A combined study of whole-exome sequencing and structural neuroimaging markers in bipolar disorder

Bipolar disorder (BD) is a highly heritable psychiatric disorder. An increasing number of whole-exome sequencing (WES) studies have been conducted on psychiatric research. However, few studies have investigated the association between single nucleotide variants (SNVs) in WES and structural brain changes in patients with BD. We conducted WES on 93 patients with BD and 161 healthy controls (HCs) to detect germline variants and copy number alterations (CNAs), as well as the gene-based effects of rare variants on BD. The impact of genetic factors on structural neuroimaging markers, including cortical thickness and white matter tract integrity, was examined using neuroimaging-genetic association analysis. We identified 382 BD-related genes, including SYNE1, PKHD1L1, FRAS1, and ZFHX4, from a systematic review, and the most frequently mutated genes. We identified a new gene, GNB3, which harbors a significant burden of rare nonsynonymous variants that affect BD. By integrating WES and structural neuroimaging data, we found that the single nucleotide polymorphism (SNP) rs56850341 in KMT2C was substantially correlated with structural neuroimaging measures, including cortical thickness and white matter tract integrity. In the present study, we suggest that rare nonsynonymous variants in GNB3 may be involved in the pathophysiology of BD, and that highly contributing heritable genetic variant in KMT2C may influence brain structural changes.