Post by Admin on Oct 18, 2020 20:57:24 GMT
Kenneth Baillie of the University of Edinburgh, an intensive care physician and geneticist, led the new study, which he discussed on 2 October at an online meeting1 of a data-pooling effort called the COVID-19 Host Genetics Initiative. He’s hoping the results, also posted as a preprint on medRxiv2, will speed treatments, although he cautions that any clinical trial inspired by the findings should wait for the study’s acceptance in a peer-reviewed journal. “Because the epidemic is progressing at such an alarming rate, even a few months of time saved will save lots of lives,” Baillie says.
In a standard approach to finding genes that influence a condition, geneticists scan the DNA of large numbers of people for millions of marker sequences, looking for associations between specific markers and cases of the disease. In June, one such genomewide association study in The New England Journal of Medicine (NEJM)3 found two “hits” linked to respiratory failure in 1600 Italian and Spanish COVID-19 patients: a marker within the ABO gene, which determines a person’s blood type, and a stretch of chromosome 3 that holds a half-dozen genes. Those two links have also emerged in other groups’ data, including some from the DNA testing company 23andMe4.
The new study confirmed the chromosome 3 region’s involvement. And because 74% of its patients were so sick that they needed invasive ventilation, it had the statistical strength to reveal other markers, elsewhere in the genome, linked to severe COVID-19. One find is a gene called IFNAR2 that codes for a cell receptor for interferon, a powerful molecular messenger that rallies the immune defenses when a virus invades a cell. A variant of IFNAR2 found in one in four Europeans raised the risk of severe COVID-19 by 30%. Baillie says the IFNAR2 hit is “entirely complementary” to a finding reported in Science last month: very rare mutations that disable IFNAR2 and seven other interferon genes may explain about 4% of severe COVID-19 cases. Both studies raise hopes for ongoing trials of interferons as a COVID-19 treatment.
A more surprising hit from the U.K. study points to OAS genes, which code for proteins that activate an enzyme that breaks down viral RNA. A change in one of those genes might impair this activation, allowing the virus to flourish. The U.K. data suggest there is a variant as common and influential on COVID-19 as the interferon genetic risk factor.
Other genes identified by Baillie’s team could ramp up the inflammatory responses to lung damage triggered by SARS-CoV-2, reactions that can be lethal to some patients. One, DPP9, codes for an enzyme known to be involved in lung disease; another, TYK2, encodes a signaling protein involved in inflammation. Drugs that target those two genes’ proteins are already in use—inhibitors of DPP9’s enzyme for diabetes and baricitinib, which blocks TYK2’s product, for arthritis. Baricitinib is in early clinical testing for COVID-19, and the new data could push it up the priority list, Baillie says.
The chromosome 3 region still stands out as the most powerful genetic actor: A single copy of the disease-associated variant more than doubles an infected person’s odds of developing severe COVID-19. Evolutionary biologists reported last month in Nature5 that this suspicious region actually came from Neanderthals, through interbreeding with our species tens of thousands of years ago. It is now found in about 16% of Europeans and 50% of South Asians.
But the specific chromosome 3 gene or genes at play remain elusive. By analyzing gene activity data from normal lung tissue of people with and without the variant, the U.K. team homed in on CCR2, a gene that encodes a receptor for cytokine proteins that play a role in inflammation. But other data discussed at last week’s meeting point to SLC6Z20, which codes for a protein that interacts with the main cell receptor used by SARS-CoV-2 to enter cells. “I don’t think anyone at this point has a clear understanding of what are the underlying genes” for the chromosome 3 link, says Andrea Ganna of the University of Helsinki, who co-leads the COVID-19 Host Genetics Initiative.
The U.K. genetics study did not confirm that the ABO variants affect the odds of severe disease. Some studies looking directly at blood type, not genetic markers, have reported that type O blood protects against COVID-19, whereas A blood makes a person more vulnerable. It may be that blood type influences whether a person gets infected, but not how sick they get, says Stanford University geneticist Manuel Rivas. In any case, O blood offers at best modest protection. “There are a lot of people with O blood that have died of the disease. It doesn’t really help you,” says geneticist Andre Franke of the Christian-Albrecht University of Kiel, a coleader of the NEJM study.
