A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program

Abstract

Background There are certain pre-existing conditions which leads in increased risk of coronavirus disease 2019 (COVID-19) severity and mortality. The objective of this study is to determine shared genetic architecture between COVID-19 severity and other medical conditions using electronic health record (EHR) data from diverse patient populations. Methods and Findings: We conducted Phenome-wide association study (PheWAS) of genetic variants associated with severe COVID-19 in two biobanks with EHR and genomic data: 1) Veteran Affairs (VA) Million Veteran Program (MVP), 2) United Kingdom Biobank (UKBB). Genetic variants associated with critical illness (n=48) or hospitalization (n=39) due to COVID-19 from COVID-19 Host Genetics Initiative genome-wide association studies. Phenotypes defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods; pre-COVID-19 data used to avoid potential confounding. Among 455,683 US Veterans from MVP, variants associated with severe COVID-19 tested for association across 1,559 phenotypes; 353,365 UK Biobank participants, and 1,064 phenotypes tested. Genetic variants at ABO locus (rs550057, rs505922) associated with the largest number of phenotypes (nrs55057= 53 and nrs505922=61); strongest association with venous embolism, odds ratio (OR)rs550057 1.27 (p=5.28 x 10-116), and thrombosis ORrs505922 1.31, p=3.5 x10-183. Among 67 respiratory conditions tested, only idiopathic pulmonary fibrosis, OR rs2277732 1.17, p=1.3410-05, and asthma ORrs143334143 0.94, p=2.31 x10-04, shared variants with severe COVID-19. The RAVER1 locus (rs74956615) associated with reduced risk for autoimmune conditions, e.g. psoriasis OR 0.71, p= 1.53 x10-22, rheumatoid arthritis, OR 0.78, p=1.04 x 10-09; findings replicated in UKBB. A known functional missense variant (rs34536443, TYK2) in the region had the highest linkage disequilibrium with rs74956615, suggesting signal was likely from TYK2. In MVP, PheWAS results stratified by genetic ancestry did not demonstrate significant difference in associations across ancestry. Conclusions Shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes; associations similar across genetic ancestries. Divergent association between inflammatory conditions and severe COVID may be explained by known pathway impairing signaling of inflammatory cytokines, reducing risk for autoimmunity; same pathway reduces type 1 interferon signaling, critical for viral host defense. Caution needed when targeting pathways that may balance immune tolerance and immunodeficiency to treat COVID-19.

A comprehensive knowledgebase of known and predicted human genetic variants associated with COVID-19 susceptibility and severity

“…The copyright holder for this preprint this version posted November 7, 2022. ; https://doi.org/10.1101/2022.11.03.22281867 doi: medRxiv preprint and immunodeficiency, as well as autoimmune diseases including SLE. These results support the previous studies suggesting that TYK2 has opposing associations with COVID-19 susceptibility and predisposition to autoimmune conditions 32,36 . Notably, the results of all geneset enrichment and pathway analyses are indicative of a role for COVID-19-associated genes in essential immune processes, thereby emphasizing the likely importance of underlying genetic variation on the impaired host immune response to COVID-19 1,3 .…”

“…The other significant finding from PheWAS in the HA cohort was the association of rs35705950 in the proximity of MUC5B with alveolar or parietoalveolar pneumonitis. Our findings support the results of previous studies that showed the rs35705950-T allele being associated with idiopathic pulmonary fibrosis while being a protective variant for COVID-19 32 . Finally, PheWAS in the HA cohort also revealed an association of the rs12979860-T allele in IFNL4 with viral hepatitis and cirrhosis.…”

COVID-19 is associated with the risk of cardiovascular disease death: A two-sample Mendelian randomization study

“…A noteworthy study by Anurag Verma and Matteo D'Antonio showed that rs2277732 was associated with hospitalization and severity of COVID-19, respectively (19,20), whilst the results of the present study similarly found that rs2277732 was associated with both hospitalization and severity of COVID-19 and CVD death, but there exist no studies involving the association of rs2277732 with CVD death. These results suggest that the above-mentioned COVID-19-related SNPs may indirectly increase CVD death through other factors such as blood type, but this is only an inference and needs to be verified by further studies.…”

“…The results of Anurag Verma et al showed that the rs505922 SNP in the ABO blood group gene was significantly associated with COVID-19 severity and hospitalization ( 17 ). Similarly, our findings found an association between both COVID-19 severity and hospitalization and CVD death, with rs505922.…”

A Population-Level Analysis of the Protective Effects of Androgen Deprivation Therapy Against COVID-19 Disease Incidence and Severity

“…Ptpn1 then dephosphorylates the TYK2 protein thereby impeding TYK2-mediated T helper-1 (Th1) differentiation and interferon signaling essential for innate and acquired immune responses to viruses. Recently, a TYK2 missense mutation has been reported to confer high risk for COVID-19 severity ( 32 ). Consequently, androgen suppression of TYK2 signaling in T lymphocytes may be an important determinant of COVID-19 outcome.…”