GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19

被引：79

作者：

Pairo-Castineira, Erola ^{[1
,2
,3
]}

Rawlik, Konrad ^{[1
]}

Bretherick, Andrew D. ^{[1
,2
,4
]}

Qi, Ting ^{[5
,6
]}

Wu, Yang ^{[7
]}

Nassiri, Isar ^{[8
]}

McConkey, Glenn A. ^{[9
]}

Zechner, Marie ^{[1
,3
]}

Klaric, Lucija ^{[2
]}

Griffiths, Fiona ^{[1
,3
]}

Oosthuyzen, Wilna ^{[1
,3
]}

Kousathanas, Athanasios ^{[10
]}

Richmond, Anne ^{[2
]}

Millar, Jonathan ^{[1
,3
,11
]}

Russell, Clark D. ^{[1
]}

Malinauskas, Tomas ^{[8
]}

Thwaites, Ryan ^{[12
]}

Morrice, Kirstie ^{[13
]}

Keating, Sean ^{[11
]}

Maslove, David ^{[14
,15
]}

Nichol, Alistair ^{[16
]}

Semple, Malcolm G. ^{[17
,18
]}

Knight, Julian ^{[8
]}

Shankar-Hari, Manu ^{[11
,19
]}

Summers, Charlotte ^{[20
]}

Hinds, Charles ^{[21
]}

Horby, Peter ^{[22
]}

Ling, Lowell ^{[23
]}

McAuley, Danny ^{[24
,25
]}

Montgomery, Hugh ^{[26
]}

Openshaw, Peter J. M. ^{[12
,27
]}

Begg, Colin ^{[28
]}

Walsh, Timothy ^{[11
]}

Tenesa, Albert ^{[2
,3
,29
]}

Flores, Carlos ^{[30
,31
,32
,33
]}

Riancho, Jose A. ^{[34
,35
,36
]}

Rojas-Martinez, Augusto ^{[37
,38
]}

Lapunzina, Pablo ^{[39
,40
,41
]}

Yang, Jian ^{[5
,6
]}

Ponting, Chris P. ^{[2
]}

Wilson, James F. ^{[2
,29
]}

Vitart, Veronique ^{[2
]}

Abedalthagafi, Malak ^{[42
,43
]}

Luchessi, Andre D. ^{[44
,45
]}

Parra, Esteban J. ^{[45
]}

Cruz, Raquel ^{[39
,46
]}

Carracedo, Angel ^{[39
,46
,47
,48
]}

Fawkes, Angie ^{[13
]}

Murphy, Lee ^{[13
]}

Rowan, Kathy ^{[49
]}

机构：

[1] Univ Edinburgh, Queens Med Res Inst, Ctr Inflammat Res, Baillie Gifford Pandem Sci Hub, Edinburgh, Midlothian, Scotland

[2] Univ Edinburgh, Inst Genet & Canc, Western Gen Hosp, MRC,Human Genet Unit, Edinburgh, Midlothian, Scotland

[3] Univ Edinburgh, Roslin Inst, Edinburgh, Midlothian, Scotland

[4] Ninewells Hosp & Med Sch, Pain Serv, NHS Tayside, Dundee, Scotland

[5] Westlake Univ, Sch Life Sci, Hangzhou, Peoples R China

[6] Westlake Lab Life Sci & Biomed, Hangzhou, Peoples R China

[7] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia

[8] Univ Oxford, Wellcome Ctr Human Genet, Oxford, England

[9] Univ Leeds, Fac Biol Sci, Leeds, W Yorkshire, England

[10] Genom England, London, England

[11] Royal Infirm Edinburgh NHS Trust, Intens Care Unit, Edinburgh, Midlothian, Scotland

[12] Imperial Coll London, Natl Heart & Lung Inst, London, England

[13] Univ Edinburgh, Western Gen Hosp, Edinburgh Clin Res Facil, Edinburgh, Midlothian, Scotland

