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Biol Psychiatry. 2019 Aug 5. pii: S0006-3223(19)31558-6. doi: 10.1016/j.biopsych.2019.06.031. [Epub ahead of print]

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

Collaborators (199)

Wray NR, Ripke S, Mattheisen M, Trzaskowski M, Byrne EM, Abdellaoui A, Adams MJ, Agerbo E, Air TM, Andlauer TFM, Bacanu SA, Bækvad-Hansen M, Beekman ATF, Bigdeli TB, Binder EB, Bryois J, Buttenschøn HN, Bybjerg-Grauholm J, Cai N, Castelao E, Christensen JH, Clarke TK, Coleman JRI, Colodro-Conde L, Couvy-Duchesne B, Craddock N, Crawford GE, Davies G, Deary IJ, Degenhardt F, Derks EM, Direk N, Dolan CV, Dunn EC, Eley TC, Escott-Price V, Hassan Kiadeh FF, Finucane HK, Foo JC, Forstner AJ, Frank J, Gaspar HA, Gill M, Goes FS, Gordon SD, Grove J, Hall LS, Hansen CS, Hansen TF, Herms S, Hickie IB, Hoffmann P, Homuth G, Horn C, Hottenga JJ, Hougaard DM, Howard DM, Ising M, Jansen R, Jones I, Jones LA, Jorgenson E, Knowles JA, Kohane IS, Kraft J, Kretzschmar WW, Kutalik Z, Li Y, Lind PA, MacIntyre DJ, MacKinnon DF, Maier RM, Maier W, Marchini J, Mbarek H, McGrath P, McGuffin P, Medland SE, Mehta D, Middeldorp CM, Mihailov E, Milaneschi Y, Milani L, Mondimore FM, Montgomery GW, Mostafavi S, Mullins N, Nauck M, Ng B, Nivard MG, Nyholt DR, O'Reilly PF, Oskarsson H, Owen MJ, Painter JN, Pedersen CB, Pedersen MG, Peterson RE, Pettersson E, Peyrot WJ, Pistis G, Posthuma D, Quiroz JA, Qvist P, Rice JP, Riley BP, Rivera M, Mirza SS, Schoevers R, Schulte EC, Shen L, Shi J, Shyn SI, Sigurdsson E, Sinnamon GCB, Smit JH, Smith DJ, Stefansson H, Steinberg S, Streit F, Strohmaier J, Tansey KE, Teismann H, Teumer A, Thompson W, Thomson PA, Thorgeirsson TE, Traylor M, Treutlein J, Trubetskoy V, Uitterlinden AG, Umbricht D, Van der Auwera S, van Hemert AM, Viktorin A, Visscher PM, Wang Y, Webb BT, Weinsheimer SM, Wellmann J, Willemsen G, Witt SH, Wu Y, Xi HS, Yang J, Zhang F, Arolt V, Baune BT, Berger K, Boomsma DI, Cichon S, Dannlowski U, de Geus EJC, DePaulo JR, Domenici E, Domschke K, Esko T, Grabe HJ, Hamilton SP, Hayward C, Heath AC, Kendler KS, Kloiber S, Lewis G, Li QS, Lucae S, Madden PA, Magnusson PK, Martin NG, McIntosh AM, Metspalu A, Mors O, Mortensen PB, Müller-Myhsok B, Nordentoft M, Nöthen MM, O'Donovan MC, Paciga SA, Pedersen NL, Penninx BWJH, Perlis RH, Porteous DJ, Potash JB, Preisig M, Rietschel M, Schaefer C, Schulze TG, Smoller JW, Stefansson K, Tiemeier H, Uher R, Völzke H, Weissman MM, Werge T, Lewis CM, Levinson DF, Breen G, Børglum AD, Sullivan PF.

Author information

1
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.
2
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.
3
Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
4
Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
5
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.
6
Discipline of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
7
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Münster, Germany; Munich Cluster for Systems Neurology (SyNergy), Münster, Germany.
8
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.
9
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.
10
Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
11
Department of Biological Psychology and EMGO+ Institute for Health and Care Research, Vrije Universiteit Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
12
NIDO | Danmark, Regional Hospital West Jutland, Herning, Denmark; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark.
13
Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
14
Department of Psychiatry, University of Münster, Münster, Germany.
15
Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Psychiatry, Dokuz Eylul University School Of Medicine, Izmir, Turkey.
16
Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts.
17
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.
18
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.
19
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
20
Department of Psychiatry, Kaiser Permanente Northern California, San Francisco, California.
21
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom.
22
Department of Psychological Medicine, University of Worcester, Worcester, United Kingdom.
23
Psychiatry and the Behavioral Sciences, University of Southern California, Los Angeles, California.
24
Institute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
25
Psychiatry and Behavioral Sciences, Stanford University, Stanford, California.
26
Division of Psychiatry, University College London, London, United Kingdom.
27
Max Planck Institute of Psychiatry, Munich, Germany.
28
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
29
Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.
30
Department of Psychiatry, Amsterdam Universiteit Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
31
iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark; Psychosis Research Unit, Aarhus University Hospital, Risskov, Aarhus, Denmark.
32
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada; Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada.
33
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.
34
Psychiatry, University of Iowa, Iowa City, Iowa.
35
Department of Psychiatry, University Hospital of Lausanne, Prilly, Switzerland.
36
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.
37
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
38
Behavioral Health Services, Kaiser Permanente Washington, Seattle, Washington.
39
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
40
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
41
Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Child and Adolescent Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands; Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.
42
Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
43
Division of Epidemiology, New York State Psychiatric Institute, New York, New York; Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York.
44
Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.

Abstract

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.

KEYWORDS:

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

PMID:
31570195
DOI:
10.1016/j.biopsych.2019.06.031
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