, and may direct future efforts at developing novel therapeutics for the treatment of psychiatric disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 67 | Eur Neuropsychopharmacol 2015 Dec 25: 2262-70 |
| PMID | 26475575 |
| Title | A common risk variant in CACNA1C supports a sex-dependent effect on longitudinal functioning and functional recovery from episodes of schizophrenia-spectrum but not bipolar disorder. |
| Abstract | Sex is a powerful modulator of disease susceptibility, course and outcome. The gene CACNA1C is among the best replicated vulnerability genes of bipolar disorder and schizophrenia. The aim of the present study was to investigate whether sex and a variant in CACNA1C (rs10774035 as a proxy for the well-acknowledged risk variant rs1006737) influence psychosocial adaptation in a large German patient sample with schizophrenia-spectrum (n=297) and bipolar (n=516) disorders. We analyzed Global Assessment of Functioning (GAF) scores, retrospectively collected for different time points during disease course. We investigated whether CACNA1C sex-dependently modulates longitudinal GAF scores and recovery from episodes of psychiatric disturbance in the above mentioned disorders. Psychosocial recovery was measured as difference score between the current GAF score (assessing the last remission) and the worst GAF score ever during an illness episode. Covariate- adjusted association analyses revealed a sex × rs10774035 genotype interaction on longitudinal GAF and recovery from illness episodes only in schizophrenia-spectrum but not in bipolar disorders. In schizophrenia-spectrum affected males, rs10774035 minor allele (T) carriers had higher GAF scores at three time points (premorbid, worst ever, current). In contrast, females carrying rs10774035 minor alleles had impaired recovery from schizophrenia-spectrum episodes. These results encourage further investigations of gene × sex interactions and longitudinal quantitative phenotypes to unravel the rich variety of behavioral consequences of genetic individuality. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 68 | J Child Adolesc Psychopharmacol 2015 Nov 25: 701-10 |
| PMID | 26401721 |
| Title | Variation in CACNA1C is Associated with Amygdala Structure and Function in Adolescents. |
| Abstract | Genome-wide association studies have identified allelic variation in CACNA1C as a risk factor for multiple psychiatric disorders associated with limbic system dysfunction, including bipolar disorder, schizophrenia, and depression. The CACNA1C gene codes for a subunit of L-type voltage-gated calcium channels, which modulate amygdala function. Although CACNA1C genotype appears to be associated with amygdala morphology and function in adults with and without psychopathology, whether genetic variation influences amygdala structure and function earlier in development has not been examined. In this first investigation of the neural correlates of CACNA1C in young individuals, we examined associations between two single nucleotide polymorphisms in CACNA1C (rs1006737 and rs4765914) with amygdala volume and activation during an emotional processing task in 58 adolescents and young adults 13-20 years of age. Minor (T) allele carriers of rs4765914 exhibited smaller amygdala volume than major (C) allele homozygotes (?=-0.33, p=0.006). Furthermore, minor (A) allele homozygotes of rs1006737 exhibited increased blood-oxygen-level-dependent (BOLD) signal in the amygdala when viewing negative (vs. neutral) stimuli (?=0.29, p=0.040) and decreased BOLD signal in the amygdala when instructed to downregulate their emotional response to negative stimuli (?=-0.38, p=0.009). Follow-up analyses indicated that childhood trauma did not moderate the associations of CACNA1C variation with amygdala structure and function (ps>0.170). Findings indicate that CACNA1C-related differences in amygdala structure and function are present by adolescence. However, population stratification is a concern, given the racial/ethnic heterogeneity of our sample, and our findings do not have direct clinical implications currently. Nevertheless, these results suggest that developmentally informed research can begin to shed light on the time course by which genetic liability may translate into neural differences associated with vulnerability to psychopathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 69 | Schizophr. Res. 2015 Oct 168: 429-33 |
| PMID | 26276307 |
| Title | Meta-analysis of data from the Psychiatric Genomics Consortium and additional samples supports association of CACNA1C with risk for schizophrenia. |
