Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19

Gaziano, Liam; Giambartolomei, Claudia; Pereira, Alexandre C.; Gaulton, Anna; Posner, Daniel; Swanson, Sonja A.; Ho, Yuk‐Lam; Iyengar, Sudha K.; Kosik, Nicole; Vujkovic, Marijana; Gagnon, David; Bento, A. Patrícia; Barrio-Hernandez, Iñigo; Rönnblom, Lars; Hagberg, Niklas; Lundtoft, Christian; Langenberg, Claudia; Pietzner, Maik; Valentine, Dennis; Gustincich, Stefano; Tartaglia, Gian Gaetano; Allara, Elias; Surendran, Praveen; Burgess, Stephen; Zhao, Jing Hua; Peters, James E.; Prins, Bram P.; Angelantonio, Emanuele Di; Devineni, Poornima; Shi, Yunling; Lynch, Kristine E.; DuVall, Scott L.; Garcon, Helene; Thomann, Lauren O.; Zhou, Jin; Gorman, Bryan R.; Huffman, Jennifer E.; O’Donnell, Christopher J.; Tsao, Philip S.; Beckham, Jean C.; Pyarajan, Saiju; Muralidhar, Sumitra; Huang, Grant D.; Ramoni, Rachel; Beltrão, Pedro; Danesh, John; Hung, Adriana M.; Chang, Kyong–Mi; Sun, Yan V.; Joseph, Jacob; Leach, Andrew R.; Edwards, Todd L.; Cho, Kelly; Gaziano, J. Michael; Butterworth, Adam S.; Casas, Juan P.

doi:10.1038/s41591-021-01310-z

Cited by 156 publications

(154 citation statements)

References 61 publications

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“…This association has also been observed in other GWAS [ 15 , 17 ] but not all [ 16 ]. Several other putative genome-wide associations have been identified in individual studies with various approaches, including antiviral effectors OAS1, OAS2, OAS3; TYK2; IL10RB ; and ACE2 [ 16 , 17 , 19 ] (Table 1 ). Interestingly, these studies have not identified a significant association in the human leukocyte antigen (HLA) locus, although two targeted analyses of HLA types have reported significant associations with SARS-CoV-2 infection [ 20 , 21 ].…”

Section: Genome-wide Association Studies Of Severe Covid-19mentioning

confidence: 99%

Host genetics of pediatric SARS-CoV-2 COVID-19 and multisystem inflammatory syndrome in children

Schulert

Blum

Cron

2021

Current Opinion in Pediatrics

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Purpose of review This review is meant to describe the genetic associations with pediatric severe COVID-19 pneumonia and the postinfectious complication of the multisystem inflammatory syndrome in children (MIS-C). Multiple genetic approaches have been carried out, primarily in adults with extrapolation to children, including genome-wide association studies (GWAS), whole exome and whole genome sequencing (WES/WGS), and target gene analyses. Recent findings Data from adults with severe COVID-19 have identified genomic regions (human leukocyte antigen locus and 3p21.31) as potential risk factors. Genes related to viral entry into cells (ABO blood group locus, ACE2, TMPRS22 ) have been linked to severe COVID-19 patients by GWAS and target gene approaches. Type I interferon (e.g. IFNAR2 ) and antiviral gene (e.g. TLR7 ) associations have been identified by several genetic approaches in severe COVID-19. WES has noted associations with several immune regulatory genes (e.g. SOCS1 ). Target gene approaches have identified mutations in perforin-mediated cytolytic pathway genes in children and adults with severe COVID-19 and children with MIS-C. Summary Several genetic associations have been identified in individuals with severe COVID-19 and MIS-C via various genetic approaches. Broadly speaking, COVID-19 genetic associations include genes involved with antiviral functions, viral cell entry, immune regulation, chemotaxis of white blood cells, and lymphocyte cytolytic function.

