Integrative Genome-Wide Association Studies of COVID-19 Susceptibility and Hospitalization Reveal Risk Loci for Long COVID

Long COVID presents a significant public health challenge, characterized by over 200 reported symptoms spanning multiple organ systems, and genome-wide association studies (GWAS) have been hindered by the disorders symptom heterogeneity and the limited power of available datasets. To overcome the challenges of limited sample size or heterogeneity of long COVID cohorts, a proxy-based, hypothesis-generating strategy is conducted to prioritize candidate risk loci that may contribute to long COVID by analyzing GWAS summary statistics for COVID-19 susceptibility and hospitalization, as well as long COVID from the COVID-19 Host Genetics Initiative (HGI, Release 7), resulting in 62 candidate loci represented by independent single nucleotide polymorphisms (SNPs). These SNPs are categorized into three groups based on their association with acute-phase COVID-19: (1) severe COVID-19-specific SNPs, such as SNPs mapped to two well-known loci involved in SARS-CoV2 entry (ACE2 [rs190509934] and TMPRSS2 [rs12329760]), as well as variants of DPP9 (rs7251000), FOXP4 (rs12660421) and HLA-DQA1 (rs17219281), exhibiting associations with severe COVID-19 but displaying weaker signals in non-hospitalized COVID-19 cases; (2) SNPs associated with both severe and mild COVID-19, including the SNP close to ABO (rs505922); and (3) non-hospitalization-specific SNPs, such as variants in KCTD16 (rs62401842) and WASF3 (rs56143829), highlighting genetic contributors specific to mild COVID-19 cases. These candidate SNPs are investigated with recently published long COVID GWAS data from HGI, revealing most of these candidate SNPs display much weaker association with long COVID. Further transcriptome-wide association studies (TWASs) for GWASs of COVID-19 hospitalization/susceptibility/long COVID across 48 GTEx tissues demonstrate that genes adjacent to these candidate SNPs (43 out of 62 SNPs) exhibits relatively weaker association signals in long COVID across heart, brain, and muscle-related tissues, particular for notable TWAS hits, DPP9 (rs7251000), CCR1 (rs17078348), and THBS3 (rs41264915) that display much weaker association in long COVID compared to acute-phase COVID-19. Phenome-wide TWASs also link HLA-DQA1 (rs17219281), HLA-A (rs9260038), and HLA-C (rs1634761), GSDMB (rs9916158) and FOXP4 (rs12660421) with other phenotypes closely relevant to long COVID. These results provide new insights to long COVID by leveraging acute-phase COVID-19.