Disentangling the common genetic architecture and causality of rheumatoid arthritis and systemic lupus erythematosus with COVID-19 outcomes: genome-wide cross trait analysis and bi-directional Mendelian randomization study

COVID-19 may cause a dysregulation of the immune system and has complex relationships with multiple autoimmune diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, little is known about their common genetic architecture. We analysed summary-level genetic data from the latest COVID-19 host genetics consortium and consortia on RA and SLE to examine the shared genetic etiology and causal relationship between COVID-19 and RA/SLE. The cross-trait meta-analysis identified 46, 47, and 19 shared genetic loci for severe COVID-19, COVID-19 hospitalization, and SARS-CoV-2 infection with RA, and 19, 24, and 11 shared loci with SLE, respectively. Shared genes were significantly enriched in the spleen, lung, whole blood, and small intestine, and involved in immune function, inflammation and coagulation process. Co-localization analysis identified eight shared loci in TYK2, IKZF3, COL11A2, PSORS1C1, MANEAL and COG6 genes for COVID-19 with RA, and four in CRHR1, FUT2 and NXPE3 genes for COVID-19 with SLE. Bi-directional Mendelian randomization analysis suggested RA is associated with a higher risk of COVID-19 hospitalization, and COVID-19 is not related to RA or SLE. Our novel findings improved the understanding of the common genetic aetiology shared by COVID-19, RA and SLE, and suggested an increased risk of COVID-19 hospitalization in people with higher genetic liability to RA.