The virus pushes on a pressure point in the human immune system
A sweeping genetic study of more than 658,000 military veterans has revealed that the biological vulnerabilities making some people susceptible to severe COVID-19 are not unique to the virus — they are woven into the same genetic fabric that predisposes individuals to diabetes, heart disease, blood clots, and certain lung conditions. Published in PLOS Genetics, the findings suggest that for some, severe illness is less a matter of bad luck than of inherited immune architecture. The discovery invites a deeper reckoning with how the body's ancient balancing act — fighting infection without turning on itself — can become a point of catastrophic failure, and how understanding that balance might one day reshape how medicine responds to viral threats.
- The same DNA variants that raise the risk of severe COVID-19 also appear in people with Type 2 diabetes, venous blood clots, and ischemic heart disease — conditions already known to worsen COVID-19 outcomes, now linked at the genetic root.
- Not all respiratory diseases share this genetic kinship: while idiopathic pulmonary fibrosis and chronic alveolar lung disease showed genetic overlap with severe COVID-19, COPD and influenza did not — suggesting the danger lies in specific immune pathways, not simply damaged lungs.
- A striking ancestry gap emerged: genetic links between severe COVID-19 and dangerously low white blood cell counts appeared in people of African and Hispanic descent but were absent in those of European ancestry, exposing how unevenly genetic risk is distributed across populations.
- Some variants tied to severe COVID-19 were associated with lower risk of autoimmune diseases like lupus and psoriasis, hinting that the immune traits protecting against self-attack may leave people more exposed to viral devastation.
- Researchers believe mapping these shared genetic pathways could redirect treatment development — away from symptom management and toward targeted interventions that address the immune imbalances at the heart of severe disease.
A study of more than 658,000 military veterans has found that the genetic variants making some people vulnerable to severe COVID-19 are the same ones linked to diabetes, blood clots, heart disease, and certain lung conditions. Published in PLOS Genetics, the research used a phenome-wide association study to cross-reference veterans' DNA with their electronic health records, revealing a shared genetic architecture across multiple serious diseases.
The connections were precise rather than sweeping. Genetic overlap appeared between severe COVID-19 and idiopathic pulmonary fibrosis and chronic alveolar lung disease — but not with COPD or influenza, despite both being respiratory conditions that worsen COVID-19 outcomes. This distinction points to specific immune pathways, not simply the presence of lung disease, as the underlying vulnerability.
Ancestry proved to be a meaningful variable. Genetic links between severe COVID-19 and neutropenia — abnormally low levels of infection-fighting white blood cells — were found in people of African and Hispanic ancestry but not in those of European descent, reinforcing the importance of diverse representation in genetic research.
Perhaps most intriguingly, some variants associated with severe COVID-19 were linked to reduced risk of autoimmune conditions like psoriasis and lupus. Co-author Dr. Katherine Liao of Brigham and Women's Hospital described the virus as pressing on a pressure point in the immune system — one that must constantly balance fighting infection against attacking the body itself. Those genetically shielded from autoimmunity may, paradoxically, be more exposed to severe viral illness.
The researchers see these findings as a map toward new treatments — ones that target the root immune imbalances in genetically vulnerable populations rather than simply managing symptoms after the fact.
Researchers analyzing the genetic makeup of more than 658,000 military veterans have uncovered a striking pattern: the DNA variants that make some people vulnerable to severe COVID-19 are the same ones that predispose them to diabetes, blood clots, heart disease, and certain lung conditions. The finding, published Thursday in PLOS Genetics, suggests that severe illness from the virus exploits weaknesses in the immune system that are already present in people carrying these genetic markers.
The study used a technique called phenome-wide association study, which allowed scientists to cross-reference genetic information with electronic health records and identify connections between variants found in veterans who experienced severe COVID-19 and those linked to a broad range of medical conditions. What emerged was a web of shared genetic architecture—permanent changes in DNA that increase risk across multiple diseases. Genetic variants associated with severe COVID-19 appeared in people with venous blood clots, Type 2 diabetes, and ischemic heart disease. All three conditions are already known to raise the risk of serious COVID-19 illness, and blood clots in particular are a frequent complication in those who develop severe disease.
