NEW YORK – It is not every day investigators launch a longitudinal genetic study in the hopes that it will be underpowered to deliver significant associations. But that is the situation 23andMe's Adam Auton finds himself in.
"It is the nature of genetic studies that the larger the number of individuals you can have in your study, the more power there is to detect associations," said Auton, a principal scientist at the consumer genomics company. "This is a situation where, if we fail to find anything, that's probably good news."
Auton is part of team that is a reaching out to 23andMe customers in the US for a study on genetic factors in the host contributing to COVID-19 infection severity. The California-based firm launched the project this week.
"We predominantly decided to focus on severity, because that's where we think we have the most potential for our data to help the scientific community," Auton explained.
Uncovering variants involved in severity could ultimately help to identify risk-associated biological pathways and perhaps flag individuals at increased risk of the most dire COVID-19 outcomes. Depending on the strength of such associations, though, researchers suspect it may take a large number of affected individuals to find such variants, which no one wants to see.
"The best outcome of this study might be that we fail to find anything. That may indicate that the pandemic wasn't quite as widespread as we first imagined," he explained. "This isn't a study where we are hoping to find lots and lots of things, because that probably means things were quite bad."
Participants in the new study will be asked to fill out monthly online surveys documenting any SARS-CoV-2 symptoms and related testing, diagnoses, or hospitalizations, if any, along with details on disease course and outcomes for those who do develop COVID-19, Auton noted. Those responses will be analyzed alongside individuals' array-based genotyping profiles and imputed variant profiles.
"Obviously, for people who are very severely affected by disease, this is not high on their priority list of things to do. So in order to address that, this is a project that we expect will be ongoing," he said. "For people who choose to participate now, we'll ask them to fill out a baseline survey, but we'll also be recontacting them on a monthly basis to ask if there have been updates in their condition."
The direct-to-consumer testing company will initially focus on adult 23andMe customers in the US who have already consented to participate in research. It is also seeking information on participants' affected first- and second-degree relatives.
"If individuals have a family member who has had a severe outcome for COVID-19, then that's potentially valuable for trying to understand the genetics of severity," Auton said. "Even if people are not affected themselves, they can still contribute."
The information being gathered falls under 23andMe's existing informed consent for research, which has been approved by its Institutional Review Board (IRB), Auton said. The IRB has also reviewed and approved survey materials for the COVID-19 genetic susceptibility study.
Further down the line, 23andMe may consider expanding the study to include customers in other countries, though the US-focused approach was deemed the fastest way to get informative data in the short term.
"The US makes up the majority of our customer base, so that's where we wanted to start, and our IRB approval is within the United States," Auton said. "We'll look at expanding into other areas, but obviously we're trying to put things together in a reasonably timely fashion, and want to do things carefully as well."
The team expects to keep the study going for at least a couple of months but will adjust as needed and as the extent of the pandemic becomes clearer.
As the COVID-19 pandemic continues to dramatically disrupt and claim lives, the 23andMe researchers reasoned that the company's customer database might offer clues on the host side of the SARS-CoV-2 infection, particularly when trying to understand why some individuals develop severe or fatal infections and others do not.
"We were very interested in trying to figure out how 23andMe could make a meaningful contribution to the scientific research that's going on in that area," Auton said. "Obviously a major strength that we have is in genetic research: we have access to this extremely powerful database of genetic data and we have a long track record of being able to use that data to make discoveries that potentially provide meaningful insight into the biology of disease."
The firm has applied similar GWAS approaches to assess a wide range of human traits and conditions, including a GWAS and fine-mapping analysis of host response to other infectious diseases such as hepatitis A or B virus, mumps, scarlet fever, pneumonia, or the common cold — work published in Nature Communications in 2017 that highlighted the human leukocyte antigen (HLA) region and other parts of the genome involved in immunity and embryonic development.
The 23andMe team is not alone in looking to the human genome for some answers during the COVID-19 pandemic. As the outbreak continues, investigators from around the world have been marshaling genotyping and sequencing technologies, biobank resources, and more to look for genetic factors that might contribute to SARS-CoV-2 infection susceptibility and severity.
Moreover, preprint articles from groups in China and Italy have already come out on sites such as MedRxiv, pointing to possible genetic contributions to SARS-CoV-2 infection susceptibility or severity.
For example, a team led by investigators at the Southern University of Science and Technology in Shenzhen identified apparent differences in COVID-19 infection rates depending on individuals' ABO blood type, while researchers at the University of Siena and other centers in Italy narrowed in on potential COVID-19 susceptibility-related variants in the gene coding for an ACE2 receptor protein involved in viral entry, using exome sequence data for thousands of individuals assessed through the Network of Italian Genomes.
Auton said 23andMe has not ruled out the possibility of collaborating with academic teams that have host genetic studies on COVID-19 underway, though it is just beginning to explore such possibilities.
"Because of the position we're in with our very large database," he noted, "we were hoping that we could participate in some of that work, and be able to provide insight that otherwise wouldn't be possible, in large part because understanding the genetics of disease requires a large number of individuals."