| Abstract | Recently, numerous genome-wide association studies (GWASs) have identified numerous risk loci for schizophrenia, but follow-up studies are still essential to confirm those results. Therefore, we followed up on top GWAS hits by genotyping implicated loci in additional schizophrenia family samples from our own collection. Five-hundred thirty-six Asian families (comprising 1633 members including 698 schizophrenics) were genotyped in this study. We analyzed 12 single nucleotide polymorphisms (SNPs) in strongly implicated candidate genes revealed by GWASs and their follow-up studies. We then used meta-analysis to combine our results with those of the schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC). In our newly genotyped samples, there were no significant associations of any of the 12 candidate SNPs with schizophrenia; however, all genome-wide significant results from the schizophrenia PGC analysis were maintained after combination with our new data by meta-analysis. One SNP (rs4765905 in CACNA1C) showed a stronger effect and decreased p-value (5.14e-17) after meta-analysis relative to the original PGC results, with no significant between-study heterogeneity. The findings of this study support the significant results in the PGC, especially for CACNA1C. The sample size in our study was considerably smaller than that in the PGC-SCZ study; thus, the weights carried by our samples in the meta-analysis were small. Therefore, our data could not vastly reduce PGC association signals. However, we considered that the well replicated results from the PGC hold up in our new samples, and may suggest that the top hits from the PGC are generalizable, even to other ancestral groups. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 70 | PLoS ONE 2015 -1 10: e0133247 |
| PMID | 26204268 |
| Title | Schizophrenia Related Variants in CACNA1C also Confer Risk of Autism. |
| Abstract | Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with a strong genetic component. Many lines of evidence indicated that ASD shares common genetic variants with other psychiatric disorders (for example, schizophrenia). Previous studies detected that calcium channels are involved in the etiology of many psychiatric disorders including schizophrenia and autism. Significant association between CACNA1C (calcium channel, voltage-dependent, L type, alpha 1C subunit) and schizophrenia was detected. Furthermore, rare mutation in CACNA1C is suggested to cause Timothy syndrome, a multisystem disorder including autism-associated phenotype. However, there is no evidence for association between CACNA1C and autism in Chinese Han population. To investigate the association between single nucleotide polymorphisms (SNP) in CACNA1C and autism, we first performed a family-based association study between eighteen SNPs in CACNA1C and autism in 239 trios. All SNPs were genotyped by using Sequenom genotyping platform. Two SNPs (rs1006737 and rs4765905) have a trend of association with autism. To further confirm the association between these two SNPs with autism, we expanded the sample size to 553 trios by adding 314 trios. Association analyses for SNPs and haplotype were performed by using family-based association test (FBAT) and Haploview software. Permutation tests were used for multiple testing corrections of the haplotype analyses (n=10,000). The significance level for all statistical tests was two-tailed (p<0.05). The results demonstrated that G allele of rs1006737 and G allele of rs4765905 showed a preferential transmission to affected offspring in 553 trios (p=0.035). Haplotype analyses showed that two haplotypes constructed from rs1006737 and rs4765905 were significantly associated with autism (p=0.030, 0.023, respectively; Global p=0.046). These results were still significant after permutation correction (n=10,000, p=0.027). Our research suggests that CACNA1C might play a role in the genetic etiology of autism in Chinese Han population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 71 | Front Behav Neurosci 2015 -1 9: 141 |
| PMID | 26136667 |
| Title | Comprehensive behavioral analysis of voltage-gated calcium channel beta-anchoring and -regulatory protein knockout mice. |
| Abstract | Calcium (Ca(2+)) influx through voltage-gated Ca(2+) channels (VGCCs) induces numerous intracellular events such as neuronal excitability, neurotransmitter release, synaptic plasticity, and gene regulation. It has been shown that genes related to Ca(2+) signaling, such as the CACNA1C, CACNB2, and CACNA1I genes that encode VGCC subunits, are associated with schizophrenia and other psychiatric disorders. Recently, VGCC beta-anchoring and -regulatory protein (BARP) was identified as a novel regulator of VGCC activity via the interaction of VGCC ? subunits. To examine the role of the BARP in higher brain functions, we generated BARP knockout (KO) mice and conducted a comprehensive battery of behavioral tests. BARP KO mice exhibited greatly reduced locomotor activity, as evidenced by decreased vertical activity, stereotypic counts in the open field test, and activity level in the home cage, and longer latency to complete a session in spontaneous T-maze alteration test, which reached "study-wide significance." Acoustic startle response was also reduced in the mutants. Interestingly, they showed multiple behavioral phenotypes that are seemingly opposite to those seen in the mouse models of schizophrenia and its related disorders, including increased working memory, flexibility, prepulse inhibition, and social interaction, and decreased locomotor activity, though many of these phenotypes are statistically weak and require further replications. These results demonstrate that BARP is involved in the regulation of locomotor activity and, possibly, emotionality. The possibility was also suggested that BARP KO mice may serve as a unique tool for investigating the pathogenesis/pathophysiology of schizophrenia and related disorders. Further evaluation of the molecular and physiological phenotypes of the mutant mice would provide new insights into the role of BARP in higher brain functions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 72 | Psychiatr. Genet. 2015 Aug 25: 163-7 |
