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Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression

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  • Kylie P Glanville, Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom. Electronic address: kylie.glanville@kcl.ac.uk.
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  • Jonathan R I Coleman, Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre South London and Maudsley National Health Service Trust, King's College London, London, United Kingdom.
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  • Ken B Hanscombe, Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
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  • Jack Euesden, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, PO80, De De Crespigny Park, Denmark Hill United Kingdom.
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  • Shing Wan Choi, Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, New York, New York.
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  • Kirstin L Purves, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, PO80, De De Crespigny Park, Denmark Hill United Kingdom.
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  • Gerome Breen, Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre South London and Maudsley National Health Service Trust, King's College London, London, United Kingdom.
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  • Tracy M Air, Discipline of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
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  • Till F M Andlauer, Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Münster, Germany; Munich Cluster for Systems Neurology (SyNergy), Münster, Germany.
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  • Bernhard T Baune, Department of Psychiatry, Melbourne Medical School, University of Melbourne, Melbourne, Victoria, Australia; Florey Institute for Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia; Department of Psychiatry, University of Münster, Münster, Germany.
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  • Elisabeth B Binder, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Emory University, Atlanta, Georgia; Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Münster, Germany.
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  • Douglas H R Blackwood, Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
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  • Dorret I Boomsma, Department of Biological Psychology and EMGO+ Institute for Health and Care Research, Vrije Universiteit Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
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  • Henriette N Buttenschøn
  • Lucía Colodro-Conde, Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
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  • Udo Dannlowski, Department of Psychiatry, University of Münster, Münster, Germany.
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  • Nese Direk, Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Psychiatry, Dokuz Eylul University School Of Medicine, Izmir, Turkey.
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  • Erin C Dunn, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, United States; Department of Psychiatry, Harvard Medical School, Boston, MA, United States; Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge, MA, United States; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, United States.
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  • Andreas J Forstner, Institute of Human Genetics, School of Medicine and University Hospital Bonn, University of Bonn, Bonn, Germany; Centre for Human Genetics, University of Marburg, Marburg, Germany; Department of Psychiatry, University of Basel, Basel, Switzerland; Department of Biomedicine, University of Basel, Basel, Switzerland.
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  • Eco J C de Geus, Department of Biological Psychology and EMGO+ Institute for Health and Care Research, Vrije Universiteit Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Amsterdam Public Health Institute, Vrije Universiteit Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
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  • Hans J Grabe, Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
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  • Steven P Hamilton, Department of Psychiatry, Kaiser Permanente Northern California, San Francisco, California.
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  • Ian Jones, Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom.
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  • Lisa A Jones, Department of Psychological Medicine, University of Worcester, Worcester, United Kingdom.
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  • James A Knowles, Department of Psychiatry and The Behavioral Sciences, University of Southern California, Los Angeles, CA, USA.
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  • Zoltán Kutalik, Institute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
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  • Douglas F Levinson, Stanford University
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  • Glyn Lewis, Division of Psychiatry, University College London (UCL), London, United Kingdom.
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  • Penelope A Lind, Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
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  • Susanne Lucae, Max Planck Institute of Psychiatry, Munich, Germany.
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  • Patrik K Magnusson, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
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  • Peter McGuffin, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, PO80, De De Crespigny Park, Denmark Hill United Kingdom.
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  • Andrew M McIntosh, Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, United Kingdom.
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  • Yuri Milaneschi, Vrije Universiteit Amsterdam
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  • Ole Mors
  • Sara Mostafavi, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada; Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada.
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  • Bertram Müller-Myhsok, University of Liverpool, Liverpool, United Kingdom; Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Münster, Germany; Munich Cluster for Systems Neurology (SyNergy), Münster, Germany.
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  • Nancy L Pedersen, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
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  • Brenda W J H Penninx, Vrije Universiteit Amsterdam
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  • James B Potash, Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA.
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  • Martin Preisig, Department of Psychiatry, University Hospital of Lausanne, Prilly, Switzerland.
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  • Stephan Ripke, Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts; Department of Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Department of Psychiatry and Psychotherapy, Universitätsmedizin Berlin Campus Charité Mitte, Berlin, Germany.
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  • Jianxin Shi, Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
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  • Stanley I Shyn, Behavioral Health Services, Kaiser Permanente Washington, Seattle, Washington.
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  • Jordan W Smoller, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, United States; Department of Psychiatry, Harvard Medical School, Boston, MA, United States; Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge, MA, United States; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, United States.
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  • Fabian Streit, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, D-68159 Mannheim, Germany.
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  • Patrick F Sullivan, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17176, Sweden; Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USA.
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  • Henning Tiemeier, ISGlobal Center for Research in Environmental Epidemiology, Doctor Aiguader 88, 08003 Barcelona, Spain; Pompeu Fabra University, Carrer Ramon Trias Fargas, 25-27, 08005 Barcelona, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5, Madrid, Spain; Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Centre-Sophia Children's Hospital, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
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  • Rudolf Uher, d Department of Psychiatry , Dalhousie University , Halifax , Nova Scotia , Canada.
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  • Sandra Van der Auwera, Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
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  • Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

BACKGROUND: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression.

METHODS: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10-6) and a candidate threshold (1.6 × 10-4).

RESULTS: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97-0.99).

CONCLUSIONS: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.

Original languageEnglish
JournalBiological Psychiatry
Volume87
Issue5
Pages (from-to)419-430
Number of pages12
ISSN0006-3223
DOIs
Publication statusPublished - 1 Mar 2020

    Research areas

  • Autoimmune disorder, Complement, Genetic association, Human leukocyte antigen, Major depressive disorder, Major histocompatibility complex

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