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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, K, Di Florio, Arianna, 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, Ian, Jones, L A, Hultman, C M, Perlis, R H, Purcell, S M, McCarroll, S A, Pato, C N, Pato, M T, Craddock, Nicholas, Landén, M, Smoller, J W and Sklar, P 2017. Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder. Translational Psychiatry 7 (1) , e993. 10.1038/tp.2016.242

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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 Disorder Working 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 and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2 = 0.35; BD II SNP-h2 = 0.25; P = 0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: B Philosophy. Psychology. Religion > BF Psychology
R Medicine > R Medicine (General)
Publisher: Nature Publishing Group
ISSN: 2158-3188
Date of First Compliant Deposit: 22 February 2017
Date of Acceptance: 28 September 2016
Last Modified: 25 Jun 2019 20:50
URI: http://orca.cf.ac.uk/id/eprint/98475

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