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

Kylie P. Glanville, Jonathan R. I. Coleman, Ken B. Hanscombe, Jack Euesden, Shing Wan Choi, Kirstin Purves, Gerome Breen, Tracy M. Air, Till M. F. Andlauer, Bernhard T. Baune, Elisabeth B. Binder, Douglas H. R. Blackwood, Dorret I. Boomsma, Henriette N. Buttenschøn, Lucía Colodro-Conde, Udo Dannlowski, Nese Direk, Erin C. Dunn, Andreas J. Forstner, Eco J. C. de GeusHans Joergen Grabe, Steven P. Hamilton, Ian Jones, Lisa A. Jones, James A. Knowles, Zoltan Kutalik, Douglas F. Levinson, Glyn Lewis, Penelope A. Lind, Susanne Lucae, Susanne Lucae, Patrick K.E. Magnusson., Peter McGuffin, Andrew McIntosh, Yuri Milaneschi, Cathryn M. Lewis, Sara Mostafavi, Bertram Muller-Myhsok, Nancy L. Pedersen, Brenda W. Penninx, James B. Potash, Martin Preisig, Stephan Ripke, Jianxin Shi, Stanley I Shyn, Jordan W. Smoller, Fabian Streit, Patrick F. Sullivan, H Tiemeier, Rudolf Uher, Sandra Van der Auwera, Myrna M. Weissman, Paul F. O'Reilly, Cathryn M. Lewis

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Background: The prevalence of depression is higher in individuals suffering from 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.

Method: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 Human Leukocyte Antigen (HLA) alleles and four Complement Component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium (PGC) Major Depressive Disorder (MDD) working group and the UK Biobank (UKB). 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-e6) and a candidate threshold (1.6e-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% CI = 0.97-0.99).

Discussion: 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 are either rare or have very modest effect sizes.
Original languageEnglish
Pages (from-to)419-430
Number of pages12
JournalBiological psychiatry
Issue number5
Early online date5 Aug 2019
Publication statusPublished - 1 Mar 2020


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


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