| PMID | 26049408 |
| Title | CACNA1C gene and schizophrenia: a case-control and pharmacogenetic study. |
| Abstract | The present study aimed to explore whether 24 single nucleotide polymorphisms (SNPs) within the CACNA1C gene were associated with schizophrenia (SCZ) and antipsychotic response. A sample of 176 SCZ inpatients and 326 healthy controls of Korean ethnicity was collected for this purpose. Psychopathological status was evaluated at baseline and at discharge using the Positive and Negative Syndrome Scale (PANSS). In the case-control study, rs1006737 (P=0.05) and rs2239104 (P=0.03) were associated with SCZ. Further, the rs10848635-rs1016388-rs1006737 haplotype was also associated with SCZ (P=0.03, simulate P=0.02). In the pharmacogenetic analyses, we did not find any association among the investigated SNPs and improvement in the PANSS total score. However, rs723672 and rs1034936 were associated with improvement in the PANSS positive subscale (respectively, P=0.02 and 0.05), rs2283271 in the negative subscale (P=0.01), rs10848635 and rs1016388 in the general subscale (respectively, P=0.03 and 0.04), and the rs3819536-rs2238062 haplotype (global statistics, P=0.1; simulate P=0.04). Our findings further support a role for the CACNA1C gene, particularly for the rs1006737, in SCZ. Further, five SNPs were associated with improvement in PANSS subscales, suggesting a role for this gene in antipsychotic response as well. However, taking into account the limitations of the present study, further research is needed to confirm our findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 73 | Mol. Psychiatry 2015 Jul 20: 820-6 |
| PMID | 25869805 |
| Title | Targeting the schizophrenia genome: a fast track strategy from GWAS to clinic. |
| Abstract | The Psychiatric Genomics Consortium-schizophrenia Workgroup (PGC-SCZ) has recently published a genomewide association study (GWAS) identifying >100 genetic loci, encompassing a total of 341 protein-coding genes, attaining genomewide significance for susceptibility to schizophrenia. Given the extremely long time (12-15 years) and expense (>$1 billion) associated with the development of novel drug targets, repurposing of drugs with known and validated targets may be the most expeditious path toward deriving clinical utility from these GWAS findings. In the present study, we examined all genes within loci implicated by the PGC-SCZ GWAS against databases of targets of both approved and registered pharmaceutical compounds. We identified 20 potential schizophrenia susceptibility genes that encode proteins that are the targets of approved drugs. Of these, we prioritized genes/targets that are of clear neuropsychiatric interest and that are also sole members of the linkage disequilibrium block surrounding a PGC-SCZ GWAS hit. In addition to DRD2, 5 genes meet these criteria: CACNA1C, CACNB2, CACNA1I, GRIN2A and HCN1. An additional 20 genes coding for proteins that are the targets of drugs in registered clinical trials, but without approved indications, were also identified. Although considerable work is still required to fully explicate the biological implications of the PGC-SCZ GWAS results, pathways related to these known, druggable targets may represent a promising starting point. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 74 | Sleep 2015 Sep 38: 1371-80 |
| PMID | 25845695 |
| Title | Cacna1c (Cav1.2) Modulates Electroencephalographic Rhythm and Rapid Eye Movement Sleep Recovery. |
| Abstract | The CACNA1C gene encodes the alpha 1C (?1C) subunit of the Cav1.2 voltage-dependent L-type calcium channel (LTCC). Some of the other voltage-dependent calcium channels, e.g., P-/Q-type, Cav2.1; N-type, Cav2.2; E-/R-type, Cav2.3; and T-type, Cav3.3 have been implicated in sleep modulation. However, the contribution of LTCCs to sleep remains largely unknown. Based on recent genome-wide association studies, CACNA1C emerged as one of potential candidate genes associated with both sleep and psychiatric disorders. Indeed, most patients with mental illnesses have sleep problems and vice versa. To investigate an impact of Cav1.2 on sleep-wake behavior and electroencephalogram (EEG) activity, polysomnography was performed in heterozygous CACNA1C (HET) knockout mice and their wild-type (WT) littermates under baseline and challenging conditions (acute sleep deprivation and restraint stress). HET mice displayed significantly lower EEG spectral power than WT mice across high frequency ranges (beta to gamma) during wake and rapid eye movement (REM) sleep. Although HET mice spent slightly more time asleep in the dark period, daily amounts of sleep did not differ between the two genotypes. However, recovery sleep after exposure to both types of challenging stress conditions differed markedly; HET mice exhibited reduced REM sleep recovery responses compared to WT mice. These results suggest the involvement of CACNA1C (Cav1.2) in fast electroencephalogram oscillations and REM sleep regulatory processes. Lower spectral gamma activity, slightly increased sleep demands, and altered REM sleep responses found in heterozygous CACNA1C knockout mice may rather resemble a sleep phenotype observed in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 75 | Asia Pac Psychiatry 2015 Sep 7: 260-7 |