[14] Queens Univ, Dept Crit Care Med, Kingston, ON, Canada

[15] Kingston Hlth Sci Ctr, Kingston, ON, Canada

[16] Univ Coll Dublin, St Vincents Univ Hosp, Clin Res Ctr, Dublin, Ireland

[17] Univ Liverpool, Inst Infect Vet & Ecol Sci, NIHR Hlth Protect Res Unit Emerging & Zoonot Infe, Liverpool, Merseyside, England

[18] Univ Liverpool, Alder Hey Childrens Hosp, Resp Med, Inst Pk, Liverpool, Merseyside, England

[19] Univ Edinburgh, Queens Med Res Inst, Ctr Inflammat Res, Edinburgh, Midlothian, Scotland

[20] Univ Cambridge, Dept Med, Cambridge, England

[21] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England

[22] Univ Oxford, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford, England

[23] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Anaesthesia & Intens Care, Hong Kong, Peoples R China

[24] Queens Univ Belfast, Wellcome Wolfson Inst Expt Med, Belfast, Antrim, North Ireland

[25] Royal Victoria Hosp, Dept Intens Care Med, Belfast, Antrim, North Ireland

[26] UCL Ctr Human Hlth & Performance, London, England

[27] Imperial Coll Healthcare NHS Trust, London, England

[28] Royal Hosp Children, Glasgow, Lanark, Scotland

[29] Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland

[30] Inst Tecnol & Energias Renovables, Genom Div, Santa Cruz De Tenerife, Spain

[31] Hosp Univ NS Candelaria, Res Unit, Santa Cruz De Tenerife, Spain

[32] Inst Salud Carlos III, Ctr Biomed Network Res Resp Dis CIBERES, Madrid, Spain

[33] Univ Fernando Pessoa Canarias, Dept Clin Sci, Las Palmas Gran Canaria, Spain

[34] IDIVAL, Santander, Spain

[35] Univ Cantabria, Santander, Spain

[36] Hosp UM Valdecilla, Santander, Spain

[37] Tecnol Monterrey, Escuela Med & Ciencias Salud, Monterrey, Mexico

[38] Hosp San Jose TecSalud, Monterrey, Mexico

[39] Inst Salud Carlos III, Ctr Biomed Network Res Rare Dis CIBERER, Madrid, Spain

[40] Hosp Univ La Paz, IDIPAZ, Inst Genet Med & Mol INGEMM, Madrid, Spain

[41] ERN ITHACA European Reference Network, Paris, France

[42] King Fahad Med City, Genom Res Dept, Riyadh, Saudi Arabia

[43] Emory Univ Hosp, Dept Pathol & Lab Med, 1364 Clifton Rd NE, Atlanta, GA 30322 USA

[44] Univ Fed Rio Grande do Norte, Dept Clin Anal & Toxicol, Natal, RN, Brazil

[45] Univ Toronto, Dept Anthropol, Mississauga, ON, Canada

[46] Univ Santiago de Compostela, Ctr Singular Invest Med Mol & Enfermedades Cron C, Santiago De Compostela, Spain

[47] Inst Invest Sanitaria Santiago IDIS, Santiago De Compostela, Spain

[48] Fdn Publ Galega Med Xenom Sistema Galego Saude SE, Santiago De Compostela, Spain

[49] Intens Care Natl Audit & Res Ctr, London, England

[50] Univ Sao Paulo, Heart Inst, Butanta, Brazil

来源：

NATURE | 2023年 / 617卷 / 7962期

基金：

英国惠康基金; 英国生物技术与生命科学研究理事会; 英国医学研究理事会;

关键词：

INTEGRATION; EXPRESSION; EQTL;

D O I：

10.1038/s41586-023-06034-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown(1) to be highly efficient for discovery of genetic associations(2). Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group(3). Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A). An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

引用

页码：764 / +

页数：30

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