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Evidence For Genetic Heterogeneity Between Clinical Subtypes of Bipolar Disorder

Charney, A.W., Ruderfer, D.M., Stahl, E.A., Moran, J.L., Chambert, K., Belliveau, R.A., Forty, L., Gordon-Smith, Katherine, Di Florio, A., Lee, P.H., Bromet, E.J., Buckley, P.F., Escamilla, M.A., Fanous, A.H., Fochtmann, L.J., Lehrer, D.S., Malaspina, D., Marder, S.R., Morley, C.P., Nicolini, H., Perkins, D.O., Rakofsky, J.J., Rapaport, M.H., Medeiros, H., Sobell, J.L., Green, E.K., Backlund, L., Bergen, S.E., Juréus, A., Schalling, M., Lichtenstein, P., Roussos, P., Knowles, J.A., Jones, Lisa, Hultman, C.M., Perlis, R., Purcell, S.M., McCarroll, S.A., Pato, C.N., Pato, M.T., Craddock, N., Landén, M., 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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