Genetic Variation in CACNA1C, a Gene Associated with Bipolar Disorder, Influences Brainstem Rather than Gray Matter Volume in Healthy Individuals

Background: Genetic variation in CACNA1C has been repeatedly shown to increase risk for psychiatric disorders, with the strongest evidence for involvement in bipolar disorder. To elucidate the mechanisms by which such effects on psychiatric disease are brought about by genetic factors, we investigated the influence of CACNA1C polymorphisms on brain structure. Methods: In 585 healthy volunteers, for whom magnetic resonance imaging data at 1.5 T (n = 282) or 31 (n = 304) were available, we tested 193 single nucleotide polymorphisms (SNPs) in or near CACNA1C for association with FSL FIRST-segmented subcortical brain structures and hippocampus as well as SPM5-derived total brain volume and global gray and white matter volume using PLINK. Results: A study-wide significant association of SNPs in intron 3 of the CACNA1C gene was found for brainstem volume (lowest p value = 3.62E-05) and was confirmed by voxel-based morphometry. An effect on gray matter volume of the bipolar disorder-associated SNP rs1006737, as reported earlier in a sample of 77 healthy adults, could not be confirmed. Conclusions: Genetic variation in the pleiotropic psychiatric disease gene CACNA1C is associated with brainstem volume. Modulation of this structure, with its central control over motor, cognitive, affective, and arousal functions, constitutes an interesting novel potential mode of action of psychiatric risk factors.