Dissecting the Shared Genetic Architecture of Modifiable Physical Activity and Autoimmune Diseases

BackgroundAutoimmune diseases (ADs) represent a diverse group of chronic conditions that significantly contribute to global disease burden and mortality. Physical activities (PAs) are recognized as key modifiable lifestyle factors for ADs, with numerous epidemiological studies confirming their strong association. Despite this established link, the shared genetic determinants underlying these associations remain largely unexplored. MethodsUsing large-scale and comprehensive GWAS summary statistics, we investigated the shared genetic basis between PAs and ADs and explored their vertical and horizontal pleiotropy in detail, including causal relationships, single nucleotide polymorphisms, genes, and biological pathways. Our study revealed extensive genetic associations and overlaps between PAs and ADs. ResultsActive PAs generally show negative genetic correlations with ADs, whereas inactive PAs demonstrate positive genetic correlations. From the standpoint of vertical pleiotropy, our results established causal links between specific trait pairs, including Leisure screen time (LST)-Rheumatoid arthritis, LST-Systemic lupus erythematosus, and Sedentary commuting-Type 1 diabetes. In terms of horizontal pleiotropy, we identified 226 loci encompassing 324 significant pleiotropic genes. Notably, GPX1, RHOA, BSN, and MST1 (all located at 3p21.31) emerged as key genes, underscoring the critical roles of T cell activation and lysosomal trafficking pathways in mediating the genetic associations between PAs and ADs. ConclusionsOur findings suggest a shared genetic architecture and underlying mechanisms between PAs and ADs. This study presents the first comprehensive effort of the shared genetic architecture between physical activities and autoimmune diseases but also opens new avenues for the prevention of ADs through increased PAs.