HLA-disease association and pleiotropy landscape in over 235,000 Finns

The human leukocyte antigen (HLA) system is the single most important genetic susceptibility factor for many autoimmune diseases and immunological traits. For systematic population-level analysis of HLA-phenotype association landscape we imputed the alleles of classical HLA genes in a discovery cohort of 146,630 and replication cohort of 89,340 Finns of whom SNP genotype data and 3,355 disease phenotypes were available as part of the FinnGen project. In total, 3,649 statistically significant single HLA allele associations in 368 phenotypes were found. Known susceptibility associations clearly dominated the landscape but we discovered also a few previously poorly established HLA associations such as DQA1*01:03 and DQB1*06:03 with mental and behavioural disorders due to cannabinoids (p-value = 10^-5; beta = 0.6). As certain HLAs were found to be involved in both autoimmune and infectious diseases, we studied further the independence of their associations and statistical pleiotropy. We found that altogether 11 shared HLA alleles were associated independently with both autoimmune and infectious diseases. The most prominent of these were DQA1*03:01 and DQB1*03:02 both of which associated with three infectious and three autoimmune phenotypes. All the shared HLAs showed risk effects in both disease groups, suggesting that infections can increase the risk for autoimmune diseases. The population-level landscape analysis is an excellent resource for estimating the contribution and genetic models of HLA genes in many different phenotypes and for fine-mapping primary associations.