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More Genetic Clues to COVID-19 Susceptibility and Severity

Posted on by Dr. Francis Collins

DNA with coronavirus. A doctor tends to a woman patient in a hospital bed.

Many factors influence our risk of illness from SARS-CoV-2, the coronavirus responsible for COVID-19. That includes being careful to limit our possible exposures to the virus, as well as whether we have acquired immunity from a vaccine or an earlier infection. But once a person is infected, a host of other biological factors, including age and pre-existing medical conditions, will influence one’s risk of becoming severely ill.

While earlier studies have tied COVID-19 severity to genetic variations in a person’s antiviral defenses and blood type, we still have a lot to learn about how a person’s genetic makeup influences COVID-19 susceptibility and severity. So, I was pleased to see the recent findings of an impressive global effort to map the genetic underpinnings of SARS-CoV-2 infection and COVID-19 severity, which involved analyzing the genomes of many thousands of people with COVID-19 around the globe.

This comprehensive search led to the identification of 13 regions of the human genome that appear to play a role in COVID-19 infection or severity. Though more research is needed to sort out these leads, they represent potentially high-quality clues to the pathways that this virus uses to cause illness, and help to explain why some people are more likely to become infected with SARS-CoV-2 or to develop severe disease.

The international effort, known as The COVID-19 Host Genetics Initiative, is led by Andrea Ganna, Institute for Molecular Medicine Finland, Helsinki, and colleagues in the United States and around the world. Teasing out those important genetic influences is no easy task. It requires vast amounts of data, so Ganna reached out to the scientific community via Twitter to announce a new COVID-19 gene-hunting effort and ask for help. Thousands of researchers around the world answered his call. The new study, published in the journal Nature, includes data collected through the initiative as of January 2021, and represents nearly 50,000 COVID-19 patients and another 2 million uninfected controls [1].

In search of common gene variants that may influence who becomes infected with SARS-CoV-2 and how sick they will become, Ganna’s international team turned to genome-wide association studies (GWAS). As part of this, the team analyzed patient genome data for millions of so-called single-nucleotide polymorphisms, or SNPs. While these single “letter” nucleotide substitutions found all across the genome are generally of no health significance, they can point the way to the locations of gene variants that turn up more often in association with particular traits or conditions—in this case, COVID-19 susceptibility or severity. To find them, the researchers compared SNPs in people with COVID-19 to those in about 2 million healthy blood donors from the same population groups. They also looked for variants that turned up significantly more often in people who became severely ill.

Their analyses uncovered a number of gene variants associated with SARS-CoV-2 infection or severe COVID-19 in 13 regions of the human genome, six of which were new. Four of the 13 affect a person’s risk for becoming infected with SARS-CoV-2. The other nine influence a person’s risk for developing severe illness following the infection.

Interestingly, some of these gene variants already were known to have associations with other types of lung or autoimmune diseases. The new findings also help to confirm previous studies suggesting that the gene that determines a person’s blood type may influence a person’s susceptibility to SARS-CoV-2 infection, along with other genes that play a role in immunity. For example, the findings show overlap with variants within a gene called TYK2, which was earlier shown to protect against autoimmune-related diseases. Some of the variants also point to the need for further work to study previously unexplored biological processes that may play potentially important roles in COVID-19.

Two of the new variants associated with disease severity were discovered only by including individuals with East Asian ancestry, highlighting the value of diversity in such analyses to gain a more comprehensive understanding of the biology. One of these newfound variants is close to a gene known as FOXP4, which is especially intriguing because this gene is known to play a role in the airways of the lung.

The researchers continue to look for more underlying clues into the biology of COVID-19. In fact, their latest unpublished analysis has increased the number of COVID-19 patients from about 50,000 to 125,000, making it possible to add another 10 gene variants to the list.


[1] Mapping the human genetic architecture of COVID-19. COVID-19 Host Genetics Initiative. Nature. 2021 Jul 8.


COVID-19 Research (NIH)

The COVID-19 Host Genetics Initiative


  • R Hathaway says:

    Could you tell us what these genes mean for a layman- blood type, other discernable markers/

  • sarah busk says:

    Regarding mounting breakouts of fully vaccinated, is a breakout patient able to infect a nonvaccinated? Any studies?

  • Joanne M Giannini says:

    I’m so happy to see that you are now looking at this from the perspective that we are truly not ALL alike and that there may not be just one solution route to this complex illness.

