Study details and key findings

For over three years, the global COVID-19 Host Genetics Initiative has been searching for potential DNA sequences associated with a risk of developing severe COVID-19. So far, the effort has identified genes involved in the immune system and in allowing the coronavirus to enter cells. The new pre-print long COVID study is a spin-off from this original initiative.

In the new study published in medRxiv, researchers analyzed data from 24 studies that included 6,450 individuals diagnosed with long COVID, as well as 1,093,995 controls, from 16 countries.

In one analysis of 11 studies, researchers identified a DNA sequence near the FOXP4 gene that was associated with a roughly 1.6-fold higher risk of developing long COVID.  The FOXP4 gene is active in the lungs and other organs. It has also been linked to an increased risk of severe COVID-19, as well as lung cancer.

Although having severe COVID-19 will increase an individual's risk of long COVID, the researchers found that the DNA variant's association to long COVID risk was too large to be explained by just its link to severe COVID-19.

"This variant has a much stronger impact on long COVID than its impact on severity," said Hugo Zeberg, a geneticist at the Karolinska Institute in Stockholm and a lead author of the study.

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The study's data is still preliminary, and more research is needed to validate the findings.

According to Zhongshan Cheng, a bioinformatician at St. Jude Children's Research Hospital, much of the data used in the current study was also used in the analysis that originally found an association between the FOXP4 gene and severe COVID-19. New data would help rule out the possibility of other factors, such as lung cancer, influencing the association with the FOXP4 gene.

"It's very important that this type of study is being done," said Chris Ponting, who studies medical bioinformatics at the University of Edinburgh. "It will gain momentum and greater power as the case number increases."

Stéphanie Longet, an immunologist at Jean Monnet University, agreed with Ponting, saying that genetic studies will help researchers learn more about the causes of long COVID, which could then aid both prevention and treatment.

"There are several key topics which are essential for patients, including treatments and prevention," she said. "When causes, maybe multifactorial, [are] clearly understood, it will help to treat patients who will be more susceptible to develop long COVID and potentially prevent long COVID."

Going forward, future studies will likely uncover more genetic factors that influence long COVID risk. "It won't just be a single answer, there will be a whole variety of people's vulnerabilities contributing to why they haven't recovered from COVID," Ponting said.

"It is very complicated, but also very important to pick apart," he added. "The health and socio-economic costs of long COVID are enormous." (Ledford, Nature, 7/11; Lammi et al., medRxiv, 7/1)

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