Researchers expect to pin down more COVID-19 risk genes—already, after folding in the U.K. data plumbed by Baillie’s team, the COVID-19 Host Genetics Initiative has found another hit, a gene called FOXP4 implicated in lung cancer. And in a new medRxiv preprint posted last week6, the company Ancestry.com reports that a gene previously connected to the effects of the flu may also boost COVID-19 susceptibility only in men, who are more likely to die of the disease than women.
Geneticists have had little luck so far identifying gene variants that explain why COVID-19 has hit Black people in the United States and United Kingdom particularly hard. The chromosome 3 variant is absent in most people of African ancestry. Researchers suspect that socioeconomic factors and preexisting conditions may better explain the increased risks. But several projects, including Baillie’s, are recruiting more people of non-European backgrounds to bolster their power to find COVID-19 gene links. And in an abstract for an online talk later this month at the American Society of Human Genetics annual meeting, the company Regeneron reports it has found a genome region that may raise the risk of severe disease mainly in people of African ancestry.
4003 - Trans-ancestry imputation and exome sequencing of 868,021 individuals identifies 4 loci and 3 genes associated with Covid-19 susceptibility and hospitalization.
October 28, 2020, 5:30 PM - 5:45 PM
Author
J. Kosmicki1, J. Mbatchou1, C. O'Dushlaine1, A. Marcketta1, J. Horowitz1, D. Sun1, A. Li1, N. Banerjee1, M. Cantor1, D. Ledbetter2, A. Baris1, J. L. Marchini1, G. Abecasis1, M. A. R. Ferreira1, DiscovEHR, Regeneron Genetics Center;
1Regeneron Genetics Center, Tarrytown, NY, USA, 2Geisinger Health System, Danville, PA, USA.
Abstract
Covid-19 symptoms vary widely, ranging from asymptomatic in some patients to fatal in others. Elucidating the host genetics of Covid-19 holds the potential for understanding both susceptibility of SARS-CoV-2 infection as well as heterogeneity in patient presentation and outcome. Prior work focused on identifying common variants associated with Covid-19 susceptibility and severity, but little has been done to explore the entire allele frequency spectrum of genetic variation, from common to rare exonic variants. Here, we present the largest trans-ancestry exome sequencing study of Covid-19 to date in 579,799 individuals, with a larger set of 868,021 individuals with imputed data, across 6 studies and 4 ancestries. We identified 4 loci and 3 genes from rare variant burden tests. We tested three phenotypes: susceptibility, defined by SARS-CoV-2 infection (7156 cases; 860865 controls), and severity, proxied first by hospitalization (2933 cases; 655085 controls), and secondly by patients who had passed away or required ventilation (2058 cases; 487175 controls). Prior GWAS of Covid-19 identified 2 loci: the gene-rich 3p21.31 locus and the ABO locus. We replicated the 3p21.31 locus in all 3 phenotypes; the effect size increasing with the Covid-19 severity (susceptibility: P =5e-9; OR=1.2±0.1; hospitalization: P =2e-14; OR=1.6±0.2; severe: P =3e-11; OR=2±0.3), indicating this locus contributes to heterogeneity in case presentation. Of the 13 genes in the LD with the lead SNP, only CCRL2 demonstrated a nominal association from gene burden tests of rare protein truncating and missense variants. The ABO locus did not replicate in any of our analyses, suggesting it may be a false positive. Beyond previously reported associations, we also identified 3 novel loci and 3 genes associated with Covid-19. For susceptibility, gene burden tests identified 3 novel genes, GPS2 ( P =4e-8), METTL7B ( P =1e-6), and PLPPR3 ( P =2e-6). Amongst hospitalized cases, we identified 1 gene, GPS2 ( P =2e-6) and three novel loci: a locus enriched in individuals of African ancestry on 1p31.1 ( P= 3e-8), 16q24.3 ( P =4e-8), and 22q21.1 ( P =1e-9). The lead SNP on 22q21.1 is in high LD with 2 missense variants in the interferon receptor, IFNAR2 , which is dysregulated in severe patients and currently in clinical trials for Covid-19. Our data represents the most comprehensive survey of the trans-ancestry common and rare coding variation associated with Covid-19 to date. We identify 3 novel loci and 3 genes contributing to susceptibility of SARS-CoV-2 infection and severity in Covid-19 outcomes.