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Section: Genome-wide Association Studies Of Severe Covid-19mentioning

confidence: 99%

Host genetics of pediatric SARS-CoV-2 COVID-19 and multisystem inflammatory syndrome in children

Schulert

Blum

Cron

2021

Current Opinion in Pediatrics

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“…A genetic instrument for IL-6R was found to be associated with a lower risk of hospitalization for COVID-19, suggesting the relevance of therapeutic inhibition of IL-6R, which has now been confirmed in clinical trials (Bovijn et al 2020; The WHO Rapid Evidence Appraisal for COVID-19 Therapies (RE-ACT) Working Group et al 2021). MR has also been used to systematically scan hundreds of druggable proteins to prioritize targets for drug trials, for example, highlighting OAS1 as a candidate for drug development (Gaziano et al 2021;Zhou et al 2021). Additional studies point toward host antiviral defense mechanisms and mediators of inflammatory organ damage as mechanisms underlying critical illness in COVID-19 (Pairo-Castineira et al 2021).…”

Section: Trends and Future Developmentsmentioning

confidence: 99%

Causal Inference with Genetic Data: Past, Present, and Future

Pingault

Richmond

Smith

2021

Cold Spring Harb Perspect Med

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The set of methods discussed in this collection has emerged from the convergence of two scientific fields-genetics and causal inference. In this introduction, we discuss relevant aspects of each field and show how their convergence arises from the natural experiments that genetics offer. We present introductory concepts useful to readers unfamiliar with genetically informed methods for causal inference. We conclude that existing applications and foreseeable developments should ensure that we rapidly reap the rewards of this relatively new field, not only in terms of our understanding of human disease and development, but also in terms of tangible translational applications.

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“…A dysregulated type I interferon (IFN) system is typical of SLE (5)(6)(7). Type I IFNs are key components of the innate and adaptive immune responses to new pathogens, and their pivotal role in antiviral immunity is well established, including unbalanced inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (8,9). Preliminary data suggest that patients with SLE do not have an increased risk of SARS-CoV-2 infection, or severe COVID-19, compared with the general population (2,10,11).…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Antibody Isotypes in Systemic Lupus Erythematosus Patients Prior to Vaccination: Associations With Disease Activity, Antinuclear Antibodies, and Immunomodulatory Drugs During the First Year of the Pandemic

et al. 2021

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ObjectivesImpact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic on individuals with arthritis has been highlighted whereas data on other rheumatic diseases, e.g., systemic lupus erythematosus (SLE), are scarce. Similarly to SLE, severe SARS-CoV-2 infection includes risks for thromboembolism, an unbalanced type I interferon response, and complement activation. Herein, SARS-CoV-2 antibodies in longitudinal samples collected prior to vaccination were analyzed and compared with SLE progression and antinuclear antibody (ANA) levels.MethodsOne hundred patients (83 women) with established SLE and a regular visit to the rheumatologist (March 2020 to January 2021) were included. All subjects donated blood and had done likewise prior to the pandemic. SARS-CoV-2 antibody isotypes (IgG, IgA, IgM) to the cell receptor-binding S1-spike outer envelope protein were detected by ELISA, and their neutralizing capacity was investigated. IgG-ANA were measured by multiplex technology.ResultsDuring the pandemic, 4% had PCR-confirmed infection but 36% showed SARS-CoV-2 antibodies of ≥1 isotype; IgA was the most common (30%), followed by IgM (9%) and IgG (8%). The antibodies had low neutralizing capacity and were detected also in prepandemic samples. Plasma albumin (p = 0.04) and anti-dsDNA (p = 0.003) levels were lower in patients with SARS-CoV-2 antibodies. Blood group, BMI, smoking habits, complement proteins, daily glucocorticoid dose, use of hydroxychloroquine, or self-reported coronavirus disease 2019 (COVID-19) symptoms (except fever, >38.5°C) did not associate with SARS-CoV-2 antibodies.ConclusionOur data from early 2021 indicate that a large proportion of Swedish SLE patients had serological signs of exposure to SARS-CoV-2 but apparently with a minor impact on the SLE course. Use of steroids and hydroxychloroquine showed no distinct effects, and self-reported COVID-19-related symptoms correlated poorly with all antibody isotypes.

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Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19

Cited by 156 publications

References 61 publications

Host genetics of pediatric SARS-CoV-2 COVID-19 and multisystem inflammatory syndrome in children

Host genetics of pediatric SARS-CoV-2 COVID-19 and multisystem inflammatory syndrome in children

Causal Inference with Genetic Data: Past, Present, and Future

SARS-CoV-2 Antibody Isotypes in Systemic Lupus Erythematosus Patients Prior to Vaccination: Associations With Disease Activity, Antinuclear Antibodies, and Immunomodulatory Drugs During the First Year of the Pandemic

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