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

TitleRare variants in neuronal excitability genes influence risk for bipolar disorder.
Publication TypeJournal Article
Year of Publication2015
AuthorsAment SA, Szelinger S, Glusman G, Ashworth J, Hou L, Akula N, Shekhtman T, Badner JA, Brunkow ME, Mauldin DE, Stittrich A-B, Rouleau K, Detera-Wadleigh SD, Nurnberger JI, Edenberg HJ, Gershon ES, Schork N, Price ND, Gelinas R, Hood L, Craig D, McMahon FJ, Kelsoe JR, Roach JC
Corporate AuthorsBipolar Genome Study
JournalProc Natl Acad Sci U S A
Volume112
Issue11
Pagination3576-81
Date Published2015 Mar 17
ISSN1091-6490
KeywordsBipolar Disorder, Case-Control Studies, European Continental Ancestry Group, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Humans, Male, Neurons, Pedigree, Polymorphism, Single Nucleotide, Risk Factors, Signal Transduction
Abstract<p>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.</p>
DOI10.1073/pnas.1424958112
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID25730879
PubMed Central IDPMC4371952
Grant ListR01 MH059556 / MH / NIMH NIH HHS / United States
MH059556 / MH / NIMH NIH HHS / United States
MH59533 / MH / NIMH NIH HHS / United States
R01 MH059535 / MH / NIMH NIH HHS / United States
MH059534 / MH / NIMH NIH HHS / United States
R01 MH059567 / MH / NIMH NIH HHS / United States
R01 MH059545 / MH / NIMH NIH HHS / United States
5K02DA021237 / DA / NIDA NIH HHS / United States
P01 CA089392 / CA / NCI NIH HHS / United States
1Z01MH002810-01 / MH / NIMH NIH HHS / United States
MH59553 / MH / NIMH NIH HHS / United States
MH059548 / MH / NIMH NIH HHS / United States
UL1 TR001108 / TR / NCATS NIH HHS / United States
R01 MH059548 / MH / NIMH NIH HHS / United States
R01 MH059534 / MH / NIMH NIH HHS / United States
/ / Intramural NIH HHS / United States
MH59545 / MH / NIMH NIH HHS / United States
MH60068 / MH / NIMH NIH HHS / United States
R01 MH059533 / MH / NIMH NIH HHS / United States
P50 GM076547 / GM / NIGMS NIH HHS / United States
MH59567 / MH / NIMH NIH HHS / United States
MH59535 / MH / NIMH NIH HHS / United States
K02 DA021237 / DA / NIDA NIH HHS / United States
R01 MH094483 / MH / NIMH NIH HHS / United States
Z01 MH002810 / MH / NIMH NIH HHS / United States
P50CA89392 / CA / NCI NIH HHS / United States
R01 MH059553 / MH / NIMH NIH HHS / United States
R01 MH060068 / MH / NIMH NIH HHS / United States