Common variants in CACNA1C and MDD susceptibility: A comprehensive meta-analysis.

Major depressive disorder (MDD) is one of the most common psychiatric disorders with a relatively high heritability (35-40%). Though rs1006737 in the CACNA1C gene showed significant association with MDD in a British large-scale candidate association study, most of the replication analyses with relatively small sample size reported negative association. Moreover, this locus has never been identified in previous genome-wide association studies (GWAS) for MDD. Here, we conducted a comprehensive meta-analysis of the association between CACNA1C variants and MDD risk by combining all published data. Genetic data from one European GWAS and five individual follow-up studies, which include up to 12,629 patients of MDD and 28,653 controls, that is, the largest sample size on CACNA1C to date, were collected. Rs1006737 showed significant association with MDD in the fixed-effect model (Z = 2.56, P = 0.011, OR = 1.08, 95%CI = 1.04-1.12) and the association remained after reanalyzing the data according to ethnicity. We additionally analyzed other 25 SNPs, genotyped in only one replication study, across the CACNA1C locus, and found that two SNPs, rs4765905 (P = 0.041, OR = 1.05, 95%CI 1.00-1.09) and rs4765937 (P = 0.025, OR = 1.05, 95%CI 1.01-1.09) showed nominal association with MDD, while rs2239073 (P = 0.002, OR = 1.07, 95%CI 1.02-1.11) exhibited significant association with MDD, which survived from multiple corrections. Our study provides support for positive association between CACNA1C and MDD; however, the current data suggest the necessity of replication analyses in a larger-scale sample.