Rare susceptibility variants for bipolar disorder suggest a role for G protein-coupled receptors.
Mol Psychiatry
; 23(10): 2050-2056, 2018 10.
Article
in En
| MEDLINE
| ID: mdl-29158579
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Bipolar Disorder
/
Receptors, G-Protein-Coupled
Type of study:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Adult
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Mol Psychiatry
Journal subject:
BIOLOGIA MOLECULAR
/
PSIQUIATRIA
Year:
2018
Type:
Article
Affiliation country:
Canada