The respiratory picture was more nuanced. Researchers found genetic links between severe COVID-19 and two specific lung diseases—idiopathic pulmonary fibrosis and chronic alveolar lung disease—both of which cause life-threatening breathing problems. But they found no shared genetic architecture with chronic obstructive pulmonary disease, or COPD, or with the flu, despite these being respiratory conditions that also increase COVID-19 risk. The distinction suggests that genetic vulnerability to severe COVID-19 is not simply about having any respiratory disease, but rather about specific immune pathways.
Ancestry emerged as a significant variable. Researchers identified genetic links between severe COVID-19 and neutropenia—an abnormally low concentration of neutrophils, a type of white blood cell—but only in people of African and Hispanic ancestry. This same genetic association did not appear in people of European ancestry, highlighting how genetic risk factors can vary across populations and underscoring the importance of diverse representation in genetic research.
Dr. Katherine Liao, an associate professor of medicine at Brigham and Women's Hospital in Boston and a co-author of the study, described the findings as revealing how the virus "pushes on a pressure point in the human immune system." The immune system, she explained, must constantly balance fighting infection while maintaining enough control to avoid turning against the body itself—what happens in autoimmune diseases. Interestingly, some genetic variants associated with severe COVID-19 were linked with reduced risk for autoimmune conditions like psoriasis and lupus, suggesting that the genetic factors protecting against autoimmunity may leave people more vulnerable to severe viral illness.
The implications for treatment development are substantial. Understanding which genetic pathways drive severe COVID-19 could point researchers toward new therapeutic targets. Rather than treating the disease as a single entity, clinicians and drug developers might focus on the specific immune imbalances that occur in genetically vulnerable populations. Liao noted that one striking finding was the sheer number of immune-mediated conditions that shared genetic architecture with severe COVID-19 manifestations, suggesting that the virus's severity in some people reflects deeper vulnerabilities in how their immune systems are wired.
The research builds on earlier work identifying genetic variants linked to dementia that also increase COVID-19 severity. As the pandemic continues and new variants emerge, mapping these genetic connections becomes increasingly valuable—not just for understanding who is at highest risk, but for developing treatments that address the root immune system imbalances rather than simply managing symptoms.
Notable Quotes
The nature of the associations brought to light how the virus pushes on a pressure point in the human immune system— Dr. Katherine Liao, Brigham and Women's Hospital
The immune system has a constant balancing act of fighting infection while maintaining enough control so that it does not also become an autoimmune process— Dr. Katherine Liao
The Hearth Conversation Another angle on the story
So the study found that people with diabetes or heart disease are genetically predisposed to severe COVID-19. Does that mean their conditions caused the severity, or is it something else?
Neither, exactly. It's that they share the same genetic variants—the same inherited DNA changes. Those variants make the immune system work a certain way. That same way of working makes you vulnerable to diabetes, to blood clots, and to severe COVID-19. The conditions themselves aren't causing each other. They're all downstream of the same genetic blueprint.
That's interesting. So if you have the variant, you might get diabetes, or you might get severe COVID, or both?
Potentially, yes. Or you might have the variant and never develop either. Genetics loads the gun, but environment and other factors pull the trigger. What matters is that the researchers found a pattern—a shared vulnerability in how certain immune systems are built.
You mentioned ancestry differences. Why would African and Hispanic populations show a genetic link to low white blood cells that European populations don't?
That's the honest answer: we don't fully know yet. It could be that the variant is more common in those populations, or that it has different effects depending on genetic background. It's a reminder that most genetic research has been done on people of European ancestry, so we're still learning how disease genetics plays out across different groups.
If we understand these genetic pathways, what can doctors actually do differently?
Instead of treating severe COVID as one disease, you could potentially target the specific immune imbalance in a patient. If someone's genetic variant makes their immune system struggle to balance fighting infection without attacking itself, you might develop a drug that helps with that balance specifically. It's more precise medicine.
And the finding about autoimmune diseases—that's counterintuitive, right?
Very. The variants that protect you from lupus or psoriasis seem to leave you more vulnerable to severe COVID. It's as if the immune system made a trade-off: better at fighting viruses, worse at controlling itself. That's the pressure point the researchers mentioned.