A large international genetic study has identified specific variants of the FOXP4 gene as key risk factors for developing long COVID, shedding new light on the biology behind the lingering illness.
Researchers analyzed genetic data from nearly 16,000 people with long COVID and close to 1.9 million without it, spanning 19 countries. Their findings, published in Nature Genetics, highlight a strong connection between the FOXP4 gene and long COVID that appears separate from FOXP4’s previously known link to severe COVID-19. This points to the importance of lung-related biology in the development of the condition.
Understanding Long COVID
Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is a condition where people continue to experience symptoms like fatigue, breathing problems, and brain fog for months after recovering from COVID-19. According to the World Health Organization (WHO), these symptoms must appear within three months after infection and last at least two months.
Even though many studies have looked into who is most at risk, the biological reasons behind long COVID remain unclear. To better understand this, the International COVID-19 Host Genetics Initiative (COVID-19 HGI) was formed. It brings together researchers from around the world to study how genes influence COVID-19 and its aftermath.
The Study and Its Approach
The new study used a method called genome-wide association study (GWAS). This method scans people’s DNA to find genetic variants that are more common in those with a specific disease—in this case, long COVID. Researchers then pooled results from 33 different studies, each of which had collected and analyzed genetic data on their own.
They grouped participants into two main categories: people who had long COVID and those who didn’t. The controls included both the general population and people who recovered from COVID-19 without long-term symptoms.
Using a range of analytical tools, including Mendelian randomization (a method to test causal links using genetics), the researchers looked for patterns. They also studied how genes might interact with factors like smoking and whether certain biological pathways were involved in the condition.
Key Findings: FOXP4’s Role in Long COVID
The study found that people with a particular version of the FOXP4 gene—specifically the C allele at a genetic site called rs9367106—had a higher risk of developing long COVID. This variant’s frequency differs among populations, from 1.6% in non-Finnish Europeans to 36% in East Asians, which may affect how easily its effects are detected in different groups.
Further analysis confirmed the link in other groups and pointed to another variant, rs9381074, as a likely contributor to the disease. Notably, people who inherited two copies of the risk allele had a significantly higher risk.
The FOXP4 gene plays a role in lung function and immune response and has previously been linked to severe COVID-19 and lung cancer. Its strong presence in this study supports the theory that lung-related processes are central to long COVID.
Blood samples also showed that long COVID patients had higher levels of FOXP4 expression. This means that not only is the gene present—it may also be more active in people with long COVID.
Other Risk Factors and Protective Elements
The study also confirmed that people who had more severe COVID-19 infections were more likely to develop long COVID. This was shown through genetic markers related to COVID-19 severity.
Smoking was looked at as a possible risk factor. While there was a weak association, it didn’t hold up after adjusting for multiple tests. This suggests that environmental factors like smoking may still play a role, but genetics alone cannot fully explain it.
Vaccination appeared to reduce the risk of long COVID. The link between the FOXP4 variant and long COVID was not significant in people who had been vaccinated, although the sample size for that group was very small—only 40 vaccinated individuals who developed long COVID—so more research is needed.
The gene’s effect also seemed to be stronger before vaccines were widely available and when the virus’s earlier strains, like the original and Alpha variants, were more common.
Low Heritability, High Complexity
While the study found some genetic clues, it also showed that long COVID is not strongly inherited. Heritability estimates ranged from just under 1% to about 12%, depending on how long COVID was defined. This means that most of the risk likely comes from a mix of genetic, environmental, and personal health factors.
Conclusion
This study offers new insight into the genetic basis of long COVID and points to FOXP4 as a key player. It strengthens the link between lung function and long-term effects of COVID-19. The findings also support the idea that long COVID may be influenced by how severe the initial infection was, with a possible role for other factors like smoking
