Two of the four genome-wide significant signals in our analysis localise to introns of brain-expressed genes encoding L-type voltage-gated calcium-channel subunits (CACNA1C and CACNB2). Previous disorder-specific GWAS, overlapping with the samples included here, identified CACNA1C as a susceptibility gene for bipolar disorder,7,31 schizophrenia,6 and major depressive disorder.32 Gain-of-function mutations in CACNA1C cause Timothy syndrome, a developmental disorder in which the phenotypic range includes autism.33 Consistent with a pleiotropic role, neuroimaging studies have documented effects of CACNA1C variants on a range of structural and functional brain phenotypes, including circuitry involved in emotion processing,34 executive function,34 attention,35 and memory.36 CACNB2 encodes an auxiliary voltage-gated calcium-channel subunit that interacts with L-type calcium-channel subunits (including CACNA1C, CACNA1D, and CACNA1S) to promote their trafficking to the plasma membrane, increase their function, and regulate their modulation by other signalling proteins and molecules.3 Although previous PGC analyses (schizophrenia and bipolar disorder) did not identify CACNB2 as a risk gene, a variant in CACNB2 (52 kb from our peak SNP) was one of the main signals in an independent GWAS of bipolar disorder in Han Chinese individuals.19
