Large-scale genomic analysis highlights risk factors for COVID-19
An unprecedented study involving more than 3,500 researchers and physicians from 25 countries around the world reveals several genetic markers associated with the infection and/or development of severe forms of COVID-19. The results of the study conducted by the "COVID-19 Host Genetics Initiative" consortium, in which scientists from the University of Liège, the University Hospital of Liège and the CHC Mont Légia participated, have been published in the scientific journal Nature. These are promising results that could help provide targets for future therapies.
In March 2020, thousands of scientists around the world decided to join forces to answer an urgent and complex question: what genetic factors cause some patients with COVID-19 to develop a severe, life-threatening disease requiring hospitalization, while others get by with mild symptoms or no symptoms at all? This question is now being answered by the large-scale study conducted by the COVID-19 Host Genetics Initiative consortium, launched by Andrea Ganna, Group Leader at the Finnish Institute of Molecular Medicine (FIMM) at the University of Helsinki, and Mark Daly, Director of FIMM and a member of the Broad Institute at MIT and Harvard, which brought together more than 3,500 researchers and physicians from around the world. A full summary of the results to date is published in the scientific journal Nature. It reveals 13 loci - or locations in the human genome - that are strongly associated with the infection or development of severe forms of COVID-19. The researchers also identified causal factors such as smoking or high body mass index. These results are from one of the largest genome-wide association studies ever conducted, which includes nearly 50,000 patients with COVID-19 and two million uninfected "control" individuals. These results could help provide targets for future therapies and illustrate the power of genetic studies to learn more about infectious diseases.
To conduct their analyses, the consortium members pooled clinical and genetic data from nearly 50 000 patients who tested positive for the virus, and 2 million controls from numerous biobanks, clinical studies and genetics companies such as 23andMe, a US-based company that offers genetic analysis of individuals. With the large amount of data from around the world, the scientists were able to produce statistically robust analyses much faster, and from a wider range of populations, than any one group could have done alone.
Of the thirteen loci identified by the team to date, two had higher frequencies in patients of East Asian or South Asian ancestry than in those of European ancestry, underscoring the importance of diversity in genetic data sets. "We've been much more successful than past efforts in sampling genetic diversity because we've made a concerted effort to reach populations around the world," said Mark Daly. "I think we still have a long way to go, but we are making very good progress."
The team specifically identified one of these two loci, located near the FOXP4 gene, which is linked to lung cancer. The FOXP4 variant associated with severe COVID-19 increases the expression of this gene, suggesting that inhibition of this gene could be a potential therapeutic strategy. Other loci associated with severe COVID-19 included the DPP9 gene, which is also involved in lung cancer and pulmonary fibrosis, and the TYK2 gene, which is involved in certain autoimmune diseases.
The researchers will continue to study other data as it comes in and will update their findings in Nature's Matters Arising section. They will also look at the reasons that differentiate long-haulers - patients whose COVID-19 symptoms persist for months - from others, and will continue to identify other loci associated with infection and the severe form of the disease.
"We would like to be able to propose some very concrete hypotheses or therapeutic avenues over the next year," said Mark Daly. "Realistically, we will most likely be dealing with COVID-19 as a serious health problem for a long time. Any therapeutics that emerge this year, for example by repurposing an existing drug based on clear genetic knowledge, would have a big impact."
A new space for genetics
Scientists have been able to find strong genetic signals through their collaborative efforts, a cohesive spirit of data sharing and transparency, and the urgency of the same global threat, at the same time. Geneticists, who regularly work with large datasets, have long known the benefits of open collaboration. "This just illustrates how much better science is - how much faster it goes and how much more we discover - when we work together," said Andrea Ganna, co-instigator of the movement. According to the researchers, the insights gained from this work are unique and have the potential to be a game-changer in the field of human genetics, which has been dominated by studies of common chronic diseases, rare genetic diseases and cancer.
"These findings have been very instructive and have made us realise that there is a lot of untapped potential in using genetics to understand and potentially develop therapies for infectious diseases," concluded Mark Daly. "I hope this will serve as an example for how we migrate into the future."
