Novel genetic loci, lifestyle factors, and inflammatory markers identified as risk factors for sarcoidosis

Abstract We carried out a genome-wide association and Mendelian randomization analysis to probe genetic and environmental risk factors for sarcoidosis. We performed a genome-wide meta-analysis in 5,194 sarcoidosis cases and 777,559 non-cases from the FinnGen and UK Biobank studies. We estimated the heritability, pinpointed genomic risk loci, predicted deleteriousness, mapped corresponding genes, and enriched gene expression to tissues using FUMA (Functional Mapping and Annotation) and MAGMA (Multi-marker Analysis of GenoMic Annotation) softwares. We performed Mendelian randomization analyses to investigate the links between 6 modifiable factors and 66 inflammatory markers in relation to sarcoidosis. Genetic variants associated with these exposures at the genome-wide significance level and in low linkage disequilibrium were used as instrumental variables. The heritability of sarcoidosis explained by common genetic variants was around 12%. We annotated 14 genomic loci that surpassed the genome-wide significance threshold of which 6 loci were previously unreported. The locus proximal to TYK2 had a high potential deleterious impact on protein function. MAGMA revealed notable gene expression patterns in whole blood, spleen, and lung. Genetically predicted lower levels of physical activity and higher levels of body mass index, interleukin-23 receptor, and interleukin 1 receptor-like 2 were associated with a heighted risk of sarcoidosis.