The search for answers to the genetic impact on case severity


Watch the AMA's daily COVID-19 update, with insights from AMA leaders and experts about the pandemic.



In the first of a two-part series, AMA Chief Experience Officer Todd Unger discusses genetics at play in COVID-19 with experts  Wendy Chung, MD, PhD, Robert Green, MD, MPH, and AMA’s Chief Health and Science Officer Mira Irons, MD.

Learn more at the AMA COVID-19 resource center.


  • Mira Irons, MD, chief health and science officer, AMA
  • Wendy Chung, MD, PhD, Kennedy Family professor, Columbia University
  • Robert Green, MD, MPH, director, Genomes2People Research Program, Brigham and Women's Hospital

AMA COVID-19 Daily Video Update

AMA’s video collection features experts and physician leaders discussing the latest on the pandemic.

Unger: Hello. This is the American Medical Association's COVID-19 update. This is part one of a two-part series, looking at genetics and COVID-19. I'm joined today by Dr. Wendy Chung, Kennedy Family Professor of Pediatrics and Medicine and Chief of Clinical Genetics at Columbia University in New York. Dr. Robert Green, Professor of Medicine at Harvard Medical School and a physician-scientist, who directs the Genomes to People, or G2P, research program at Brigham and Women's Hospital and the Broad Institute in Boston. And Dr. Mira Irons, AMA's Chief Health and Science Officer in Chicago. I'm Todd Unger, AMA's Chief Experience Officer in Chicago.

Unger: One of the ongoing mysteries about COVID-19 has been why some experience deadly infections, while others escape with mild or no symptoms. What role do genetics play and what do we know so far? Doctor Chung, why don't you start?

Dr. Chung: Sure. There's a lot that we don't know, but we have a lot of hypotheses based on some of the clinical data so far. And I'll say that the genetic data are coming in and are going to give us a lot more answers very soon. We do know that there are differences by some genetic things, like sex, for instance. Men do worse than women do in general, with this. We know there are differences by race, ethnicity. How much of this is genetically determined versus social determinants of health, I think is one of the things we don't yet know and is a really important question coming up.

We also know that there are preexisting health conditions which predispose to worse outcomes. And those include many, many different things, but things like hypertension, diabetes, obesity, preexisting heart disease. In some of those cases, there may be genetic determinants or at least genetic risk factors that go with those factors. And then there are some emerging data, which are exciting, that are based on genome-wide association studies. They're looking for more common variants. So one of the things that was early recognized was, for instance, blood type. Type A seems to be increased susceptibility. Type O seems to be protective. And additionally, there's a locus. We're not sure of exactly the gene, but a locus that's around CCR9 that may be increasing risk and there's some hints of others as well.

Unger: Doctor Green?

Dr. Green: Well that was a fantastic summary and I don't have a lot to add except to sort of sound a few cautionary notes. One is I think what we're seeing, far and away, is that social determinants of health are extremely important in terms of who gets infected, how it is spread and the severity with which this impacts people. And we don't want to use genetics, and I think Wendy meant this as well, we don't want to ever use genetics as an excuse to explain away some of these social determinants of health, which are so important in the disparities that people in our society are experiencing.

Having said that, I think it's really interesting to look at, perhaps for example, the healthy individuals and see that some healthy individuals are getting mild or completely asymptomatic cases and some healthy individuals are getting some devastating cases. And there are clues. Wendy mentioned the blood group clues. She mentioned the GWA study that's recently come out.

There's also clues, for example, in the ACE2 receptor, this is the receptor that the spikes on the virus itself actually connect to, to invade your cells. And there are genetic variants in the code and in the protein of the ACE2 receptor and we already know that some of them have a little greater affinity for the virus than others that do not. So the hope is that clues like this are probably not going to be so important for predicting anything about who is vulnerable or who is not, but rather give us insights into the pathophysiology that will accelerate the hunt for treatments and vaccines.

Unger: Well apparently I was one of 100 patients that called his physician about that information about blood type to find out which one I was. Doctor Irons, let's talk about prior infectious diseases. What have we learned from the role that genetics play? What can we learn from the past in terms of research?

Dr. Irons: Any time we're faced with a new virus or a new condition, it's really important to understand the natural history of the disorder. And as you've heard from Wendy and Robert, this virus acts like no other. There are so many questions we have about its natural history and it seems as though every day we hear of a new subgroup or a new subpopulation of people. And in genetics, it always helps to study the outliers. And so one example of something that came in the past was in the early days of HIV.

We started to recognize that there were a group of people who were resistant to HIV, even with repeated exposures. And so the ability to study those people led to the CCR5 gene, which actually codes for a cell receptor, that allows that virus to enter a cell and found out that there was a mutation within that gene. Most common in older people from the Northern European population, but basically if you had two copies of the abnormal gene, it coded for a nonfunctional receptor. So the virus couldn't enter the cell. If you had one copy, about 50% of your receptors were abnormal, but that information not only allowed us to understand how the disease affects those patients, but also told us something about how the disease operates, what the pathophysiology is of the disease and that drug targets could then be developed for them.

Unger: How about H1N1? Do we see anything similar?

