Copy number variations in RNF216 and postsynaptic membrane-associated genes are associated with bipolar disorder: a case-control study in the Japanese population

Abstract

Aim: Bipolar disorder (BD) is a common psychiatric disorder characterized by alterations between manic/hypomanic and depressive states. Rare pathogenic copy number variations (CNVs) that overlap with exons of synaptic genes have been associated with BD. However, no study has comprehensively explored CNVs in synaptic genes associated with BD. Here, we evaluated the relationship between BD and rare CNVs that overlap with synaptic genes, not limited to exons, in the Japanese population.

Methods: Using array comparative genome hybridization, we detected CNVs in 1839 patients with BD and 2760 controls. We used the Synaptic Gene Ontology database to identify rare CNVs that overlap with synaptic genes. Using gene-based analysis, we compared their frequencies between the BD and control groups. We also searched for synaptic gene sets related to BD. The significance level was set to a false discovery rate of 10%.

Results: The RNF216 gene was significantly associated with BD (odds ratio, 4.51 [95% confidence interval, 1.66-14.89], false discovery rate < 10%). The BD-associated CNV that corresponded with RNF216 also partially overlapped with the minimal critical region of the 7p22.1 microduplication syndrome. The integral component of the postsynaptic membrane (Gene Ontology:0099055) was significantly associated with BD. The CNV overlapping with the intron region of GRM5 in this gene set showed a nominal significant association between cases and controls (P < 0.05).

Conclusion: We provide evidence that CNVs in RNF216 and postsynaptic membrane-related genes confer a risk of BD, contributing to a better understanding of the pathogenesis of BD.

Keywords: RNF216; array comparative genome hybridization; bipolar disorder; pathogenic copy number variation; synaptic gene.

Fig. 1

Copy number variations (CNVs) detected in RNF216 in patients with bipolar disorder (BD) and controls. UCSC Genome Browser view for the region chr7:5,610,000–6,015,000. Genomic coordinates are based on hg38. The upper track shows the genomic locations of the detected duplications and deletions in the following order: patients with BD and healthy controls were evaluated using Agilent aCGH, validation samples were evaluated using NimblGen aCGH, and patients with BD and their parents were evaluated using whole exome sequencing (WES). Duplicates are indicated by blue bars and deletions by red bars. Sample numbers do not correspond to the sample numbers in Supplementary Fig. S1. The second track from the bottom shows annotations for SDs. The bottom track shows the gene annotations in Gencode V43 and 463792__DUP of gnomAD CNVs V4. Other variants registered in gnomAD are not shown.