Abstract

BackgroundThe 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. MethodsWe 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). ResultsNo 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). ConclusionsWe 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.

Highlights

  • The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown

  • The major histocompatibility complex (MHC) is divided into 3 functionally distinct regions: class I and II regions contain highly polymorphic human leukocyte antigen (HLA) genes that are strongly associated with risk for autoimmune disease [19,20,21], and the class III region contains complement component 4 (C4) genes, which are strongly associated with risk for schizophrenia [22]

  • To further understand the mechanisms driving comorbid autoimmunity and depression, we investigated evidence for shared genetic influences in the MHC, a region harboring genetic risk for autoimmune diseases and psychiatric disorders

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Summary

Introduction

The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 3 1026) and a candidate threshold (1.6 3 1024). RESULTS: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. 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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