1. www.covid19hg.org/blog/2020-10-05-october-2-2020-meeting/
2. www.medrxiv.org/content/10.1101/2020.09.24.20200048v2
3. www.nejm.org/doi/full/10.1056/NEJMoa2020283
4. www.medrxiv.org/content/10.1101/2020.09.04.2018
5. www.nature.com/articles/s41586-020-2818-38318v1
6. www.medrxiv.org/content/10.1101/2020.10.06.20205864v1
In a standard approach to finding genes that influence a condition, geneticists scan the DNA of large numbers of people for millions of marker sequences, looking for associations between specific markers and cases of the disease. In June, one such genomewide association study in The New England Journal of Medicine (NEJM)3 found two “hits” linked to respiratory failure in 1600 Italian and Spanish COVID-19 patients: a marker within the ABO gene, which determines a person’s blood type, and a stretch of chromosome 3 that holds a half-dozen genes. Those two links have also emerged in other groups’ data, including some from the DNA testing company 23andMe4.
The new study confirmed the chromosome 3 region’s involvement. And because 74% of its patients were so sick that they needed invasive ventilation, it had the statistical strength to reveal other markers, elsewhere in the genome, linked to severe COVID-19. One find is a gene called IFNAR2 that codes for a cell receptor for interferon, a powerful molecular messenger that rallies the immune defenses when a virus invades a cell. A variant of IFNAR2 found in one in four Europeans raised the risk of severe COVID-19 by 30%. Baillie says the IFNAR2 hit is “entirely complementary” to a finding reported in Science last month: very rare mutations that disable IFNAR2 and seven other interferon genes may explain about 4% of severe COVID-19 cases. Both studies raise hopes for ongoing trials of interferons as a COVID-19 treatment.
A more surprising hit from the U.K. study points to OAS genes, which code for proteins that activate an enzyme that breaks down viral RNA. A change in one of those genes might impair this activation, allowing the virus to flourish. The U.K. data suggest there is a variant as common and influential on COVID-19 as the interferon genetic risk factor.
Other genes identified by Baillie’s team could ramp up the inflammatory responses to lung damage triggered by SARS-CoV-2, reactions that can be lethal to some patients. One, DPP9, codes for an enzyme known to be involved in lung disease; another, TYK2, encodes a signaling protein involved in inflammation. Drugs that target those two genes’ proteins are already in use—inhibitors of DPP9’s enzyme for diabetes and baricitinib, which blocks TYK2’s product, for arthritis. Baricitinib is in early clinical testing for COVID-19, and the new data could push it up the priority list, Baillie says.
The chromosome 3 region still stands out as the most powerful genetic actor: A single copy of the disease-associated variant more than doubles an infected person’s odds of developing severe COVID-19. Evolutionary biologists reported last month in Nature5 that this suspicious region actually came from Neanderthals, through interbreeding with our species tens of thousands of years ago. It is now found in about 16% of Europeans and 50% of South Asians.
But the specific chromosome 3 gene or genes at play remain elusive. By analyzing gene activity data from normal lung tissue of people with and without the variant, the U.K. team homed in on CCR2, a gene that encodes a receptor for cytokine proteins that play a role in inflammation. But other data discussed at last week’s meeting point to SLC6Z20, which codes for a protein that interacts with the main cell receptor used by SARS-CoV-2 to enter cells. “I don’t think anyone at this point has a clear understanding of what are the underlying genes” for the chromosome 3 link, says Andrea Ganna of the University of Helsinki, who co-leads the COVID-19 Host Genetics Initiative.
The U.K. genetics study did not confirm that the ABO variants affect the odds of severe disease. Some studies looking directly at blood type, not genetic markers, have reported that type O blood protects against COVID-19, whereas A blood makes a person more vulnerable. It may be that blood type influences whether a person gets infected, but not how sick they get, says Stanford University geneticist Manuel Rivas. In any case, O blood offers at best modest protection. “There are a lot of people with O blood that have died of the disease. It doesn’t really help you,” says geneticist Andre Franke of the Christian-Albrecht University of Kiel, a coleader of the NEJM study.
Researchers expect to pin down more COVID-19 risk genes—already, after folding in the U.K. data plumbed by Baillie’s team, the COVID-19 Host Genetics Initiative has found another hit, a gene called FOXP4 implicated in lung cancer. And in a new medRxiv preprint posted last week6, the company Ancestry.com reports that a gene previously connected to the effects of the flu may also boost COVID-19 susceptibility only in men, who are more likely to die of the disease than women.
