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

Coronavirus Disease (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. 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 bidirectional Mendelian randomization (MR). 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. Bidirectional MR 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 genetic etiology shared by COVID-19, RA and SLE, and suggested an increased risk of COVID-19 hospitalization in people with higher genetic liability to RA.

Identifying shared genetic loci between coronavirus disease 2019 and cardiovascular diseases based on cross-trait meta-analysis.

People with coronavirus disease 2019 (COVID-19) have different mortality or severity, and this clinical outcome is thought to be mainly attributed to comorbid cardiovascular diseases. However, genetic loci jointly influencing COVID-19 and cardiovascular disorders remain largely unknown. To identify shared genetic loci between COVID-19 and cardiac traits, we conducted a genome-wide cross-trait meta-analysis. Firstly, from eight cardiovascular disorders, we found positive genetic correlations between COVID-19 and coronary artery disease (CAD, R g = 0.4075, P = 0.0031), type 2 diabetes (T2D, R g = 0.2320, P = 0.0043), obesity (OBE, R g = 0.3451, P = 0.0061), as well as hypertension (HTN, R g = 0.233, P = 0.0026). Secondly, we detected 10 shared genetic loci between COVID-19 and CAD, 3 loci between COVID-19 and T2D, 5 loci between COVID-19 and OBE, and 21 loci between COVID-19 and HTN, respectively. These shared genetic loci were enriched in signaling pathways and secretion pathways. In addition, Mendelian randomization analysis revealed significant causal effect of COVID-19 on CAD, OBE and HTN. Our results have revealed the genetic architecture shared by COVID-19 and CVD, and will help to shed light on the molecular mechanisms underlying the associations between COVID-19 and cardiac traits.