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Genome-wide association study identifies multiple HLA loci for sarcoidosis susceptibility

Sarcoidosis is a complex systemic disease. Our study aimed to 1) identify novel alleles associated with sarcoidosis susceptibility; 2) provide an in-depth evaluation of HLA alleles and sarcoidosis susceptibility; 3) integrate genetic and transcription data to identify risk loci that may more directly impact disease pathogenesis. We report a genome-wide association study of 1,335 sarcoidosis cases and 1,264 controls of European descent (EA) and investigate associated alleles in a study of African Americans (AA: 1,487 cases and 1,504 controls). The EA cohort was recruited from National Jewish Health, Cleveland Clinic, University of California San Francisco, and Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis. The AA cohort was from a previous study with subjects enrolled from multiple United States sites. HLA alleles were imputed and tested for association with sarcoidosis susceptibility. Expression quantitative locus and colocalization analysis were performed using a subset of subjects with transcriptome data. 49 SNPs in HLA-DRA, -DRB9, -DRB5, -DQA1, and BRD2 genes were significantly associated with sarcoidosis susceptibility in EA. Among them, rs3129888 was also a risk variant for sarcoidosis in AA. Classical HLA alleles DRB1*0101, DQA1*0101, and DQB1*0501, which are highly correlated, were also associated with sarcoidosis. rs3135287 near HLA-DRA was associated with HLA-DRA expression in peripheral blood mononuclear cells and bronchoalveolar lavage. In summary, we identified several novel SNPs and three HLA alleles associated with sarcoidosis susceptibility in the largest EA population evaluated to date using an integrative analysis of genetics and transcriptomics. We also replicated our findings in an AA population.