Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 11, Pages 3576-3581Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1424958112
Keywords
bipolar disorder; family genomics; regulatory variants; GABA(A) receptor; voltage-gated calcium channel
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Funding
- NIMH Bipolar Disorder Genetics Initiative [MH59545, MH059534, MH59533, MH59553, MH60068, MH059548, MH59535, MH59567, MH059556, 1Z01MH002810-01]
- NIH from the National Cancer Institute [P50CA89392]
- NIH from the National Institute of Drug Abuse [5K02DA021237]
- University of Luxembourg Institute for Systems Biology Strategic Partnership
- National Institute of General Medical Sciences Center for Systems Biology [P50 GM076547]
- NIMH [R01 MH094483]
- Intramural Research Program of the NIMH
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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 GABA(A) 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, C4CNG2, 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.
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