Rare variants in neuronal excitability genes influence risk for bipolar disorder.
Publication Title
Proceedings of the National Academy of Sciences of the United States of America
Document Type
Article
Publication Date
3-17-2015
Keywords
washington; isb; Bipolar Disorder; Case-Control Studies; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Humans; Male; Neurons; Pedigree; Polymorphism, Single Nucleotide; Risk Factors; Signal Transduction; White People
Abstract
We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genome-wide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABAA receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5' and 3' UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD.
Area of Special Interest
Mental Health
Specialty/Research Institute
Institute for Systems Biology
Specialty/Research Institute
Behavioral Health
DOI
10.1073/pnas.1424958112
