@misc{10481/72164,
year = {2021},
month = {3},
url = {http://hdl.handle.net/10481/72164},
abstract = {Background: There is considerable variability in COVID-19 outcomes amongst younger
adults—and some of this variation may be due to genetic predisposition. We characterized the
clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent
effect, using individual-level data in a large international multi-centre consortium.
Method: The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by
the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive
patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this
genetic marker with mortality, COVID-19-related complications and laboratory values. We next
examined if the magnitude of these associations varied by age and were independent from
known clinical COVID-19 risk factors.
Findings: We found that rs10490770 risk allele carriers experienced an increased risk of
all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2–1·6) and COVID-19
related mortality (HR 1·5, 95%CI 1·3–1·8). Risk allele carriers had increased odds of several
COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6),
venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI
1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure
(OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction
p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory
COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers,
compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes.
Prediction of death or severe respiratory failure among those ≤ 60 years improved when
including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770
risk allele was similar to, or better than, most established clinical risk factors.
Interpretation: The major common COVID-19 risk locus on chromosome 3 is associated with
increased risks of morbidity and mortality—and these are more pronounced amongst individuals
≤ 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk
factors, suggesting potential implications for clinical risk management.},
organization = {Academy of
Finland Fellow grant N. 323116},
organization = {Academy of Finland for PREDICT consortium N.
340541.},
organization = {Canadian Institutes of Health Research
(CIHR) (365825 and 409511)},
organization = {Lady Davis Institute of the Jewish General Hospital},
organization = {Canadian Foundation for Innovation (CFI)},
organization = {NIH Foundation},
organization = {Cancer Research UK},
organization = {Genome Québec},
organization = {Public Health Agency of Canada},
organization = {McGill Interdisciplinary Initiative in
Infection and Immunity and the Fonds de Recherche Québec Santé (FRQS)},
organization = {Japan Society for the Promotion of Science for Young
Scientists},
organization = {CIHR scholarship and a joint FRQS and Québec Ministry of
Health and Social Services scholarship},
organization = {FRQS Clinical Research
Scholarship},
organization = {Calcul Québec},
organization = {Compute Canada},
organization = {Welcome Trust},
organization = {Medical Research Counc},
organization = {European Union},
organization = {National Institute for Health Research-funded BioResource},
organization = {Clinical Research Facility
and Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust},
organization = {King’s College London},
organization = {Genome Québec},
organization = {Public Health Agency of Canada},
organization = {McGill Interdisciplinary
Initiative in Infection and Immunity},
organization = {Fonds de Recherche Québec Santé},
organization = {(DFG Grant: “EXC2167”)},
organization = {(CompLS grant 031L0165)},
organization = {Stein Erik Hagen},
organization = {"Grupo de Trabajo en Medicina Personalizada contra el COVID-19 de Andalucia"},
organization = {Instituto de Salud Carlos III (CIBERehd and CIBERER)},
organization = {COVID-19-GWAS},
organization = {COVID-PREMED initiatives},
organization = {"Consejeria de
Salud y Familias" of the Andalusian Government},
organization = {Andalusian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018)},
organization = {Columbia University},
organization = {National
Center for Advancing Translational Sciences},
organization = {NIH Grant Number UL1TR001873},
organization = {Consejería de Economía, Conocimiento, Empresas y
Universidad #CV20-10150},
organization = {MIUR grant “Dipartimenti di Eccellenza 2018-2020”},
organization = {“Intesa San Paolo
2020 charity fund” dedicated to the project NB/2020/0119},
organization = {Tuscany Region “Bando Ricerca COVID-19 Toscana”},
organization = {CINECA
consortium},
organization = {Network for Italian Genomes (NIG)},
organization = {COVID-19 Host Genetics Initiative},
organization = {Genetic Biobank of Siena},
organization = {EuroBioBank},
organization = {RD-Connect},
organization = {Ricerca Corrente (Italian Ministry of Health)},
organization = {Fondazione
Humanitas per la Ricerca},
organization = {Banca Intesa San Paolo},
organization = {Dolce&Gabbana Fashion Firm},
organization = {COVID-19 Biobank},
organization = {Fondazione
IRCCS Cà Granda Milano},
organization = {MyFirst Grant AIRC n.16888},
organization = {Ricerca
Finalizzata Ministero della Salute RF-2016-02364358},
organization = {Ricerca corrente Fondazione IRCCS
Ca’ Granda Ospedale Maggiore Policlinico},
organization = {European Union (EU) Programme Horizon
2020 (under grant agreement No. 777377)},
organization = {“Photonics” “101016726”},
organization = {Fondazione Patrimonio Ca’ Granda “Liver Bible” PR-0361},
organization = {CV PREVITAL “Strategie di prevenzione primaria nella popolazione Italiana” Ministero della
Salute, and Associazione Italiana per la Prevenzione dell’Epatite Virale (COPEV)},
organization = {"Fonds
Erasme"},
organization = {Fondation Léon Fredericq},
organization = {Fonds de la
Recherche Scientifique (FNRS)},
organization = {Consejo Superior de Investigaciones
Científicas},
organization = {German Research Foundation (LU 1944/3-1)},
organization = {SciLifeLab/KAW national COVID-19 research program project (KAW 2020.0182)},
organization = {Swedish Research Council (2014-02569 and 2014-07606)},
organization = {Jeansson Stiftelser, Magnus
Bergvalls Stiftelse},
organization = {Technical University of Munich, Munich, Germany},
organization = {Genotyping Laboratory of
Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki,
Helsinki, Finland},
publisher = {American Society for Clinical Investigation},
title = {Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality},
doi = {10.1101/2021.03.07.21252875},
author = {Nakanishi, Tomoko and Martínez Bueno, Manuel and García García, Federico and Alarcón Riquelme, Marta Eugenia and FinnGen and The COVID-19 Host Genetics Initiative},
}