Geneticists have had little luck so far identifying gene variants that explain why COVID-19 has hit Black people in the United States and United Kingdom particularly hard. The chromosome 3 variant is absent in most people of African ancestry. Researchers suspect that socioeconomic factors and preexisting conditions may better explain the increased risks. But several projects, including Baillie’s, are recruiting more people of non-European backgrounds to bolster their power to find COVID-19 gene links. And in an abstract for an online talk later this month at the American Society of Human Genetics annual meeting, the company Regeneron reports it has found a genome region that may raise the risk of severe disease mainly in people of African ancestry.
4003 - Trans-ancestry imputation and exome sequencing of 868,021 individuals identifies 4 loci and 3 genes associated with Covid-19 susceptibility and hospitalization.
October 28, 2020, 5:30 PM - 5:45 PM
Author
J. Kosmicki1, J. Mbatchou1, C. O'Dushlaine1, A. Marcketta1, J. Horowitz1, D. Sun1, A. Li1, N. Banerjee1, M. Cantor1, D. Ledbetter2, A. Baris1, J. L. Marchini1, G. Abecasis1, M. A. R. Ferreira1, DiscovEHR, Regeneron Genetics Center;
1Regeneron Genetics Center, Tarrytown, NY, USA, 2Geisinger Health System, Danville, PA, USA.
Abstract
Covid-19 symptoms vary widely, ranging from asymptomatic in some patients to fatal in others. Elucidating the host genetics of Covid-19 holds the potential for understanding both susceptibility of SARS-CoV-2 infection as well as heterogeneity in patient presentation and outcome. Prior work focused on identifying common variants associated with Covid-19 susceptibility and severity, but little has been done to explore the entire allele frequency spectrum of genetic variation, from common to rare exonic variants. Here, we present the largest trans-ancestry exome sequencing study of Covid-19 to date in 579,799 individuals, with a larger set of 868,021 individuals with imputed data, across 6 studies and 4 ancestries. We identified 4 loci and 3 genes from rare variant burden tests. We tested three phenotypes: susceptibility, defined by SARS-CoV-2 infection (7156 cases; 860865 controls), and severity, proxied first by hospitalization (2933 cases; 655085 controls), and secondly by patients who had passed away or required ventilation (2058 cases; 487175 controls). Prior GWAS of Covid-19 identified 2 loci: the gene-rich 3p21.31 locus and the ABO locus. We replicated the 3p21.31 locus in all 3 phenotypes; the effect size increasing with the Covid-19 severity (susceptibility: P =5e-9; OR=1.2±0.1; hospitalization: P =2e-14; OR=1.6±0.2; severe: P =3e-11; OR=2±0.3), indicating this locus contributes to heterogeneity in case presentation. Of the 13 genes in the LD with the lead SNP, only CCRL2 demonstrated a nominal association from gene burden tests of rare protein truncating and missense variants. The ABO locus did not replicate in any of our analyses, suggesting it may be a false positive. Beyond previously reported associations, we also identified 3 novel loci and 3 genes associated with Covid-19. For susceptibility, gene burden tests identified 3 novel genes, GPS2 ( P =4e-8), METTL7B ( P =1e-6), and PLPPR3 ( P =2e-6). Amongst hospitalized cases, we identified 1 gene, GPS2 ( P =2e-6) and three novel loci: a locus enriched in individuals of African ancestry on 1p31.1 ( P= 3e-8), 16q24.3 ( P =4e-8), and 22q21.1 ( P =1e-9). The lead SNP on 22q21.1 is in high LD with 2 missense variants in the interferon receptor, IFNAR2 , which is dysregulated in severe patients and currently in clinical trials for Covid-19. Our data represents the most comprehensive survey of the trans-ancestry common and rare coding variation associated with Covid-19 to date. We identify 3 novel loci and 3 genes contributing to susceptibility of SARS-CoV-2 infection and severity in Covid-19 outcomes.
1. www.covid19hg.org/blog/2020-10-05-october-2-2020-meeting/
2. www.medrxiv.org/content/10.1101/2020.09.24.20200048v2
3. www.nejm.org/doi/full/10.1056/NEJMoa2020283
4. www.medrxiv.org/content/10.1101/2020.09.04.2018
5. www.nature.com/articles/s41586-020-2818-38318v1
6. www.medrxiv.org/content/10.1101/2020.10.06.20205864v1