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.

PURPOSE: 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.

METHODS: Using the latest data from COVID-19 host genetics consortium and consortia on RA and SLE, we conducted a genome-wide cross-trait analysis to examine the shared genetic etiology between COVID-19 and RA/SLE and evaluated their causal associations using bi-directional Mendelian randomization.

RESULTS: The cross-trait meta-analysis identified 23, 28, and 10 shared genetic loci for severe COVID-19, COVID-19 hospitalization, and SARS-CoV-2 infection with RA, and 14, 17, and 7 shared loci with SLE, respectively. Co-localization analysis identified five causal variants in TYK2, IKZF3, PSORS1C1 and COG6 for COVID-19 with RA, and four in CRHR1, FUT2 and NXPE3 for COVID-19 with SLE, involved in immune function, angiogenesis and coagulation. 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.

CONCLUSION: Our novel findings improved the understanding of the 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. This article is protected by copyright. All rights reserved.