Phenome-wide HLA association study of Finnish biobank participants reveals infection-autoimmune disease links and modifier effects between HLA genes and alleles

The human leukocyte antigen (HLA) system is the single most important genetic susceptibility factor for many autoimmune diseases and immunological traits. However, in a range of clinical phenotypes the impact of HLA alleles or their combinations on disease risk is not comprehensively understood. For systematic population-level analysis of HLA-phenotype associations we imputed the alleles of classical HLA genes in a discovery cohort of 146,630 and a replication cohort of 89,340 Finnish individuals for whom SNP genotype data and 3,355 disease phenotypes were available as part of the FinnGen project. In total, 3,649 significant single HLA allele associations in 368 phenotypes were found in both cohorts. In addition to known susceptibility alleles, we discovered a number of previously poorly established HLA associations. For example, DRB1*04:01-DQB1*03:02, a frequent high-risk haplotype for many autoimmune diseases, was also independently associated with infectious diseases. Conditional analyses to distinguish protective effects from nonpredisposition showed that in 21 disease categories the effect of the high-risk allele was significantly decreased by a heterozygoous allele in the same locus. Furthermore, in many immunological diseases the strength of the top risk-allele was significantly modified by an HLA gene of a different class. The results highlight the complex structure of HLA-disease associations and suggest that the entire HLA composition should be considered in genetic risk estimation and functional studies. Independent cross-phenotype HLA class II associations imply pleiotropic effects particularly with autoimmune and infectious diseases, supporting a link between environmental exposure and immunogenetics in these diseases.