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... Show moreBACKGROUND: 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. Show less
Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of... Show moreDepression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (r(g) = 0.24, p = 1.8 x 10(-7) versus r(g) = -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 x 10(-4)). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD. Show less
