Genetic Study Links FOXP4 Gene to Long COVID Symptoms Worldwide

In a significant breakthrough in understanding long COVID, a recent genome-wide association study (GWAS) has identified the FOXP4 gene as a critical factor associated with prolonged symptoms following SARS-CoV-2 infection. This research, published in the esteemed journal Nature Genetics on June 16, 2025, is part of a broader effort to comprehend why certain individuals continue to experience debilitating effects long after recovering from the acute phase of COVID-19.

Long COVID, formally known as post-acute sequelae of SARS-CoV-2 infection (PASC), encompasses a wide range of symptoms including persistent fatigue, respiratory issues, and cognitive dysfunction. The World Health Organization defines long COVID as symptoms that arise within three months of infection and last for at least two months without another explanation, posing a challenge to healthcare systems worldwide.

The GWAS, spearheaded by the COVID-19 Host Genetics Initiative at the Germans Trias i Pujol Research Institute in Spain, analyzed genetic data from over 6,450 long COVID cases alongside more than one million population controls across six global ancestries. This comprehensive approach not only underscores the importance of genetic diversity in research but also aims to uncover inherited differences that may contribute to varying recovery experiences among individuals.

The researchers discovered a significant genetic association near the FOXP4 gene, particularly a variant known as rs9367106. This variant was linked to a 63% increase in the likelihood of developing long COVID symptoms among carriers compared to non-carriers. Importantly, this association persisted even among individuals who did not require hospitalization during their initial COVID-19 infection, indicating that factors beyond the severity of the initial illness are at play.

The variant's prevalence varied significantly among different populations, with approximately 1.6% of non-Finnish Europeans carrying it, compared to up to 36% of East Asians. This disparity highlights the necessity for inclusive genetic studies that represent diverse populations, as the findings could have significant implications for understanding long COVID across different demographic groups.

To elucidate the connection between FOXP4 and long COVID, the research team investigated the gene's activity in various tissues. They found that FOXP4 is particularly active in lung tissue, suggesting that genetic variations may influence lung functionality and the body's response to respiratory infections. The study revealed that individuals with higher levels of FOXP4 expression in their lungs had more than double the odds of developing long COVID symptoms, reinforcing the gene's potential role in the condition.

The implications of this research are particularly pertinent in the context of India, where a large and diverse population has faced multiple waves of COVID-19. Indian studies have reported long COVID prevalence rates ranging from 45% to nearly 80%, highlighting a significant public health concern. However, the limited representation of South Asian populations in previous genetic studies raises questions about the applicability of these findings within the Indian context.

India's GenomeIndia Project, which aims to build a comprehensive genomic database, has begun addressing these gaps. By cataloging genetic variations across diverse Indian populations, future studies can enhance understanding of genetic factors influencing long COVID locally, facilitating improved public health responses and tailored treatments.

Despite its promise, the study acknowledges several limitations. Most genetic data were collected prior to widespread vaccination and the emergence of new variants like Omicron, suggesting that the relevance of these findings may evolve. Furthermore, the research team cautioned that the overall genetic contribution to long COVID symptoms appears modest, indicating that additional factors, including immune responses and pre-existing health conditions, significantly impact recovery trajectories.

In conclusion, the identification of the FOXP4 gene as a potential contributor to long COVID symptoms marks a pivotal advancement in genetic research related to the pandemic. This study not only sheds light on the biological underpinnings of long COVID but also emphasizes the critical need for inclusive research practices that acknowledge genetic diversity. As the global community continues to grapple with the long-term effects of COVID-19, such insights will be invaluable in shaping future healthcare strategies and improving patient outcomes. Anirban Mukhopadhyay, a geneticist and science communicator from Delhi, underscores the importance of these findings in addressing the ongoing challenges posed by long COVID.