Prioritizing long COVID related single nucleotide polymorphisms by mining genome-wide association studies of COVID-19 susceptibility and hospitalization.

Long coronavirus disease (COVID) presents a significant public health challenge, characterized by over 200 reported symptoms across multiple organ systems. Genetic studies of long COVID have been hindered by the disorder's symptom heterogeneity and the limited sample size of available datasets. To overcome these challenges, a proxy-based, hypothesis-generating strategy was conducted to prioritize candidate risk loci on studying long COVID by analyzing GWAS summary statistics of coronavirus disease 2019 (COVID-19) susceptibility, hospitalization, and long COVID from the COVID-19 Host Genetics Initiative (Release 7), resulting in 62 candidate loci represented by independent variants. These variants are grouped into three categories: (1) severe COVID-19-specific variants, exhibiting reduced signals in non-hospitalized cases; (2) variants associated with both severe and mild COVID-19, and (3) non-hospitalization-specific variants associated with mild cases. Evaluation using recently published long COVID datasets from the same consortium demonstrated that most candidate variants displayed weaker associations around nominal significance, with only a single genome-wide significant signal at rs12660421 of FOXP1. Integrative gene expression analyses further demonstrated that genes near these candidate loci exhibits weaker associations with long COVID than with acute COVID-19 outcomes. However, broader phenome-wide analyses identified 52 genes linked to traits relevant to long COVID. These candidate loci are warranted for further investigation.