The Liège commitment
On the Liège side, mobilisation was very rapid. About sixty researchers and doctors from ULiège (mainly from the GIGA), the CHU of Liège and the CHC Mont Légia were quickly mobilised. Souad Rahmouni, researcher at the GIGA and coordinator of the project for ULiège recalls: "On 16 March 2020, Dr Michel Moutschen (GIGA / CHU de Liège) contacted me to start building a COVID-19 biobank. Very quickly we established a protocol for the collection of human body material which was submitted to the local ethics committee. By the time approval was obtained, the many volunteers were hard at work. We started biobanking on 23 March 2020 in an empty hospital, but for seriously ill patients, COVID-19 patients, medical staff and us."
Funding was obtained very quickly from the Walloon Region, the Léon Fredericq Foundation, the University of Liège and the FNRS. In parallel, the Liège group set up weekly meetings bringing together doctors, veterinarians, nurses and researchers with complementary skills. "The samples (RNA, DNA, plasma and serum) from more than 500 hospitalized patients with COVID-19 and more than 300 non-hospitalized subjects collected so far has allowed us to participate in the international effort within the COVID-19 genetics consortium to discover the genetic determinants of COVID-19 susceptibility, severity and outcome."
COVID-19 Host Genetics Initiative
The global gathering, called the COVID-19 Host Gnenomics Initiative, was founded in March 2020 by Andrea Ganna, Group Leader at the Finnish Institute of Molecular Medicine (FIMM), University of Helsinki, and Mark Daly, Director of FIMM and a member of the Broad Institute at MIT and Harvard. The initiative has grown to become one of the largest collaborations in human genetics and currently includes more than 3,500 authors, including 59 from ULiege, CHU Liège and CHC MontLegia, and 61 studies from 25 countries. The Belgian cohorts (BelCovid and Control Populations) include about 500 confirmed COVID cases and more than 1500 controls collected before the COVID pandemics in hospitals in the Liège region (CHU de Liège and CHC MontLegia).
The COVID-19 Host Genetics Initiative. Mapping the human genetic architecture of COVID-19. Nature. Online July 8, 2021
Large genomic analysis highlights COVID-19 risk factors
An international collaboration uncovers several genetic markers associated with SARS-CoV-2 infection and COVID-19 severity.
Contributions ULiège | CHU de Liège | CHC Mont Légia
BelCovid Liege cohort
Data Collection Lead
Souad Rahmouni (ULiege et CHU of Liege), Julien Guntz (for CHC MontLegia),
Admin Team Lead
Yves Beguin (ULiège - CHU de Liège)
Data Collection Member
GIGA - ULiège
Michel Georges, Samira Azarzar, Catherine Moermans, Sofia Melo, Nicolas Jacques, Emmanuel Di Valentin, François Giroule, Alice Collignon, Coraline Radermecker, Marielle Lebrun, Alice Collignon, Hélène Perée, Samuel Latour, Olivia Barada, Judit Sanchez, Claire Josse, Bouchra Boujemla, Margot Meunier, Emeline Mariavelle, Sandy Anania, Hélène Gazon, Monique Henket, Myriam Mni, Marie Wéry, Alicia Staderoli, Yasmine Belhaj,
CHU de Liège
Gilles Darcis, Michel Moutschen, Benoit Misset, Julien Guiot, Patricia Dellot, Stéphanie Gofflot, Axelle Bertrand, Gilles Parzibut, Mathilde Clarinval, Olivier Malaise, Kamilia El Kandoussi, Raphaël Thonon, Pascale Huynen, Alyssia Mesdagh, Danusia Juszczak, Marjorie Fadeur, Séverine Camby, Christelle Meuris, Marie Thys, Jessica Jacques, Philippe Léonard, Frederic Frippiat, Jean-Baptiste Giot, Anne-Sophie Sauvage, Christian Von Frenckell, Bernard Lambermont
Sabine Claassen, Laurent Gadot
Data Collection Lead
Edouad Louis, Michel Georges, Souad Rahmouni (ULiège – GIGA)
Data Collection Member
Myriam Mni, Jean-François Rahier