Genome-Wide Association for Sarcoidosis: a Multi-Ancestry Meta-Analysis from Four International Datasets

BACKGROUNDS Sarcoidosis is a multisystem inflammatory disease that presents a wide range of clinical manifestations but mainly affecting the lungs and lymph nodes. The etiology is unknown, although it is assumed that multiple factors, including environmental factors and genetic risk, interplay into determining the phenotype, but the precise roles of the factors are still poorly clarified. As for genetic risk, multiple genes and loci have been associated to sarcoidosis through genome-wide association studies. In our study we conducted a European ancestry, an African ancestry and a multi-ancestry meta-analyses of summary statistics of four GWAS for sarcoidosis. We aimed to identify novel ancestry-specific risk loci and compared our findings with available literature. METHODS We accessed public summary statistics from four international datasets (FinnGen freeze 12, Pan-UK Biobank Project, Million Veteran Project, and Biobank Japan) to conduct European (EUR) ancestry, African (AFR) ancestry and multi-ancestry meta-analyses, and performed risk loci plotting and annotation through FUMA GWAS. ANNOVAR and CADD were used for functional annotation. We identified novel risk loci and SNPs significantly associated to sarcoidosis and critically searched for studies in the literature that have previously identified or described a function that can be related to sarcoidosis. RESULTS We analyzed 9,659 cases and 1,665,804 controls from the four datasets. We found nineteen risk loci from EUR meta-analysis and two risk loci from AFR meta-analysis, including novel risk loci. We reviewed the following significantly associated to sarcoidosis SNPs and their nearest non-MHC genes with functional studies and GWAS available in literature: IL23R, PUS10, ACOXL, PLCL1, FAM117B, PPARG, ESYT2, ANXA11, CCDC88B, ATXN2,SH2B3, CCL24, HOMER2, CD19, UBASH3A, RNF215, MAT1A, RPS6KA4/MSK2, MACROD1, LAT,RP11-231C14.10,RP11-264B17.3 and SUMO2P. CONCLUSION In summary, we present the largest ancestry-specific GWAS meta-analysis for sarcoidosis (EUR and AFR) and the first multi-ancestry meta-analysis including EUR, AFR and East Asian ancestry (EAS) to date. A total of twenty-one loci were identified in EUR and AFR ancestry meta-analyses. We confronted significantly associated to sarcoidosis non-MHC genes and SNPs with available studies in the literature. We hope that our findings contribute to elucidate the role of genetics in sarcoidosis.