Genomics England and the GenOMICC (Genetics of Mortality in Critical Care) consortium are spearheading a human genome sequencing initiative that aims to analyze the genomes of tens of thousands of COVID-19 patients in the U.K. to try to understand how a person’s genes may affect how they react to the virus. The researchers will use the sequencing data to help provide new insights into the impact of genetic makeup on whether a patient will likely suffer only mild COVID-19 symptoms, or whether they are at risk of progressing to severe disease that requires hospitalization. The study will focus on people of all ages severely affected by COVID-19, including children and young adults.
The study initially aims to enroll 20,000 people who are currently, or were previously, in intensive care with severe COVID-19 disease, as well as 15,000 infected individuals who suffered only mild or moderate symptoms. The ultimate aim would be to sequence every COVID-19 patient in intensive care units across the NHS, said Richard Scott, MD, clinical director for Genomics England, speaking with GEN.
“While we work with our NHS partners to enroll hospitalized patients, we are encouraging people who were previously in intensive care with COVID-19, or who are, or have recovered in the community from milder COVID-19 symptoms in the community, to register their interest in the study through the Genomics England website,” Scott said. “We think that this is the largest sequencing study of its kind, and we are very hopeful that the genomic data emerging will help us to better understand genetic risk factors associated susceptibility to severe disease. While we can’t predict what the data will show, we anticipate that emerging genetic insights could be used to help stratify patients for future clinical trials of COVID-19 therapies and vaccines.” The data could also ultimately inform on patient care, monitoring, and drug prescribing, Scott suggested.
The GenOMICC Consortium, led by Kenneth Baillie, MD, at the Roslin Institute, University of Edinburgh, will head enrollment for the sequencing initiative, and has obtained DNA samples from 2,000 intensive care COVID-19 patients, Scott further explained. “GenOMICC was set up in 2016 to sequence the genomes of patients with serious diseases, primarily flu and other emerging diseases, to help understand how genetics may influence disease outcomes and severity. The consortium of GenOMICC researchers had already begun recruiting patients with COVID-19 prior to the establishment of the sequencing initiative.”
In a recent statement, Baillie commented, “Our genes play a role in determining who becomes desperately sick with infections like COVID-19. Understanding these genes will help us to choose treatments for clinical trials. The GenOMICC study was launched before this outbreak and it is recruiting in more than 160 ICUs across the country with tremendous support from the critical care community. We are excited to work with Genomics England to tackle this new and complex disease.”
Genomics England was established in 2013 to deliver the 100,000 genomes project in partnership with the NHS, which was completed in December 2018. The organization will provide the project infrastructure and know-how in terms of the large-scale genomic analyses, as well as coordinate the sequencing, and work as an enabler across the research landscapes to connect with other research groups who may want to join in the collaboration, Scott commented to GEN. “Genomics England is responsible for delivery of the sequencing components, the high-performance computing element, and for presenting the data for analysis in what we call a trusted research environment. More broadly, we are acting as a facilitator, and encouraging awareness of the research so that other researchers can be part of the work and the consortium.”
The physical sequencing will be carried out by Illumina, at the firm’s U.K. facility within the Wellcome Trust Sanger Institute, where Illumina carried out the sequencing for the 100,000 Genomes Project, together with Genomics England and the NHS. Illumina will sequence all of the 35,000 COVID-19 patient genomes at the U.K. facility, and will share some of the cost via in-kind contribution. “We have a long-standing partnership with Genomics England and are proud to support this new genomics initiative from our Cambridge-based lab,” commented Paula Dowdy, general manager and SVP, EMEA, Illumina, in a statement. “The results will establish a unique platform for researchers to understand the human response to coronavirus infection, leading towards new treatments and ways to control infection spread.”
And while the goal for the U.K. initiative is to sequence every COVID-19 patient in intensive care, Scott acknowledged that this will be a tall order. “It’s obviously hugely ambitious, because of the challenges of recruiting people who are seriously ill in intensive care, and particularly in a pandemic setting. We want to encourage as many people as possible to join, because the potential findings could have implications for future management of the disease on both a population basis, and on an individual patient basis, through diagnosis and treatment.
Analysis of the genomes will be a joint effort, Scott further outlined to GEN. “We have the expertise to carry out the major bioinformatics ‘heavy lifting,’ and in performing key analyses.” The first core analysis will be a genome-wide association study (GWAS) to compare the genomes of mild- and the severe-COVID-19 disease patients, and this will be a joint effort between Genomics England and GenOMICC. “We will be looking for loci that might increase risk of severe disease, independent of other known risk factors,” Scott noted. “Importantly, our analyses will be done on an iterative basis, so we will carry out an initial analysis on small numbers of patients as their genomes are sequenced, and then repeat as the numbers of people who join the program grow.”
Scott anticipates the data will enable a broad range of analyses that will help scientists to link genetics with disease susceptibility, severity, and clinical trial outcomes. This could potentially help to identify whether certain drugs may have more or less benefit in patients with specific gene expression profiles. “In the longer-term, the data could also help to inform vaccine design, if we can understand whether genotype can influence sustained response to a vaccine, for example. And if, ultimately, we could develop a test to identify individualized risk based on genetic factors, that would be a fantastic outcome. But until we have the data, and the numbers, we just won’t know what is possible.”
The study will establish a kind of “public observatory” where summary level data can be accessed broadly for research purposes, Scott continued. “More detailed data will be available to core groups, and to researchers who might contribute to the program through what we call our trusted research environment. This will be like a virtual desktop, into which authorized researchers can log in from anywhere in the world to run their own analyses on the data in that environment.”
Data from an individual’s genome will also be linked to the virus genome data provided through the viral sequencing program by the COVID-19 Genomics UK Consortium (COG-UK), a partnership of NHS organizations, U.K. public health agencies, the Sanger Institute, and U.K. academic centers. Sharon Peacock, CBE, director of COG-UK, said: “This study is a great example of how different parts of the U.K. genomics community are working together to get a full genomic picture of the spread and impact of the virus. In COG-UK we have already sequenced over 10,000 virus genomes from patients with COVID-19. Linking this data to the patient’s own genome data in the Genomics England-GenOMICC study may provide unique insights into how the patient and virus genomes act together to influence the patient’s response to the infection and will help inform and improve our response to future outbreaks.”
The U.K. initiative is the largest of its sort of which Scott is aware. “There are efforts planned in Canada and in New York, on a smaller scale,” he commented to GEN. International collaboration is also vital, he asserted. Genomics England is part of an international collaboration, the COVID-19 Host Genetics Initiative, which is bringing together the human genetics community to share and analyze data on the genetic determinants of COVID-19 susceptibility, severity, and outcomes. “This is a fantastic collaboration of people who have the ability to provide valuable insight into COVID-19 patient genomics research by leveraging data from bespoke, larger sequencing studies, or through the use of cohorts of existing genomic data, or just as valuable data from smaller-scale genomic studies that may have just a handful of patients involved. By sharing data and expertise we can achieve best-in-class analyses. It’s absolutely essential that we also do this internationally to maximize our chances of finding useful answers that will impact on disease management for patients and populations.”
The U.K. COVID-19 patient sequencing project is backed by £28 million from Genomics England, UK Research and Innovation, the Department of Health and Social Care, and the National Institute for Health Research.