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Evidence For Genetic Heterogeneity Between Clinical Subtypes of Bipolar Disorder

Charney, A.W. and Ruderfer, D.M. and Stahl, E.A. and Moran, J.L. and Chambert, K. and Belliveau, R.A. and Forty, L. and Gordon-Smith, Katherine and Di Florio, A. and Lee, P.H. and Bromet, E.J. and Buckley, P.F. and Escamilla, M.A. and Fanous, A.H. and Fochtmann, L.J. and Lehrer, D.S. and Malaspina, D. and Marder, S.R. and Morley, C.P. and Nicolini, H. and Perkins, D.O. and Rakofsky, J.J. and Rapaport, M.H. and Medeiros, H. and Sobell, J.L. and Green, E.K. and Backlund, L. and Bergen, S.E. and Juréus, A. and Schalling, M. and Lichtenstein, P. and Roussos, P. and Knowles, J.A. and Jones, Lisa and Hultman, C.M. and Perlis, R. and Purcell, S.M. and McCarroll, S.A. and Pato, C.N. and Pato, M.T. and Craddock, N. and Landén, M. and Smoller, J.W. and Sklar, P. (2017) Evidence For Genetic Heterogeneity Between Clinical Subtypes of Bipolar Disorder. Translational Psychiatry, 7 (e993). ISSN 2158-3188

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Abstract

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P = 3.28 × 10 − 8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia (SCZ) and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I h2 = 0.35; BD II h2 = 0.25; P = 0.02) with a genetic correlation between BD I and BD II of 0.78,compared with a genetic correlation of 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for SCZ and BD in patients with BD I compared with patients with BD II, and a greater load of SCZ risk alleles in the bipolar type of schizoaffective disorder (SAB) compared with both other BD subtypes. These results point to a partial difference in genetic architecture of BD subtypes, and are suggestive of a molecular correlate for the clinical division of BD into subtypes.

Item Type: Article
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Uncontrolled Keywords: Bipolar disorder, Genome-wide association (GWAS), clinical subtypes
Subjects: B Philosophy. Psychology. Religion > BF Psychology
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Divisions: Academic Departments > Institute of Health and Society
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Copyright Info: Open Access article distributed under terms of the Creative Commons Attribution License
Depositing User: Katherine Gordon-Smith
Date Deposited: 03 Jan 2017 10:01
Last Modified: 11 Jan 2017 10:57
URI: https://eprints.worc.ac.uk/id/eprint/5165

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