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Objectives: Genome-wide association studies have identified a significant risk gene, CACNA1C, for schizophrenia. In this study, we comprehensively investigated a large set of CACNA1C single-nucleotide polymorphisms (SNPs) to identify the replicable risk alleles for schizophrenia and explore their biological functions. Methods: One Jewish (1044 cases vs 2052 controls), one European (1350 cases vs 1378 controls) and one exploratory African American samples (98 cases vs 20 controls) were analyzed to identify replicable single-nucleotide polymorphism–schizophrenia associations. The regulatory effects of risk alleles on CACNA1C messenger RNA expression were examined. The most robust risk tagSNP (rs1006737) was meta-analyzed on 17 studies (74,122 cases vs 109,062 controls), and associated with the gray matter volumes of seven subcortical structures in 38,258 Europeans, and the surface areas and thickness of 34 cortical regions in 33,992 Europeans and 2944 non-Europeans. Results: Forty-seven replicable risk single-nucleotide polymorphisms, including a 20-single-nucleotide polymorphism haplotype block, were identified in our samples (1.8 × 10−4 ⩽  p ⩽ 0.049). This variant block was consistently associated with schizophrenia across four independent Psychiatric Genomics Consortium cohorts (79,645 cases vs 109,590 controls; 2.5 × 10–17 ⩽  p ⩽ 0.017). This block showed significant expression quantitative trait loci in three independent European brain cohorts (5.1 × 10–12 ⩽  p ⩽ 8.3 × 10–3) and could be tagged by the most significant risk single-nucleotide polymorphism rs1006737. The minor allele A of rs1006737 significantly increased risk for schizophrenia across the Jewish and European samples ( p = 0.029 and 0.004, respectively), and this association was highly significant in the meta-analysis ( p = 1.62 × 10–42). This allele also significantly altered the CACNA1C messenger RNA expression in five brain regions (5.1 × 10–12 ⩽  p ⩽ 0.05), decreased the gray matter volume of thalamus ( p = 0.010), the surface area of isthmus cingulate cortex ( p = 0.013) and the thickness of transverse temporal and superior temporal sulcus cortexes (0.005 ⩽  p ⩽ 0.043). Conclusion: We identified an independent, replicable, functional, and significant risk variant block at CACNA1C for schizophrenia, which could be tagged by the most robust risk marker rs1006737, suggesting an important role of CACNA1C in the pathogenesis of schizophrenia.

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Background Neuropsychiatric disorders are highly heritable and have overlapping genetic underpinnings. Single nucleotide polymorphisms (SNPs) in the gene CACNA1C have been associated with several neuropsychiatric disorders, across multiple genome-wide association studies. Method A total of 70,711 subjects from 37 independent cohorts with 13 different neuropsychiatric disorders were meta-analyzed to identify overlap of disorder-associated SNPs within CACNA1C. The differential expression of CACNA1C mRNA in five independent postmortem brain cohorts was examined. Finally, the associations of disease-sharing risk alleles with total intracranial volume (ICV), gray matter volumes (GMVs) of subcortical structures, cortical surface area (SA), and average cortical thickness (TH) were tested. Results Eighteen SNPs within CACNA1C were nominally associated with more than one neuropsychiatric disorder (P < .05); the associations shared among schizophrenia, bipolar disorder, and alcohol use disorder survived false discovery rate correction (five SNPs with P < 7.3 × 10−4 and q < 0.05). CACNA1C mRNA was differentially expressed in brains from individuals with schizophrenia, bipolar disorder, and Parkinson’s disease, relative to controls (three SNPs with P < .01). Risk alleles shared by schizophrenia, bipolar disorder, substance dependence, and Parkinson’s disease were significantly associated with ICV, GMVs, SA, or TH (one SNP with P ≤ 7.1 × 10−3 and q < 0.05). Conclusion Integrating multiple levels of analyses, we identified CACNA1C variants associated with multiple psychiatric disorders, and schizophrenia and bipolar disorder were most strongly implicated. CACNA1C variants may contribute to shared risk and pathophysiology in these conditions.