By Pooja Toshniwal PahariaReviewed by Lexie CornerMay 30 2025A recent study published in Nature Genetics reports a genome-wide association study (GWAS) aimed at identifying genetic factors linked to long-term effects of coronavirus disease 2019 (COVID-19), also known as post-acute sequelae of COVID-19 (PASC).
The study found that variants of the forkhead box P4 (FOXP4) gene are associated with an increased risk of PASC. The findings contribute to an improved understanding of the genetic basis of PASC, which may help inform future therapeutic research. Genetic pathways involving FOXP4 may represent potential targets for intervention.
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Understanding PASC and Its Complexity
According to the World Health Organization (WHO), PASC refers to symptoms that persist beyond three months after SARS-CoV-2 infection and last for at least two additional months. Common symptoms include pulmonary dysfunction, fatigue, and cognitive difficulties.
The wide variability in clinical presentation underscores the complexity of PASC and the importance of research into its underlying molecular and genetic mechanisms.
Study Overview
This meta-analysis explored genetic and molecular contributors to PASC. It included data from 6,450 PASC cases and 1,093,995 controls across 24 GWAS datasets from 16 countries. Cases were classified based on test-confirmed infection (strict definition) and clinician-diagnosed or self-reported symptoms (broad definition).
Controls included both individuals without COVID-19 and those who recovered from acute infection. Common symptoms in case groups included fatigue, shortness of breath, memory loss, and concentration issues.
Key Methods and Genetic Analyses
The researchers identified associations between FOXP4 expression and PASC. They analyzed genetic variants within 30 kilobases (kb) of rs9367106, the primary variant of interest in FOXP4, focusing on individuals of European ancestry from the 1000 Genomes Project and Human Genome Diversity Project.
Linkage disequilibrium (LD) and co-localization analyses were used to assess non-random allele associations and overlap between gene expression signals and PASC risk. Single-cell sequencing (Tabula Sapiens data) was used to identify cell types expressing FOXP4.
Statistical fine mapping was conducted to investigate potentially causal variants. Data from ENCODE, VannoPortal, and RegulomeDB helped assess possible regulatory functions of these variants.
Phenome-wide association studies (PheWAS) were conducted using Biobank Japan data to evaluate FOXP4 variant associations across various diseases. Additional datasets from Open Targets and FinnGen were also analyzed. The team investigated relationships between PASC and traits, including cardiometabolic, psychiatric, and behavioral variables.
Mendelian randomization (MR) assessed genetic contributions to risk, including two-sample MR to examine links between COVID-19 hospitalization and PASC. Sensitivity analyses such as MR-PRESSO and MR-Egger were included to test the robustness of findings.
A fixed-effects inverse variance-weighted (IVW) method was used for the meta-analysis. Researchers also examined how SARS-CoV-2 strain types, disease severity, and vaccination status affected PASC risk. They evaluated the association of FOXP4 with PASC symptoms using data from the Million Veteran Program (MVP) and FinnGen.
Results
The study found that the FOXP4 transcription factor is associated with PASC, independently of its previously reported association with acute COVID-19 severity. This association was replicated in a secondary sample of 9,500 PASC cases and 798,835 controls. FOXP4 is known to play a role in pulmonary conditions, suggesting a potential connection to lung-related symptoms in PASC.
The C allele of the rs9367106 variant in FOXP4 was associated with increased PASC risk (odds ratio: 1.6; risk allele frequency: 4.2 %). PheWAS results showed that this allele was also modestly associated with lung cancer (odds ratio: 1.1). Fine-mapping analyses suggested rs9381074 as a likely causal variant for the FOXP4-PASC association.
Further analyses indicated that PASC is associated with COVID-19-related hospitalization and differential expression of FOXP4 in lung tissue, particularly in type 2 alveolar cells. The FOXP4 variant was also associated with PASC during the early pandemic period, including infections by wild-type and Alpha variants of SARS-CoV-2. Vaccination was found to reduce PASC risk.
Associations were also identified between FOXP4 and specific symptoms (e.g., fatigue) and with the use of certain medications, such as beta-adrenergic blockers.
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Conclusion
The findings suggest that genetic variation in the FOXP4 locus is associated with increased susceptibility to PASC. Elevated FOXP4 expression in lung cells and its known involvement in pulmonary disease suggest a possible role in PASC pathogenesis.
These results highlight the importance of considering genetic risk factors when studying long COVID. Further research may explore how FOXP4-related pathways contribute to the development and progression of PASC, potentially informing clinical risk assessment and targeted interventions.
Journal Reference
Lammi, V., et al. (2025). Genome-wide association study of long COVID. Nat Genet. DOI: 10.1038/s41588-025-02100-w. https://www.nature.com/articles/s41588-025-02100-w
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