Genetic links revealed between severe COVID-19 and other diseases
Last Updated on April 29, 2022 by Joseph Gut – thasso
April 30, 2022 – In a very recent report published in PLoS Genetics by Dr. Verma of the Corporal Michael Crescenz VA Medical Center in Philadelphia, Pennsylvania, US, and colleagues, new data from the Veterans Affairs Million Veteran Program (MVP) has uncovered genetic links between COVID-19 disease severity and certain medical conditions that are known risk factors for severe COVID-19.
Some people with COVID-19 experience the disease more severely than others. Previous research has identified certain variants in specific human genes that are associated with a person experiencing more severe COVID-19 disease. Some of these variants may also be associated with other medical conditions that may already be well understood; identifying these shared variants could improve understanding of COVID-19 disease and illuminate potential new paths for treatment.
To identify shared variants, the researchers used an unprecedented dataset of genotypic information linked to electronic health record data (EHR) for more than 650,000 U.S. veterans. They conducted a type of analysis known as a phenome-wide association study (PheWAS) to examine links between variants often found in Veterans who experienced severe COVID-19 and variants associated with a broad selection of medical conditions. Overall, he analysis revealed that certain genetic variants associated with COVID-19 disease are also associated with known risk factors for COVID-19. Particularly strong links were found for variants associated with venous embolism and thrombosis, as well as type 2 diabetes and ischemic heart disease, two known phenotypic COVID-19 risk factors. The analysis also found genetic links between severe COVID-19 disease and neutropenia for Veterans of African and Hispanic ancestry; these links did not appear for those of European ancestry. Among respiratory conditions, idiopathic pulmonary fibrosis and chronic alveolar lung disease shared genetic links with severe COVID-19 disease, but other respiratory infections and chronic obstructive pulmonary disease (COPD) did not.
More detailed, the authors conducted thisPheWAS-study 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. The analysis was performed using genotype-phenotype data from the MVP program. 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 disease 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), and thrombosis (odds ratio ORrs505922 1.33). Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis (odds ratio OR 2.83); CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis (odds ratio OR 0.84). The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis (odds ratio OR 0.88), or lupus (odds ratio OR 0.84). PheWAS stratified by ancestry demonstrated differences in genotype-phenotype associations. LMNA (rs581342) associated with neutropenia (odds ratio OR 1.29) among Veterans of African and Hispanic ancestry but not European. Overall, the researchers observed a shared genetic architecture between COVID-19 disease severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Despite some limitations of the PheWAS method, these findings could help deepen understanding of COVID-19 and guide development of new treatments.
In conclusion, the study demonstrates the value and impact of large biobanks linking genetic variations with EHR data in public health response to the current and future pandemics. MVP is one of the most diverse cohorts in the US. The study addressed a unique opportunity to scan thousands of conditions documented before the COVID-19 pandemic and revealed useful insights into the genetic architecture of COVID-19 risk factors and disease complication. One thing that stood out was the high number of immune-mediated conditions that shared genetic architecture with severe manifestations of COVID-19 disease. The nature of the associations brought to light how the SARS-CoV2 virus pushes on a pressure point in the human immune system and its constant balancing act of fighting infection while maintaining enough control so that it does not also become an autoimmune process attacking self.
See here a short sequence discussing rare genetic variants and Covid-19 disease: