No evidence for association between bipolar disorder risk gene variants and brain structural phenotypes.

BACKGROUND

While recent genome-wide association studies have identified several new bipolar disorder (BD) risk variants, structural imaging studies have reported enlarged ventricles and volumetric reductions among the most consistent findings. We investigated whether these genetic risk variants could explain some of the structural brain abnormalities in BD.

METHODS

In a sample of 517 individuals (N=121 BD cases, 116 SZ cases, 61 other psychosis cases and 219 healthy controls), we tested the potential association between nine SNPs in the genes CACNA1C, ANK3, ODZ4 and SYNE1 and eight brain structural measures found to be altered in BD, and if these were specifically affecting the BD sample. We also assessed the polygenic effect of all these 9 SNPs on the brain phenotypes.

RESULTS

Our most significant result was an association between the risk allele A in CACNA1C SNP rs4775913 and decreased cerebellar volume (pnom.=0.0075) in the total sample, which did not remain significant after multiple testing correction (pthreshold<0.0064). There was no evidence for diagnostic specificity for this association in the BD group. Further, no polygenic effect of these 9 SNPs was observed.

LIMITATIONS

Low statistical power might increase our type II error rate.

CONCLUSIONS

The present findings indicate that these risk SNPs do not explain a large proportion of the structural brain alterations in BD. Thus, these genes which are all related to neuronal functions must be involved in other pathophysiological aspects of BD development.