  • Federico GZ says:

    The authors of the Nature study used Mendelian Randomization (MR) to assess the causal links of the genetic mutations in what is, at best, described as an observational study. While MR provides better protection against confounding errors, its outcomes are deeply influenced by a priori assumptions and at high risk for confirmation bias. Given this risk for bias, and given the current level of Covid-19 publication bias, the study results should be approached with a grain of salt.

  • Zuccheri Gianni says:

    Very interesting topic, on the other hand also in medical practice it happens to see a different clinical response that is sometimes difficult to identify.
    People with low vitamin D levels are often found to have worse COVID19 outcomes. To complicate the evaluation of the role and dosage of the various forms of Vitamin D in this regard, genetic factors also come into play, thus implying a different clinical response to Covid19 disease.
    Also, I would highlight the negative effect of chemical compounds called endocrine disruptors (example: Perfluoroalkyl substances (PFAS), phthalates and bisphenol A ) both on the level of vitamin D and on its mechanism of action. Several studies report this phenomenon, I will mention only a few :
    “Relationships Between Urinary Phthalate Metabolite and Bisphenol A Concentrations and Vitamin D Levels in U.S. Adults: National Health and Nutrition Examination Survey (NHANES), 2005–2010”
    Sci Rep. 2020 Oct 8;10(1):16789. doi: 10.1038/s41598-020-74026-8.
    “ Endocrine disruption of vitamin D activity by perfluoro-octanoic acid (PFOA)”
    Int J Hyg Environ Health. 2019 Mar;222(2):262-269. doi: 10.1016/j.ijheh.2018.11.003. Epub 2018 Nov 28.
    “Associations of serum perfluoroalkyl substance and vitamin D biomarker concentrations in NHANES, 2003-2010”
    We can therefore conclude that in the evolution of the Covid19 disease of each individual, if the role of Vitamin D is important, the influence of bad environmental chemical factors is not less important.
    Finally, regarding genetics, I recall the article “Dynamic View of Spike Protein Reveals Prime Targets for COVID-19 Treatments” Posted on May 6th, 2021 by Dr. Francis Collins.
    I present my hypothesis, inserted between the comments: Are Chiral forms of the virus produced?
    What should you think when only a one-year-old twin gets moderately ill with Covid19, with a short hospitalization, while the other remains unscathed?
    The mother becomes slightly ill, only the father is in a more marked form.

  • Ann O'Malley says:

    Could you specify the blood types that are more and less susceptible to Covid-19?

  • D. Delmar says:

    Did the people whose genetic information was collected give permission for their genetic data to be shared or used in this way? The article only said the investigator asked his fellow researchers. There was no mention of patient notification or consent. Or is it that once you give permission to one researcher to use your genetic information, you have no control over how that information is shared?

  • Robin Geof says:

    I thing that I am the only person who can stop coronavirus forever, the solution inside my blood

  • John says:

    Vaccines are good but are there any virus killers that are available. CRISPR editing looks like a possible answer.
    What is the status?

  • John says:

    Stem cell treatment is possible for Long Haul patients.

  • Elena Godeanu says:

    Thanks, thanks.

  • DR. SAUMYA PANDEY, PH.D. says:

    Innovative Covid-19 genetic epidemiology clinical/biomedical research snapshots!
    The study group may further investigate the Covid-19 susceptibility risk trends amongst poolant populations of genetically distinct landscapes, including Asian-Indian subsets by targeting Toll-like Receptors-Autophagy Immunogenic Cell Death intersections/networks in symptomatic mild to moderate to high-Covid-19 positivity patient-subsets stratified on basis of pre-/post-vaccinated subgroups and eventually develop predictive biomarkers for Covid-19 susceptibility and design cost-effective patient-friendly immunotherapeutic interventions and novel drugs for effective clinical management.

  • Farida muwanga says:

    Thank you for the wonderful message.

  • Kristin Maier says:

    Could you elaborate on findings associated with previously infected Covid patients that are still showing positive antibodies 12months later?

    • Zuccheri Gianni says:

      Possibility that this Covid immunity persists is derived from repeated contacts with low viral load.

  • Fahmida P. says:

    which blood types are less susceptible for COV-19?

  • Paula OB says:

    Please could you tell me how this might affect me? I have reasus O negative blood. I have had 2 doses of astra zeneca, but am concerned about having booster. How necessary is it for me to have a booster?

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