Rare variants in neuronal excitability genes influence risk for bipolar disorder

Ament, SA; Szelinger, S; Glusman, G; Ashworth, J; Hou, L; Akula, N; Shekhtman, T; Badner, JA; Brunkow, ME; Mauldin, DE; Stittrich, AB; 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

Rare variants in neuronal excitability genes influence risk for bipolar disorder

Ament, SA Szelinger, S Glusman, G Ashworth, J

Hou, L Akula, N Shekhtman, T Badner, JA Brunkow, ME Mauldin, DE Stittrich, AB 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

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Publication Type:: Journal Article
Citation:: Proceedings of the National Academy of Sciences of the United States of America, 2015, 112 (11), pp. 3576 - 3581
Issue Date:: 2015-03-17

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Field	Value	Language
dc.contributor.author	Ament, SA	en_US
dc.contributor.author	Szelinger, S	en_US
dc.contributor.author	Glusman, G	en_US
dc.contributor.author	Ashworth, J https://orcid.org/0000-0003-4835-6551	en_US
dc.contributor.author	Hou, L	en_US
dc.contributor.author	Akula, N	en_US
dc.contributor.author	Shekhtman, T	en_US
dc.contributor.author	Badner, JA	en_US
dc.contributor.author	Brunkow, ME	en_US
dc.contributor.author	Mauldin, DE	en_US
dc.contributor.author	Stittrich, AB	en_US
dc.contributor.author	Rouleau, K	en_US
dc.contributor.author	Detera-Wadleigh, SD	en_US
dc.contributor.author	Nurnberger, JI	en_US
dc.contributor.author	Edenberg, HJ	en_US
dc.contributor.author	Gershon, ES	en_US
dc.contributor.author	Schork, N	en_US
dc.contributor.author	Price, ND	en_US
dc.contributor.author	Gelinas, R	en_US
dc.contributor.author	Hood, L	en_US
dc.contributor.author	Craig, D	en_US
dc.contributor.author	McMahon, FJ	en_US
dc.contributor.author	Kelsoe, JR	en_US
dc.contributor.author	Roach, JC	en_US
dc.date.issued	2015-03-17	en_US
dc.identifier.citation	Proceedings of the National Academy of Sciences of the United States of America, 2015, 112 (11), pp. 3576 - 3581	en_US
dc.identifier.issn	0027-8424	en_US
dc.identifier.uri	http://hdl.handle.net/10453/119046
dc.description.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.	en_US
dc.relation.ispartof	Proceedings of the National Academy of Sciences of the United States of America	en_US
dc.relation.isbasedon	10.1073/pnas.1424958112	en_US
dc.subject.mesh	Neurons	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Genetic Predisposition to Disease	en_US
dc.subject.mesh	Risk Factors	en_US
dc.subject.mesh	Case-Control Studies	en_US
dc.subject.mesh	Pedigree	en_US
dc.subject.mesh	Bipolar Disorder	en_US
dc.subject.mesh	Signal Transduction	en_US
dc.subject.mesh	Polymorphism, Single Nucleotide	en_US
dc.subject.mesh	European Continental Ancestry Group	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Genetic Variation	en_US
dc.subject.mesh	Genetic Association Studies	en_US
dc.title	Rare variants in neuronal excitability genes influence risk for bipolar disorder	en_US
dc.type	Journal Article
utslib.citation.volume	11	en_US
utslib.citation.volume	112	en_US
utslib.for	MD Multidisciplinary	en_US
utslib.for	110319 Psychiatry (incl. Psychotherapy)	en_US
utslib.for	060408 Genomics	en_US
utslib.for	1701 Psychology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - C3 - Climate Change Cluster
utslib.copyright.status	closed_access
pubs.issue	11	en_US
pubs.publication-status	Published	en_US
pubs.volume	112	en_US

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.

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http://hdl.handle.net/10453/119046