| PMID | 25588813 |
| Title | Evaluating the association between CACNA1C rs1006737 and schizophrenia risk: A meta-analysis. |
| Abstract | Genetic analyses including genome-wide association studies have reported an intronic single nucleotide polymorphism (SNP) rs1006737 in CACNA1C gene (encoded calcium channel, voltage-dependent, L type, alpha 1C subunit) as a risk factor for schizophrenia in European populations. The replications in other ethnic populations such as East Asians have also been conducted, but the results were inconsistent, either likely due to the limited sample size of single study or genetic heterogeneity between continental populations on this locus. We performed a comprehensive meta-analysis of all available samples from existing studies of East Asian populations, including a total of 9,432 cases and 10,661 controls, to further confirm whether CACNA1C rs1006737 is an authentic risk SNP for schizophrenia in East Asian populations. Our results revealed a significant association between rs1006737 and schizophrenia (allelic model, P?=?4.39?×?10(-6) , pooled odds ratio [OR]?=?1.20), and the results were much strengthened when the European and East Asian samples were combined together (P?=?2.40?×?10(-17) , pooled OR?=?1.12). There is no significant heterogeneity or publication bias between individual studies, and removal of any single study still remained significant associations between rs1006737 and schizophrenia. Our results further confirmed that rs1006737 should be categorized as an authentic risk SNP for schizophrenia in the general populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 76 | Schizophr. Res. 2015 Oct 168: 429-33 |
| PMID | 26276307 |
| Title | Meta-analysis of data from the Psychiatric Genomics Consortium and additional samples supports association of CACNA1C with risk for schizophrenia. |
| Abstract | Recently, numerous genome-wide association studies (GWASs) have identified numerous risk loci for schizophrenia, but follow-up studies are still essential to confirm those results. Therefore, we followed up on top GWAS hits by genotyping implicated loci in additional schizophrenia family samples from our own collection. Five-hundred thirty-six Asian families (comprising 1633 members including 698 schizophrenics) were genotyped in this study. We analyzed 12 single nucleotide polymorphisms (SNPs) in strongly implicated candidate genes revealed by GWASs and their follow-up studies. We then used meta-analysis to combine our results with those of the schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC). In our newly genotyped samples, there were no significant associations of any of the 12 candidate SNPs with schizophrenia; however, all genome-wide significant results from the schizophrenia PGC analysis were maintained after combination with our new data by meta-analysis. One SNP (rs4765905 in CACNA1C) showed a stronger effect and decreased p-value (5.14e-17) after meta-analysis relative to the original PGC results, with no significant between-study heterogeneity. The findings of this study support the significant results in the PGC, especially for CACNA1C. The sample size in our study was considerably smaller than that in the PGC-SCZ study; thus, the weights carried by our samples in the meta-analysis were small. Therefore, our data could not vastly reduce PGC association signals. However, we considered that the well replicated results from the PGC hold up in our new samples, and may suggest that the top hits from the PGC are generalizable, even to other ancestral groups. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 77 | J. Physiol. (Lond.) 2016 Feb -1: -1 |
| PMID | 26913808 |
| Title | L-type Ca(2+) channels in mood, cognition and addiction: Integrating human and rodent studies with a focus on behavioural endophenotypes. |
