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

Abstract

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n = 35) or hospitalization (n = 42) due to severe COVID-19 using genome-wide association summary data from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828 = 53 and nrs505922 = 59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p = 1.32 x 10−199), and thrombosis ORrs505922 1.33, p = 2.2 x10-265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p = 4.12 × 10−191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p = 2.26× 10−12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p = 6.48 x10-23, lupus OR 0.84, p = 3.97 x 10−06. PheWAS stratified by ancestry demonstrated differences in genotype-phenotype associations. LMNA (rs581342) associated with neutropenia OR 1.29 p = 4.1 x 10−13 among Veterans of African and Hispanic ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets. Author summary: Large population based genomic studies have discovered genetic variations associated with severe manifestations of Coronarvirus Disease 2019 (COVID-19). In this study, we screened for other human conditions that share associations with these same variants. Understanding shared genetic variants in known conditions, where the pathophysiology is better understood, can further inform the pathways by which SARS-CoV2, the virus that causes COVID-19, impacts multiple organ systems. While genetic variants associated with severe COVID-19 were also associated with known risk factors and poor outcomes related to COVID-19 such as deep venous thrombosis, a large subset of these variants were also associated with reduced risk of conditions largely comprised of immune-mediated diseases, e.g., psoriasis, lupus, rheumatoid arthritis. With regards to the latter, the shared genetic architecture between COVID-19 and immune-mediated conditions suggests that pathways controlling both immune tolerance and immunodeficiency are important for COVID-19 severity, with implications when considering targeting these pathways for treatment.

Publication information

Originally published in PLOS Genetics on 2022-04-28. Original DOI: 10.1371/journal.pgen.1010113.

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