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A recessive genetic model and runs of homozygosity in major depressive disorder

Authors

  • Robert A. Power,

    Corresponding author
    1. MRC Social Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom
    • Correspondence to:

      Robert A. Power, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom.

      E-mail: robert.r.power@kcl.ac.uk

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  • Matthew C. Keller,

    1. Department of Psychology and Neuroscience, University of Colorado at Boulder, Boulder, Colorado
    2. Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, Colorado
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  • Stephan Ripke,

    1. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
    2. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts
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  • Abdel Abdellaoui,

    1. Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands
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  • Naomi R. Wray,

    1. The University of Queensland, Queensland Brain Institute, Brisbane, Australia
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  • Patrick F. Sullivan,

    1. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
    2. Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
    3. Department of Psychiatry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
    4. Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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  • MDD PGC Working Group,

  • Gerome Breen

    1. MRC Social Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom
    2. NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Foundation Trust, London, United Kingdom
    3. Institute of Psychiatry, King's College London, London, United Kingdom
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  • The authors declare no conflicts of interest.

Abstract

Genome-wide association studies (GWASs) of major depressive disorder (MDD) have yet to identify variants that surpass the threshold for genome-wide significance. A recent study reported that runs of homozygosity (ROH) are associated with schizophrenia, reflecting a novel genetic risk factor resulting from increased parental relatedness and recessive genetic effects. Here, we explore the possibility of such a recessive model in MDD. In a sample of 9,238 cases and 9,521 controls reported in a recent mega-analysis of 9 GWAS we perform an analysis of ROH and common variants under a recessive model. Since evidence for association with ROH could reflect a recessive mode of action at loci, we also conducted a genome-wide association analyses under a recessive model. The genome-wide association analysis using a recessive model found no significant associations. Our analysis of ROH suggested that there was significant heterogeneity of effect across studies in effect (P = 0.001), and it was associated with genotyping platform and country of origin. The results of the ROH analysis show that differences across studies can lead to conflicting systematic genome-wide differences between cases and controls that are unaccounted for by traditional covariates. They highlight the sensitivity of the ROH method to spurious associations, and the need to carefully control for potential confounds in such analyses. We found no strong evidence for a recessive model underlying MDD. © 2014 Wiley Periodicals, Inc.

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