Exome Sequencing of Familial Bipolar Disorder.
IMPORTANCE: Complex disorders, such as bipolar disorder (BD), likely result from the influence of both common and rare susceptibility alleles. While common variation has been widely studied, rare variant discovery has only recently become feasible with next-generation sequencing.
OBJECTIVE: To utilize a combined family-based and case-control approach to exome sequencing in BD using multiplex families as an initial discovery strategy, followed by association testing in a large case-control meta-analysis.
DESIGN, SETTING, AND PARTICIPANTS: We performed exome sequencing of 36 affected members with BD from 8 multiplex families and tested rare, segregating variants in 3 independent case-control samples consisting of 3541 BD cases and 4774 controls.
MAIN OUTCOMES AND MEASURES: We used penalized logistic regression and 1-sided gene-burden analyses to test for association of rare, segregating damaging variants with BD. Permutation-based analyses were performed to test for overall enrichment with previously identified gene sets.
RESULTS: We found 84 rare (frequency
CONCLUSIONS AND RELEVANCE: Our results are consistent with the presence of prominent locus and allelic heterogeneity in BD and suggest that very large samples will be required to definitively identify individual rare variants or genes conferring risk for this disorder. However, we also identify significant associations with gene sets composed of previously discovered de novo variants in autism and schizophrenia, as well as targets of the FRMP pathway, providing preliminary support for the overlap of potential autism and schizophrenia risk genes with rare, segregating variants in families with BD.
|Year of Publication||
2016 Jun 01
K01 MH093809 / MH / NIMH NIH HHS / United States
R01 MH087979 / MH / NIMH NIH HHS / United States
U01 MH105653 / MH / NIMH NIH HHS / United States
R01 MH087992 / MH / NIMH NIH HHS / United States
R01 MH106531 / MH / NIMH NIH HHS / United States
R00 MH086049 / MH / NIMH NIH HHS / United States
T32 GM007337 / GM / NIGMS NIH HHS / United States
R01 MH094145 / MH / NIMH NIH HHS / United States