Genome-wide association study of COVID-19 Breakthrough Infections and genetic overlap with other diseases: A study of the UK Biobank

Background: The COVID-19 pandemic has led to substantial health and financial burden worldwide, and vaccines provide hope to reduce the burden of this pandemic. However, vaccinated people remain at risk for SARS-CoV-2 infection. Genome-wide association studies (GWAS) may allow for the identification of potential genetic factors involved in the development of COVID-19 breakthrough infections (BI), however very few or no GWAS have been conducted for COVID-19 BI so far. Methods: We conducted a GWAS and detailed bioinformatics analysis on COVID-19 BI in a European population based on the UK-Biobank (UKBB). We conducted a series of analyses at different levels, including SNP-based, gene-based, pathway, and transcriptome-wide association analyses, to investigate genetic factors associated with COVID-19 BI and hospitalized infection. Polygenic risk score (PRS) and Hoeffding's test were performed to reveal genetic relationships between BI and other medical conditions. Results: Two independent loci (LD-clumped at r2=0.01) reached genome-wide significance (p<5e-08), including rs36170929 mapped to LOC102725191/VWDE, and rs28645263 mapped to RETREG1. Pathway enrichment analysis highlighted pathways such as viral myocarditis, Rho-selective guanine exchange factor AKAP13 signaling, and lipid metabolism. PRS analyses showed significant genetic overlap between COVID-19 BI and heart failure, HbA1c and type 1 diabetes. Genetic dependence was also observed between COVID-19 BI and asthma, lung abnormalities, schizophrenia, and type 1 diabetes, based on the Hoeffding's test. Conclusions: This GWAS study revealed two significant loci that may be associated with COVID-19 BI, and a number of genes and pathways that may be involved in BI. Genetic overlap with other diseases was identified. Further studies are warranted to replicate the findings and elucidate the mechanisms involved.