Published in “Nature Genetics,” the global study finds a strong link between FOXP4 expression and long COVID, offering new hope for diagnostic development.

A global study has uncovered genetic variants linked to an increased risk of long COVID, marking an important step toward understanding the biology of the condition and laying early groundwork for future diagnostic tools.

The recent study, “Genome-wide association study of long COVID,” is published in Nature Genetics, and it identified a significant genetic association between long COVID and variants in the FOXP4 gene, which is known to influence lung function. Higher levels of FOXP4 expression were found in individuals with long COVID, and the risk associated with these variants was consistent across different ancestry groups. This supports the idea that lung-related immune responses play a major role in long COVID, though the condition also involves a wide range of symptoms such as fatigue and cognitive dysfunction.

Future Diagnostic Advancements

For laboratory professionals, the findings from this large-scale genetic study on long COVID represent an important step toward future diagnostic innovation grounded in molecular evidence. While the identified FOXP4 variants and associated immune-lung pathways are not yet predictive at the individual level, they offer valuable insight into the underlying biology of long COVID—insight that can inform the development of biomarker assays and future diagnostic tools. As research advances, lab teams will be essential in validating and implementing potential biomarkers, integrating genetic and proteomic data into routine workflows, and supporting interdisciplinary efforts to transition these discoveries from bench to bedside. Though clinically actionable tests may still be years away, the study underscores the evolving role of the clinical lab in decoding complex, post-viral syndromes through precision diagnostics and collaborative research.

Conducted by the Long COVID Host Genetics Initiative, the study analyzed data from 33 independent studies across 19 countries, involving nearly 16,000 individuals diagnosed with long COVID and about 1.9 million control participants. The research included diverse populations across six genetic ancestries, making it one of the most comprehensive efforts to date using a genome-wide association study (GWAS) approach.

Today’s Clinical Lab reported in 2024 that “As early as spring 2020, people who had survived COVID-19 began publicly sharing their ongoing symptoms and struggles to recover. Originally driven almost entirely by patients, researchers and clinicians eventually responded to the push to investigate these reports, ultimately publishing a study showing that only one in eight participants were symptom-free two months after infection. From that point, research into the post-viral condition, popularly termed ‘long COVID,’ accelerated—from 105 articles published on the topic in 2020 to nearly 5,000 in 2023.”

Studies Continue

In addition to identifying genetic risk factors, the researchers established a causal link between SARS-CoV-2 infection and the development of long COVID, particularly in cases involving severe illness that required hospitalization. The study also explored the overlap between long COVID-associated variants and those related to other diseases, suggesting that both genetic predisposition and environmental factors contribute to the risk of developing long COVID.

Hanna Ollila, PhD, a co-author of the study from the Institute for Molecular Medicine Finland and Massachusetts General Hospital, said, “The findings from our study, and from genome-wide association studies in general, tell about biological mechanisms behind a disease. This can then help to understand the disease better. For example, is it a disease neuronal, immune, metabolic, and so on?”

She also explained that developing a diagnostic test from these findings will take time, as the genetic variants identified don’t have the strong, direct impact seen in mutations like BRCA in breast cancer.

“In other words, they do not strongly predict whether someone will develop long COVID at the individual level. Instead, they highlight the biological systems involved in the disease. In this case, our findings point to immune pathways related to lung function,” Ollila noted.

The researchers reported that as larger sample sizes become available in future studies, the accuracy and depth of genetic analyses will improve. This could help scientists more clearly define the biological underpinnings of long COVID and identify specific biomarkers for diagnosis. Despite the progress made, Ollila commented it could still take a decade or more to develop clinically useful diagnostic tools based on these genetic insights.

—Janette Wider