| Abstract | Brain Cav 1.2 and Cav 1.3 L-type Ca(2+) channels play key physiological roles in various neuronal processes that contribute to brain function. Genetic studies have recently identified CACNA1C as a candidate risk gene for bipolar disorder (BP), schizophrenia (SCZ), major depressive disorder (MDD) and autism spectrum disorder (ASD) and CACNA1D for BP and ASD, suggesting a contribution of Cav 1.2 and Cav 1.3 Ca(2+) signalling to the pathophysiology of neuropsychiatric disorders. Once considered sole clinical entities, it is now clear that BP, SCZ, MDD and ASD share common phenotypic features, most likely due to overlapping neurocircuitry and common molecular mechanisms. A major future challenge lies in translating the human genetic findings to pathological mechanisms that are translatable back to the patient. One approach for tackling such a daunting scientific endeavor for complex behaviour-based neuropsychiatric disorders is to examine intermediate biological phenotypes in the context of endophenotypes within distinct behavioural domains. This will better allow us to integrate findings from genes to behaviour across species, and improve the chances of translating preclinical findings to clinical practice. This article is protected by copyright. All rights reserved. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 78 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2016 Apr 171: 396-401 |
| PMID | 26756527 |
| Title | The impact of CACNA1C allelic variation on regional gray matter volume in Chinese population. |
| Abstract | The SNP rs1006737 in CACNA1C gene has been significantly associated with psychiatric disorders (e.g., schizophrenia and bipolar disorder) in European populations. In Han Chinese, rs1006737 is also strongly associated with schizophrenia, although the effects of the psychosis risk SNP on related brain functions and structures in this population remain unclear. Here, we examined the association of rs1006737 with gray matter volume in a sample of 278 healthy Han Chinese. A whole-brain voxel-based morphometry (VBM) analysis revealed a significant association in the region around right superior occipital gyrus (family-wise error corrected, P?=?0.023). Our data provides initial evidence for the involvement of this psychosis genetic risk locus in brain structure variations in Chinese population, and calls for further investigations. © 2016 Wiley Periodicals, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 79 | Eur Arch Psychiatry Clin Neurosci 2016 Apr 266: 269-75 |
| PMID | 26048451 |
| Title | CACNA1C risk variant is associated with increased amygdala volume. |
| Abstract | Genome-wide association studies suggest that genetic variation within L-type calcium channel subunits confer risk to psychosis. The single nucleotide polymorphism at rs1006737 in CACNA1C has been associated with both schizophrenia and bipolar disorder and with several intermediate phenotypes that may serve as neurobiological antecedents, linking psychosis to genetic aetiology. Amongst others, it has been implicated in alterations in amygdala structure and function. In the present study, we show that the risk allele (A) is associated with increased amygdala volume in healthy individuals (n = 258). This observation reinforces a hypothesis that genetic variation may confer risk to psychosis via alterations in limbic structures. Further study of CACNA1C using intermediate phenotypes for psychosis will determine the mechanisms by which variation in this gene confers risk. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 80 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2016 Mar 171: 181-202 |
| PMID | 26462458 |
| Title | Currently recognized genes for schizophrenia: High-resolution chromosome ideogram representation. |
| Abstract | A large body of genetic data from schizophrenia-related research has identified an assortment of genes and disturbed pathways supporting involvement of complex genetic components for schizophrenia spectrum and other psychotic disorders. Advances in genetic technology and expanding studies with searchable genomic databases have led to multiple published reports, allowing us to compile a master list of known, clinically relevant, or susceptibility genes contributing to schizophrenia. We searched key words related to schizophrenia and genetics from peer-reviewed medical literature sources, authoritative public access psychiatric websites and genomic databases dedicated to gene discovery and characterization of schizophrenia. Our list of 560 genes were arranged in alphabetical order in tabular form with gene symbols placed on high-resolution human chromosome ideograms. Genome wide pathway analysis using GeneAnalytics was carried out on the resulting list of genes to assess the underlying genetic architecture for schizophrenia. Recognized genes of clinical relevance, susceptibility or causation impact a broad range of biological pathways and mechanisms including ion channels (e.g., CACNA1B, CACNA1C, CACNA1H), metabolism (e.g., CYP1A2, CYP2C19, CYP2D6), multiple targets of neurotransmitter pathways impacting dopamine, GABA, glutamate, and serotonin function, brain development (e.g., NRG1, RELN), signaling peptides (e.g., PIK3CA, PIK4CA) and immune function (e.g., HLA-DRB1, HLA-DQA1) and interleukins (e.g., IL1A, IL10, IL6). This summary will enable clinical and laboratory geneticists, genetic counselors, and other clinicians to access convenient pictorial images of the distribution and location of contributing genes to inform diagnosis and gene-based treatment as well as provide risk estimates for genetic counseling of families with affected relatives. © 2015 Wiley Periodicals, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |