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Investigating the Genetic Variation Underlying Episodicity in Major Depressive Disorder: Suggestive Evidence for a Bipolar Contribution

Ferentinos, P. and Rivera, M. and Ising, M. and Spain, S.L. and Cohen-Woods, S. and Butler, A.W. and Craddock, N. and Owen, M.J. and Korszun, A. and Jones, Lisa and Jones, I. and Gill, M. and Rice, J.P. and Maier, W. and Mors, O. and Rietschel, M. and Lucae, S. and Binder, E.B. and Preisig, M. and Tozzi, F. and Muglia, P. and Breen, G. and Craig, I.W. and Farmer, A.E. and Müller-Myhsok, B. and McGuffin, P. and Lewis, C.M. (2014) Investigating the Genetic Variation Underlying Episodicity in Major Depressive Disorder: Suggestive Evidence for a Bipolar Contribution. Journal of Affective Disorders, 155. pp. 81-89. ISSN Print: 0165-0327 Online: 1573-2517

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Abstract

Background: Highly recurrent major depressive disorder (MDD) has reportedly increased risk of shifting to bipolar disorder; high recurrence frequency has, therefore, featured as evidence of ‘soft bipolarity’. We aimed to investigate the genetic underpinnings of total depressive episode count in recurrent MDD. Methods: Our primary sample included 1966 MDD cases with negative family history of bipolar disorder from the RADIANT studies. Total episode count was adjusted for gender, age, MDD duration, study and center before being tested for association with genotype in two separate genome-wide analyses (GWAS), in the full set and in a subset of 1364 cases with positive family history of MDD (FH+). We also calculated polygenic scores from the Psychiatric Genomics Consortium MDD and bipolar disorder studies. Results: Episodicity (especially intermediate episode counts) was an independent index of MDD familial aggregation, replicating previous reports. The GWAS produced no genome-wide significant findings. The strongest signals were detected in the full set at MAGI1 (p=5.1×10−7), previously associated with bipolar disorder, and in the FH+ subset at STIM1 (p=3.9×10−6 after imputation), a calcium channel signaling gene. However, these findings failed to replicate in an independent Munich cohort. In the full set polygenic profile analyses, MDD polygenes predicted episodicity better than bipolar polygenes; however, in the FH+ subset, both polygenic scores performed similarly. Limitations: Episode count was self-reported and, therefore, subject to recall bias. Conclusions: Our findings lend preliminary support to the hypothesis that highly recurrent MDD with FH+ is part of a ‘soft bipolar spectrum’ but await replication in larger cohorts.

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Uncontrolled Keywords: bipolar spectrum, major depression, episode count, family history, genome-wide association study, polygenic
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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Depositing User: Lisa Jones
Date Deposited: 16 Jan 2017 12:34
Last Modified: 16 Jan 2017 12:34
URI: https://eprints.worc.ac.uk/id/eprint/5237

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