Journal
BIOLOGICAL PSYCHIATRY
Volume 87, Issue 5, Pages 419-430Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2019.06.031
Keywords
Autoimmune disorder; Complement; Genetic association; Human leukocyte antigen; Major depressive disorder; Major histoconnpatibility complex
Categories
Funding
- UK Medical Research Council [MR/N015746/1]
- National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service (NHS) Foundation Trust and King's College London
- Medical Research Council [MR/N015746/1]
- United States National Institute of Mental Health [U01 MH109528-03]
- United States National Institute of Drug Abuse [U01 MH1095320]
- Netherlands Scientific Organization [480-05-003]
- Dutch Brain Foundation
- Vrije Universiteit Amsterdam
- Deutsche Forschungsgemeinschaft, Germany [RI 908/11-1, NO246/10-1]
- Deutsche Forschungsgemeinschaft, Germany (Excellence Cluster ImmunoSensation)
- German Federal Ministry for Education and Research (BMBF) IntegraMent, Germany [01ZX1314A/01ZX1614A, 01ZX1314G/01ZX1614G]
- BMBF NGFNplus MooDS, Germany [01GS08144, 01GS08147]
- National Health and Medical Research Council, Australia [APP1060524, 941177, 971232, 3399450, 443011]
- Lundbeck Foundation, Denmark [R24-A3242]
- Wellcome Trust, UK [104036/Z/14/Z]
- Medical Research Council, UK [G0200243, G0701420, G0901245]
- EU 6th framework, UK [LSHB-CT-2003-503428]
- EU Innovative Medicines Initiative Joint Undertaking, UK [15008]
- National Institute of Mental Health (NIMH) [R01 MH085542, R01 MH086026]
- Max Planck Society
- Max Planck Excellence Foundation
- BMBF in the National Genome Research Network framework (NGFN2) [FKZ 01GS0481]
- BMBF in the National Genome Research Network framework (NGFN-Plus) [FKZ 01GS0481]
- BMBF [FKZ 01ES0811, 01ER0816]
- German Migraine and Headache Society
- Almirall
- AstraZeneca
- Berlin Chemie
- Boehringer
- Boots Health Care
- Glaxo-Smith-Kline
- Janssen Cilag
- McNeil Pharma
- MSD Sharp and Dohme
- Pfizer
- Institute of Epidemiology and Social Medicine, University of Munster
- Geestkracht program of the Netherlands Organization for Health Research and Development (ZonMw) [10-000-1002]
- Vrije Universiteit Medical Center
- GGZ inGeest
- Leiden University Medical Center
- Leiden University
- GGZ Rivierduinen
- University Medical Center Groningen
- University of Groningen
- Lentis
- GGZ Friesland
- GGZ Drenthe
- Rob Giel Onderzoekscentrum
- Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL)
- Netherlands Organization for Scientific Research (NOW) [480-15-001/674]
- Biobanking and Biomolecular Resources Research Infrastructure [184.021.007, BBMRI-NL2.0 184.033.111]
- BBMRI-NL
- Avera Institute
- Sioux Falls
- SD
- National Institutes of Health (Genetic Association Information Network [GAIN] of the Foundation for the National Institutes of Health) [1RC2 MH089951, 1RC2 MH089995]
- Swiss National Science Foundation, Switzerland [3200B0-105993, 3200B0118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401]
- GlaxoSmithKline
- Faculty of Biology and Medicine of Lausanne
- National Institute on Alcohol Abuse and Alcoholism [AA07535, AA07728, AA10249]
- NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust, and King's College London
- NIMH, UK [U01 MH109528]
- Netherlands Organization of Scientific Research (NWO) [175.010.2005.011, 911-03-012]
- Erasmus Medical Center
- Erasmus University
- Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]
- Ministry of Cultural Affairs
- Social Ministry of the Federal State of Mecklenburg-West Pomerania
- Siemens Healthineers
- Federal State of MecklenburgWest Pomerania
- German Research Foundation [DFG: GR 1912/5-1]
- NIMH [R01 MH-072802, R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289 U01 MH46318, U01 MH79469, U01 MH79470]
- GenomeEUtwin, EU [EU/QLRT-2001-01254, QLG2-CT-2002-01254]
- Heart and Lung foundation, Sweden [20070481]
- SSF, Sweden
- Vetenskapsradet, Sweden [M-2005-1112]
- Guy's and St Thomas' Charity [TR130505]
- Maudsley Charity [980]
- Hojteknologifonden, Denmark [0001-2009-2]
- MRC [MR/L023784/2, G0701420, 1668713, G0200243, MR/N015746/1, G0901245] Funding Source: UKRI
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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 x 10(-6) ) and a candidate threshold (1.6 x 10(-4) ). RESULTS: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLAB*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.
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