TY - JOUR T1 - Genetic variation in the Major Histocompatibility Complex and association with depression JF - bioRxiv DO - 10.1101/469023 SP - 469023 AU - Kylie P Glanville AU - Jonathan R I Coleman AU - Ken B Hanscombe AU - Jack Euesden AU - Shing Wan Choi AU - Kirstin L Purves AU - Gerome Breen AU - Tracy M Air AU - Till F M Andlauer AU - Bernhard T Baune AU - Elisabeth B Binder AU - Douglas H R Blackwood AU - Dorret I Boomsma AU - Henriette N Buttenschøn AU - Lucía Colodro-Conde AU - Udo Dannlowski AU - Nese Direk AU - Erin C Dunn AU - Andreas J Forstner AU - Eco JC de Geus AU - Hans J Grabe AU - Steven P Hamilton AU - Ian Jones AU - Lisa A Jones AU - James A Knowles AU - Zoltán Kutalik AU - Douglas F Levinson AU - Glyn Lewis AU - Penelope A Lind AU - Susanne Lucae AU - Patrik K Magnusson AU - Peter McGuffin AU - Andrew M McIntosh AU - Yuri Milaneschi AU - Ole Mors AU - Sara Mostafavi AU - Bertram Müller-Myhsok AU - Nancy L Pedersen AU - Brenda WJH Penninx AU - James B Potash AU - Martin Preisig AU - Stephan Ripke AU - Jianxin Shi AU - Stanley I Shyn AU - Jordan W Smoller AU - Fabian Streit AU - Patrick F Sullivan AU - Henning Tiemeier AU - Rudolf Uher AU - Sandra Van der Auwera AU - Myrna M Weissman AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium AU - Paul F O’Reilly AU - Cathryn M Lewis Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/11/19/469023.abstract N2 - Background The prevalence of depression is higher in individuals suffering from autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Epidemiological findings point to a bi-directional relationship - that depression increases the risk of developing an autoimmune disease, and vice-versa. Shared genetic etiology is a plausible explanation for the overlap between depression and autoimmune diseases. 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). In the 26 PGC-MDD studies, cases met a lifetime diagnosis of MDD, determined by a structured diagnostic interview. In the UKB, cases and controls were identified from an online mental health questionnaire. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants in each study and performed an inverse-variance weighted meta-analysis across the PGC-MDD and UKB samples, applying both a conservative 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 conservative threshold in the PGC, UKB or meta-analysis. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold in the meta-analysis. Under the conservative threshold, 70 SNPs were detected in the UKB and 143 SNPs were detected in the meta-analysis, mirroring previous findings from highly powered GWAS of depression.Discussion We found no evidence that HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia, confer risk for depression. These results indicate that autoimmune diseases and depression do not share common risk loci of moderate or large effect in the MHC. ER -