Rare susceptibility variants for bipolar disorder suggest a role for G protein-coupled receptors.
Fiche publication
Date publication
octobre 2018
Journal
Molecular psychiatry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DARCQ Emmanuel
Tous les auteurs :
Cruceanu C, Schmouth JF, Torres-Platas SG, Lopez JP, Ambalavanan A, Darcq E, Gross F, Breton B, Spiegelman D, Rochefort D, Hince P, Petite JM, Gauthier J, Lafrenière RG, Dion PA, Greenwood CM, Kieffer BL, Alda M, Turecki G, Rouleau GA
Lien Pubmed
Résumé
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.
Mots clés
Adult, Bipolar Disorder, genetics, Case-Control Studies, Family, Female, Gene Frequency, genetics, Genetic Linkage, Genetic Predisposition to Disease, genetics, Genetic Variation, genetics, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, methods, Humans, Male, Middle Aged, Pedigree, Receptors, Corticotropin-Releasing Hormone, genetics, Receptors, G-Protein-Coupled, genetics, Exome Sequencing
Référence
Mol Psychiatry. 2018 10;23(10):2050-2056