Geneticists come together to ask: Why do some people have worse COVID-19 symptoms than others?

Even early on in the COVID-19 pandemic, it quickly became clear that some people, like the elderly or those with underlying health issues, were getting more severely ill than others. But other reasons why some people end up in intensive care while many others escape with mild or even no symptoms remain baffling.

In early March, Mark Daly, Andrea Ganna, and others at the Institute for Molecular Medicine, Finland (FIMM) sat down to talk about how genetics could help answer some key questions. Could the genomes of people affected by COVID-19 tell us more about who is at high risk of infection or severe disease and who isn't, point the way to new drugs, and help scientists gain a better understanding of COVID-19 biology?

Reaching out to colleagues at other institutions, they quickly realized they weren't the only ones thinking about the genetics of COVID-19 susceptibility.

"In the span of a couple of days we had identified at least three different activities about to begin," said Daly, who is also an institute member at the Broad Institute of MIT and Harvard and co-director of Broad's Program in Medical and Population Genetics. "We thought there was an opportunity to bring together an international effort and see what types of studies were being initiated in other places."

That realization led to the COVID-19 Host Genetics Initiative, a rapidly growing grassroots consortium that currently includes more than 300 scientists from more than 20 countries. Its focus is to accelerate research on the genetics of COVID-19 severity and susceptibility by creating a community of researchers and promoting resource-sharing and rapid dissemination of data and results.

We called Daly in Helsinki to learn more about the fledgling consortium, how it came together, and what the members hope to achieve together.

Q: How did the idea for building this consortium come about?

A: In early March, while we were still physically working from our FIMM offices, Andrea, a few others, and I talked to a colleague of ours at THL [the Finnish Institute for Health and Welfare] who was developing a protocol to recruit coronavirus cases for a clinical genetics study. We were thinking in parallel whether we could leverage the FinnGen biobank, and at the same time, Andrea found that colleagues in northern Italy were also initiating efforts to recruit very large numbers of COVID-19 patients for genetic study. 

It was our guess that many other groups were thinking about doing the same thing. And it was an easy jump to say that no one study was going to be large enough or have access to all the possible relevant types of data to be able to come up with statistically rigorous results. 

Q: It sounds like the project came together quickly.

A: In less than a week, we had built a website and sent out a tweet and emails to collaborators and various consortia, asking whether people would be interested in joining a global human genetics effort to explore whether the host genome of an infected person might contain information that might help explain why some people have extremely severe and life-threatening responses to SARS-CoV-2 infection while others have an extremely mild response.

Q: And what kind of response have you seen?

A: Within days, hundreds of scientists at different organizations rallied around the idea. More than 65 studies and centers have registered to take part, mostly in countries in Europe, Asia, and North America where the infection is most rampant at the moment.

Q: What kinds of studies or teams have signed on?

A: They largely fall into two categories. First, quite a number of biobanks are interested in participating and contributing genetic data and health information on their current participants. 

Then there's a large number of new efforts that are starting up in hospitals and academic medical centers to actively recruit COVID-19 patients. Those studies are quite diverse in design and aims, ranging from large genome-wide association studies to studies focused just on particular populations, like sequencing studies in young people who have a very severe outcome.

Q: What are the consortium's initial goals?

A: In terms of scientific output, we want to support large scale genotyping- and sequencing-based association studies to look at differences in disease outcome. There's also a lot of interest in exploring various aspects of the immune system in disease risk, whether there are any specific gene variants that confer risk or protection, and whether any of those associate with viral subtype or origin or an individual's exposure level.

But primarily we want to create opportunities where researchers and centers with specific questions or common activities in mind can come together, inform each other's study design, share data, and make more progress together than individually. 

COVID-19 Host Genetics Consortium partner sites as of April 3, 2020. (Source: www.covid19hg.org. Credit: Lauren Solomon, Broad Communications)

 

Q: What kinds of challenges do you foresee?

A: I think nailing down the right kinds of health and phenotypic data will be challenging. There's going to be a lot of variability, and also a lot of opinions about what might or might not be relevant. I think we have to make sure we don't make too many assumptions. A few weeks ago, who would have thought that a patient's sense of smell might be an important phenotype?

There is also the question of capacity. There are a number of patient collections coming together from hospitals that don't have the resources to conduct genetic studies at scale. The way to address that, I think, is for people to step forward and offer up support without necessarily knowing exactly what's going to happen, and without letting concerns about costs or credit be an impediment.

Q: Who is helping make this consortium a reality?

A: It's been great to see institutes and individual groups step forward to make a number of contributions. The International Common Disease Alliance has been instrumental in coordinating the substantial organizational and administrative activities for this. Illumina, Regeneron, FIMM, and ErasmusMC have all offered genotyping and sequencing support for consortium-related activities, especially for studies or centers with low genetics capacity. The development team behind the Broad's gnomAD browser has already built out a new website and registration system for us, and many, including members of the Broad like Ben Neale, will provide analytical support. 

Q: Why is it important for the genetics community globally to come together like this?

A: Many diverse research groups were thinking of doing the same kinds of genetics studies, and  we would each have ended up with a relatively small and under-powered effort. We've learned over the last decade of human genetics research that we as a community almost always do the same thing: start small studies individually, after a year or two, find compatriots who have done the same study, and then start to build a consortium. 

Essentially what the community has said here is, let's cut out that one to two years, come together at the outset, and do what we know will be necessary to speed up research.