Bipolar disorder (BD) is a prevalent mood disorder that tends to cluster in families. Despite high heritability estimates, few genetic susceptibility factors have been identified over decades of genetic research. One possible interpretation for the shortcomings of previous studies to detect causative genes is that BD is caused by highly penetrant rare variants in many genes. We explored this hypothesis by sequencing the exomes of affected individuals from 40 well-characterized multiplex families. We identified rare variants segregating with affected status in many interesting genes, and found an enrichment of deleterious variants in G protein-coupled receptor (GPCR) family genes, which are important drug targets. Furthermore, we showed targeted downstream GPCR dysregulation for some of the variants that may contribute to disease pathology. Particularly interesting was the finding of a rare and functionally relevant nonsense mutation in the corticotropin-releasing hormone receptor 2 (CRHR2) gene that tracked with affected status in one family. By focusing on rare variants in informative families, we identified key biochemical pathways likely implicated in this complex disorder.
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We thank the participants and their families for their contribution to this research. Furthermore, we acknowledge Karine Lachapelle and Annie Levert from the laboratory of GAR for technical assistance. This work was funded through a grant from Genome Quebec.
Conflict of Interest
The authors declare no conflict of interest.
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Cruceanu, C., Schmouth, J., Torres-Platas, S.G. et al. Rare susceptibility variants for bipolar disorder suggest a role for G protein-coupled receptors. Mol Psychiatry 23, 2050–2056 (2018). https://doi.org/10.1038/mp.2017.223
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