Dr. Irons: There was some indication. There were some associations with H1N1, but the other thing that's really important is to understand the difference between associations, things that come up. And very many have come up with COVID-19. What's the role of vitamin D? What's the role of zinc? What's the role of other things? But associations aren't always causative, so it's important to understand something that may just be associated or something that actually is important in the pathophysiology of the condition.

Unger: Doctor Green and Doctor Chung, you're both working on your own research related to COVID-19. Can you tell us what you're working on and how it's going so far? Doctor Green?

Dr. Green: I'm not a virologist or a molecular geneticist. So my role is modest in this, but I've had the privilege of helping to coordinate at our institution, the biobank response to trying to get some of these individuals who are infected, into the biobank. We already have quite a large number of people in the biobank, who either genotyped or sequenced, and we are contributing cases to the International COVID-19 Host Vulnerability Initiative, which is being coordinated out of the University of Helsinki and the Broad Institute by other folks besides me. But it's wonderful to be a part of that.

One of the things I think we've all seen and recognized is that science has accelerated in its breadth and its coordination and in its sharing, in this time period, like in no other time period in my entire life. And with this small project, this International COVID-19 Host Vulnerability Initiative, we've been contributing, but so have hundreds of other centers, to the idea that we can move fastest when we share our data and put it together. So I can't speak as a leader of that, but as a participant in that, it's been absolutely thrilling. And our first GWA studies are really coming out. We were even mentioned in the recent New England Journal of Medicine GWA article. We were mentioned because even our small number of early data actually reinforced some of their findings.

Unger: Doctor Chung?

Dr. Chung: So I am not a virologist either. I'm a geneticist and oftentimes study much rarer diseases. But what we did immediately was try and pivot, both to understand how the infection was affecting our specific communities and try and gather as much as we could to be able to understand how to support those communities and understand if they were a particular risk. As well as in a similar way, that I'll explain in a second, to what Robert's been doing up in Boston.

One of the first things that we did is, I think we had some preconceived notions that, as I said, this was going to affect the lungs. It was going to affect the heart. That we might have patients that have diseases I study, like congenital heart disease or pulmonary hypertension that would be a very, very high risk. And so in a good way, we already had, in some cases, national or even international groups of individuals identified. And we had communication channels preexisting. So we had online communities where we could very quickly send out surveys and understand the impact for them and if they were getting sick and hospitalized. And in fact, we're quite surprised that some of the people we thought would have been sickest, in fact were not. And it was very, very helpful in terms of getting the word out through the network that we had. For instance, our pulmonary hypertension network, getting that information out to the treating physicians at those centers of excellence.

We also have had, as another example, we do a lot of studies in autism and again could send out, in this case, survey-based instruments, but to over 100,000 individuals. And to be able to understand under quarantine conditions, when children weren't getting services. A lot of what they needed in terms of ABA therapy or speech therapy or special education, what impact that was having for themselves and also for their parents and their families in terms of mental health and the burden and the strain. And so we've been using that information to pivot and think about how can we do COVID safely, as things are opening up and what are the priority areas in terms of where those kiddos need the most support and where their families can use support, either with distance-based or in-person therapies as they're coming online. So those were a couple ways that we did this.

In New York we had, unfortunately, a lot of infections, as people know. And the way that our health care system worked, our network of hospitals, is that my hospital became the single hospital for children. So we took in, throughout our entire network, all of the children and that ended up giving us an enormous amount of experience very, very quickly with children. And in particular, with this disease that started emerging, not in the peak, in March or early April, but just a little bit later because it was associated after the acute infection. And so this has been called MIS-C or Kawasaki, Kawashaki. It's gone by several different names, but it's this multisystemic inflammatory condition. And so with that, we've been trying to understand both the genetics of who gets that. Is there any predisposition?

Right now, there's no immediate headline for that. So it's not clear that there's one single, strong, genetic factor in that, although I think we still need to keep working to understand this. And we also, importantly, started to understand very quickly, how to treat it. And so we actually came up with a protocol that's also been used for other conditions like this with IVIG and steroids, which has proven to be incredibly effective. And so the good news that came out of this was nationwide, internationally, we could put out what's been called The Columbia Protocol in terms of treating the kiddos with MIS-C. And thankfully, even though there were initially three deaths, we haven't had any deaths in our hospital. And now there really is a protocol to keep kids safe.

So again, not necessarily something that I do in my day job usually, but we've all hands on deck, tried to contribute what we understand about communication channels, how you do research, how you bring people together and just get it done as quickly and effectively, but with the greatest veracity of data that we can around the world, for doctors wherever they might be.

Unger: Well, Doctor Green, Doctor Chung and Doctor Irons, thanks for being with us here today and sharing your perspectives and for all the research that you're doing, still a lot of unanswered questions. One thing we do know, it's important, as we try to safely reopen. Three things, wear a mask, wash your hands and keep your physical distancing. Thank you so much. For updated resources on COVID-19, go to Thanks for joining us and take care.

Disclaimer: The viewpoints expressed in this video are those of the participants and/or do not necessarily reflect the views and policies of the AMA.