Genetic architecture of the HLA/MHC locus in cardiometabolic disease, severe mental illness, and related traits.

Abstract Background The Human Leucocyte Antigen/Major Histocompatibility Complex (HLA/MHC) locus is highly complex, with very many genetic variants, extensive linkage disequilibrium blocks, population-specific linkage disequilibrium patterns and many genes. So, whilst many traits have been associated with the HLA/MHC locus, it has largely been omitted from post-genome-wide association study analyses. Methods Here we used the UK Biobank cohort to explore the genetic architecture of the HLA/MHC locus in severe mental illness (SMI), cardiometabolic disease (CMD) and related phenotypes. We conducted genetic association analyses of 53,661 variants in up to 402,096 participants, assuming an additive genetic model and adjusting for age, sex, population structure and genotyping chip. In silico follow-up analyses were also conducted. Results We demonstrated that the HLA/MHC locus has multiple signals influencing cardiovascular (SBP, DBP, VTE), metabolic (BMI, WHRadjBMI, T2D) and SMI-related traits (mood instability, anhedonia, neuroticism, risk-taking behaviour and smoking), and provided evidence that HLA-B, HLA-C, C4A, BAG6 and ATF6B might contribute to shared mechanisms underlying CMD and SMI. Conclusions Current understanding of these candidate genes is in keeping with neuroinflammatory mechanisms linking SMI and CMD. Future analyses considering haplotypes and/or SNP scores would enable better assessment of an individual’s risk (as each SNP is considered in the context of other SNPs), allow alignment with clinically used HLA typing and therefore potential for clinical translation.