Whole-exome sequencing of 81 individuals from 27 multiply affected bipolar disorder families

Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of depression and mania. Research suggests that the cumulative impact of common alleles explains 25-38% of phenotypic variance, and that rare variants may contribute to BD susceptibility. To identify rare, high-penetrance susceptibility variants for BD, whole-exome sequencing (WES) was performed in three affected individuals from each of 27 multiply affected families from Spain and Germany. WES identified 378 rare, non-synonymous, and potentially functional variants. These spanned 368 genes, and were carried by all three affected members in at least one family. Eight of the 368 genes harbored rare variants that were implicated in at least two independent families. In an extended segregation analysis involving additional family members, five of these eight genes harbored variants showing full or nearly full cosegregation with BD. These included the brain-expressed genes RGS12 and NCKAP5, which were considered the most promising BD candidates on the basis of independent evidence. Gene enrichment analysis for all 368 genes revealed significant enrichment for four pathways, including genes reported in de novo studies of autism (padj < 0.006) and schizophrenia (padj = 0.015). These results suggest a possible genetic overlap with BD for autism and schizophrenia at the rare-sequence-variant level. The present study implicates novel candidate genes for BD development, and may contribute to an improved understanding of the biological basis of this common and often devastating disease.The study was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (grant 01ZX1314A/01ZX1614A to M.M.N. Forstner et al. Translational Psychiatry (2020) 10:57 Page 8 of 10 and S.C., grant 01ZX1314G/01ZX1614G to M.R.) and through ERA-NET NEURON, “SynSchiz—Linking synaptic dysfunction to disease mechanisms in schizophrenia—a multilevel investigation“ (01EW1810 to MR). The study was also supported by the German Research Foundation (DFG; grant FOR2107; RI908/11-1 and RI908/11–2 to M.R.; NO246/10-1 and NO 246/10-2 to M.M.N.), and the Swiss National Science Foundation (SNSF, grant 156791 to S.C.). M.M.N. is a member of the DFG-funded Excellence-Cluster ImmunoSensation.Ye