Rare variants in neuronal excitability genes influence risk for bipolar disorder

The Bipolar Genome Study

Research output: Contribution to journalArticle

65 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3576-3581
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number11
DOIs
StatePublished - Mar 17 2015

Fingerprint

Bipolar Disorder
Genes
Pedigree
5' Untranslated Regions
Genome-Wide Association Study
3' Untranslated Regions
Nerve Growth Factor
GABA-A Receptors
Calcium Channels
Ion Channels
Genome

Keywords

  • Bipolar disorder
  • Family genomics
  • GABA receptor
  • Regulatory variants
  • Voltage-gated calcium channel

ASJC Scopus subject areas

  • General

Cite this

Rare variants in neuronal excitability genes influence risk for bipolar disorder. / The Bipolar Genome Study.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 11, 17.03.2015, p. 3576-3581.

Research output: Contribution to journalArticle

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AU - Rouleau, Katherine

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AU - Gelinas, Richard

AU - Hood, Leroy

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