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Strong genetic evidence for a selective influence of GABAA receptors on a component of the bipolar disorder phenotype

Craddock, Nicholas John ORCID:, Jones, L, Jones, Ian Richard ORCID:, Kirov, George ORCID:, Green, Elaine Karen, Grozeva, Detelina ORCID:, Escott-Price, Valentina ORCID:, Nikolov, Ivan, Hamshere, Marian Lindsay ORCID:, Vukcevic, D., Caesar, S., Gordon-Smith, Katherine, Fraser, Christine, Russell, Elen Elizabeth, Norton, Nadine ORCID:, Breen, G., St Clair, D., Collier, D. A., Young, A. H., Ferrier, I. N., Farmer, A., McGuffin, P., Holmans, Peter Alan ORCID:, Donnelly, P., Owen, Michael John ORCID: and O'Donovan, Michael Conlon ORCID: 2010. Strong genetic evidence for a selective influence of GABAA receptors on a component of the bipolar disorder phenotype. Molecular Psychiatry 15 (2) , pp. 146-153. 10.1038/mp.2008.66

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Despite compelling evidence for a major genetic contribution to risk of bipolar mood disorder, conclusive evidence implicating specific genes or pathophysiological systems has proved elusive. In part this is likely to be related to the unknown validity of current phenotype definitions and consequent aetiological heterogeneity of samples. In the recent Wellcome Trust Case Control Consortium genome-wide association analysis of bipolar disorder (1868 cases, 2938 controls) one of the most strongly associated polymorphisms lay within the gene encoding the GABAA receptor β1 subunit, GABRB1. Aiming to increase biological homogeneity, we sought the diagnostic subset that showed the strongest signal at this polymorphism and used this to test for independent evidence of association with other members of the GABAA receptor gene family. The index signal was significantly enriched in the 279 cases meeting Research Diagnostic Criteria for schizoaffective disorder, bipolar type (P=3.8 × 10−6). Independently, these cases showed strong evidence that variation in GABAA receptor genes influences risk for this phenotype (independent system-wide P=6.6 × 10−5) with association signals also at GABRA4, GABRB3, GABRA5 and GABRR1. Our findings have the potential to inform understanding of presentation, pathogenesis and nosology of bipolar disorders. Our method of phenotype refinement may be useful in studies of other complex psychiatric and non-psychiatric disorders.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Neuroscience and Mental Health Research Institute (NMHRI)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RZ Other systems of medicine
Uncontrolled Keywords: bipolar disorder; schizoaffective disorder; GABAA receptors; genetic; nosology
Publisher: Nature Publishing Group
ISSN: 1359-4184
Last Modified: 06 Nov 2022 13:46

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