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J Affect Disord. 2014 Feb;155:81-9. doi: 10.1016/j.jad.2013.10.027. Epub 2013 Oct 29.

Investigating the genetic variation underlying episodicity in major depressive disorder: suggestive evidence for a bipolar contribution.

Author information

  • 1MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom. Electronic address: panagiotis.ferentinos@kcl.ac.uk.
  • 2MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom; Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, University of Granada, Spain.
  • 3Max Planck Institute of Psychiatry, Munich, Germany.
  • 4Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, United Kingdom.
  • 5Department of Psychiatry, University of Adelaide, Adelaide, Australia.
  • 6MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom; Department of Psychiatry, University of Hong Kong, Hong Kong, Special Administrative Region, China.
  • 7MRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom.
  • 8Barts and The London Medical School, Queen Mary University of London, London, United Kingdom.
  • 9Department of Psychiatry, Neuropharmacology & Neurobiology Section, University of Birmingham, Birmingham, United Kingdom.
  • 10Department of Psychiatry, Trinity Centre for Health Science, Dublin, Ireland.
  • 11Department of Psychiatry, Washington University, St. Louis, Missouri, United States.
  • 12Department of Psychiatry, University of Bonn, Bonn, Germany.
  • 13Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark.
  • 14Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
  • 15University Hospital Center and University of Lausanne, Lausanne, Switzerland.
  • 16Aptuit Center for Drug Discovery & Development, Verona, Italy.
  • 17Department of Psychiatry, University of Toronto, Toronto, Canada.
  • 18MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom; NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, King's College London, London, United Kingdom.
  • 19MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom.
  • 20MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, 16 De Crespigny Park, London SE5 8AF, United Kingdom; Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, United Kingdom.

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.

© 2013 Published by Elsevier B.V.

KEYWORDS:

Bipolar spectrum; Episode count; Family history; Genome-wide association study; Major depression; Polygenic

PMID:
24215895
[PubMed - indexed for MEDLINE]
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