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Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3576-81. doi: 10.1073/pnas.1424958112. Epub 2015 Feb 17.

Rare variants in neuronal excitability genes influence risk for bipolar disorder.

Author information

1
Institute for Systems Biology, Seattle, WA 98109;
2
Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ 85004;
3
Mood and Anxiety Disorders Section, Human Genetics Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD 20892;
4
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093;
5
Department of Psychiatry, University of Chicago, Chicago, IL 60637;
6
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202;
7
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202; and.
8
J. Craig Venter Institute, La Jolla, CA 92037.
9
Institute for Systems Biology, Seattle, WA 98109; lhood@systemsbiology.org mcmahonf@intra.nimh.nih.gov jkelsoe@ucsd.edu jroach@systemsbiology.org.
10
Mood and Anxiety Disorders Section, Human Genetics Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD 20892; lhood@systemsbiology.org mcmahonf@intra.nimh.nih.gov jkelsoe@ucsd.edu jroach@systemsbiology.org.
11
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093; lhood@systemsbiology.org mcmahonf@intra.nimh.nih.gov jkelsoe@ucsd.edu jroach@systemsbiology.org.

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.

KEYWORDS:

GABAA receptor; bipolar disorder; family genomics; regulatory variants; voltage-gated calcium channel

PMID:
25730879
PMCID:
PMC4371952
DOI:
10.1073/pnas.1424958112
[Indexed for MEDLINE]
Free PMC Article

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