A New Genetic Risk Factor for Long-COVID

By 2022, roughly 1 in 13 adults (7.5%) who have had COVID reported long COVID symptoms. This debilitating chronic condition is characterized by symptoms that weren’t present before the infection and persist for three months or longer after the initial onset of the virus. Common manifestations include chronic pain, brain fog, shortness of breath, chest pain, and profound fatigue. It’s alarming how it can impact various systems in the body, from the heart and lungs to kidneys, skin, and even the brain, potentially leading to lasting organ damage.

Certain groups, such as younger adults aged 50-59, females, and individuals who were hospitalized due to COVID-19, appear more susceptible to long-COVID.

Visual representation of COVID-19
COVID-19. Photo by Fusion Medical Animation on Unsplash

While ongoing research suggests several potential origins of long-COVID, ranging from lingering virus fragments in the body to autoimmune reactions and dormant virus reactivation, we still have much to uncover about who is most vulnerable to this condition and why.

A recently published genome-wide association study (GWAS) on long-COVID discovered genetic variants predisposing long-COVID patients to the ailment. Intriguingly, they pinpointed a link to the FOXP4 locus, setting the stage for more comprehensive research on genetic susceptibility to long-COVID.

You can use the Nebula Genome Browser to see if you have this gene variant. Keep reading to learn what this mutation is and how you check your status.

The Study

The research team harnessed data from a cohort of 6,450 long-COVID cases and over 1.09 million population controls, combining 24 previously published studies from 16 countries.

The first analysis focused on individuals confirmed positive for SARS-CoV-2 infection. Later, the researchers broadened their examination to encompass self-reported and clinically diagnosed cases to validate their preliminary findings. The control group comprised over a million people who hadn’t developed long-COVID.

Upon pinpointing the genetic variant, the team endeavored to decipher the rationale behind the association and its correlation with clinical manifestations, such as alterations in lung function.


The most striking discovery was the significant genetic correlation within the FOXP4 locus. This gene plays a pivotal role in maintaining the health and function of the lungs. The researchers linked a variant (rs9367106) in the FOXP4 locus to a 1.6-fold increased likelihood of developing long-COVID.

Interestingly, the prevalence of long-COVID-associated FOXP4 variants diverged based on ancestry. For instance, in European samples, the frequency was a mere 1.6%, but 36% in East Asian cohorts.

Explore your Genome!

Did you know you can use the Nebula Genome Browser (available with Deep and Ultra Deep WGS) to check whether you have protective variants?

Go to the Genome Browser. In the top left corner of the genome browser, you can find a search bar.

  1. The authors linked the C allele of variant rs9367106 to long COVID.
  2. Using the dbSNP database, you can find the genome coordinates in the format [chromosome number][chromosome location] is 6:41515652. (GRCh38 reference genome).
  3. Copy-paste this location into the search bar and press enter. 
  4. The genome browser will now zoom in on this location. 
  5. Activate the “Center Line” in the bar at the top to better see the location that you are looking at.
  6. You should see stacked, gray stripes. Those are your personal DNA sequencing reads that are aligned to a reference genome sequence (colored letters above). If your DNA sequence matches the reference, which is G, then the stripes are gray. Instead, if you have the C allele, the one associated with long-COVID, then you will see letters and symbols in different colors.


Genome-wide Association Study of Long COVID

Vilma Lammi, Tomoko Nakanishi, Samuel E. Jones, Shea J. Andrews, Juha Karjalainen, Beatriz Cortés, Heath E. O’Brien, Brian E. Fulton-Howard, Hele H. Haapaniemi, Axel Schmidt, Ruth E. Mitchell, Abdou Mousas, Massimo Mangino, Alicia Huerta-Chagoya, Nasa Sinnott-Armstrong, Elizabeth T. Cirulli, Marc Vaudel, Alex S.F. Kwong, Amit K. Maiti, Minttu Marttila, Chiara Batini, Francesca Minnai, Anna R. Dearman, C.A. Robert Warmerdam, Celia B. Sequeros, Thomas W. Winkler, Daniel M. Jordan, Lindsay Guare, Ekaterina Vergasova, Eirini Marouli, Pasquale Striano, Ummu Afeera Zainulabid, Ashutosh Kumar, Hajar Fauzan Ahmad, Ryuya Edahiro, Shuhei Azekawa, Long COVID Host Genetics Initiative, FinnGen, DBDS Genomic Consortium, GEN-COVID Multicenter Study, Joseph J. Grzymski, Makoto Ishii, Yukinori Okada, Noam D. Beckmann, Meena Kumari, Ralf Wagner, Iris M. Heid, Catherine John, Patrick J. Short, Per Magnus, Karina Banasik, Frank Geller, Lude H. Franke, Alexander Rakitko, Emma L. Duncan, Alessandra Renieri, Konstantinos K. Tsilidis, Rafael de Cid, Ahmadreza Niavarani, Teresa Tusié-Luna, Shefali S. Verma, George Davey Smith, Nicholas J. Timpson, Mark J. Daly, Andrea Ganna, Eva C. Schulte, J. Brent Richards, Kerstin U. Ludwig, Michael Hultström, Hugo Zeberg, Hanna M. Ollila 

medRxiv 2023.06.29.23292056; doi: https://doi.org/10.1101/2023.06.29.23292056

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