Pleiotropic Association of CACNA1C Variants With Neuropsychiatric Disorders.

Schizophrenia bulletin 2023 Sep 07

filter terms:

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. 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. 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). 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. © The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Citation

Zuxing Wang, Xiandong Lin, Xinqun Luo, Jun Xiao, Yong Zhang, Jianying Xu, Shibin Wang, Fen Zhao, Huifen Wang, Hangxiao Zheng, Wei Zhang, Chen Lin, Zewen Tan, Liping Cao, Zhiren Wang, Yunlong Tan, Wenzhong Chen, Yuping Cao, Xiaoyun Guo, Christopher Pittenger, Xingguang Luo. Pleiotropic Association of CACNA1C Variants With Neuropsychiatric Disorders. Schizophrenia bulletin. 2023 Sep 07;49(5):1174-1184