Rare variants in neuronal excitability genes influence risk for bipolar disorder.
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.
Institute for Systems Biology, Seattle, WA 98109;
Seth A
SA
Ament
Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ 85004;
Szabolcs
S
Szelinger
Institute for Systems Biology, Seattle, WA 98109;
Gustavo
G
Glusman
Institute for Systems Biology, Seattle, WA 98109;
Justin
J
Ashworth
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;
Liping
L
Hou
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;
Nirmala
N
Akula
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093;
Tatyana
T
Shekhtman
Department of Psychiatry, University of Chicago, Chicago, IL 60637;
Judith A
JA
Badner
Institute for Systems Biology, Seattle, WA 98109;
Mary E
ME
Brunkow
Institute for Systems Biology, Seattle, WA 98109;
Denise E
DE
Mauldin
Institute for Systems Biology, Seattle, WA 98109;
Anna-Barbara
AB
Stittrich
Institute for Systems Biology, Seattle, WA 98109;
Katherine
K
Rouleau
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;
Sevilla D
SD
Detera-Wadleigh
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;
John I
JI
Nurnberger
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.
Howard J
http://orcid.org/0000-0003-0344-9690
HJ
Edenberg
Department of Psychiatry, University of Chicago, Chicago, IL 60637;
Elliot S
ES
Gershon
J. Craig Venter Institute, La Jolla, CA 92037.
Nicholas
N
Schork
Institute for Systems Biology, Seattle, WA 98109;
Nathan D
ND
Price
Institute for Systems Biology, Seattle, WA 98109;
Richard
R
Gelinas
Institute for Systems Biology, Seattle, WA 98109; lhood@systemsbiology.org mcmahonf@intra.nimh.nih.gov jkelsoe@ucsd.edu jroach@systemsbiology.org.
Leroy
L
Hood
Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ 85004;
David
D
Craig
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.
Francis J
FJ
McMahon
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.
John R
JR
Kelsoe
Institute for Systems Biology, Seattle, WA 98109; lhood@systemsbiology.org mcmahonf@intra.nimh.nih.gov jkelsoe@ucsd.edu jroach@systemsbiology.org.
Jared C
JC
Roach
D001714:Bipolar Disorder / Q000235:genetics* / Q000503:physiopathology*; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D009474:Neurons / Q000502:physiology*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics; D044465:White People / Q000235:genetics
GABAA receptor; bipolar disorder; family genomics; regulatory variants; voltage-gated calcium channel