Novel genes and sex differences in COVID-19 severity

被引：47

作者：

Cruz, Raquel ^{[1
,2
,3
,4
]}

Diz-de Almeida, Silvia ^{[4
]}

Lopez de Heredia, Miguel ^{[2
]}

Quintela, Ines ^{[1
]}

Ceballos, Francisco C. ^{[5
]}

Lorenzo-Salazar, Guillermo M. ^{[7
]}

Gonzalez-Montelongo, Rafaela ^{[7
]}

Gago-Dominguez, Manuela ^{[3
,8
]}

Sevilla Porras, Marta ^{[2
,9
]}

Tenorio Castano, Jair Antonio ^{[2
,9
,10
]}

Nevado, Julian ^{[2
,9
,10
]}

Maria Aguado, Jose ^{[11
,12
,13
,14
]}

Aguilar, Carlos ^{[15
]}

Aguilera-Albesa, Sergio ^{[16
,17
]}

Almadana, Virginia ^{[18
]}

Almoguera, Berta ^{[2
,19
]}

Alvarez, Nuria ^{[6
]}

Andreu-Bernabeu, Alvaro ^{[13
,20
]}

Arana-Arri, Eunate ^{[21
,22
]}

Arango, Celso ^{[13
,20
,23
]}

Arranz, Maria J. ^{[24
]}

Artiga, Maria-Jesus ^{[25
]}

Baptista-Rosas, Raul C. ^{[26
,27
,28
]}

Barreda-Sanchez, Maria ^{[29
,30
]}

Belhassen-Garcia, Moncef ^{[31
,32
]}

Bezerra, Joao F. ^{[33
]}

Bezerra, Marcos A. C. ^{[34
]}

Boix-Palop, Lucia ^{[35
]}

Brion, Maria ^{[36
,37
]}

Brugada, Ramon ^{[37
,38
,39
,40
]}

Bustos, Matilde ^{[41
]}

Calderon, Enrique J. ^{[42
,43
,44
]}

Carbonell, Cristina ^{[32
,45
]}

Castano, Luis ^{[2
,21
,22
,46
,47
]}

Castelao, Jose E. ^{[48
]}

Conde-Vicente, Rosa ^{[49
]}

Cordero-Lorenzana, M. Lourdes ^{[50
]}

Cortes-Sanchez, Jose L. ^{[51
,52
]}

Corton, Marta ^{[2
,19
]}

Darnaude, M. Teresa ^{[53
]}

De Martino-Rodriguez, Alba ^{[54
,55
]}

del Campo-Perez, Victor ^{[56
]}

Diaz de Bustamante, Aranzazu ^{[53
]}

Dominguez-Garrido, Elena ^{[57
]}

Luchessi, Andre D. ^{[58
]}

Eiros, Rocio ^{[59
]}

Estigarribia Sanabria, Gladys Mercedes ^{[60
]}

Carmen Farinas, Maria ^{[61
,62
,63
]}

Fernandez-Robelo, Uxia ^{[64
]}

Fernandez-Rodriguez, Amanda ^{[5
,14
]}

机构：

[1] Univ Santiago de Compostela, Ctr Nacl Genotipado CEGEN, Santiago De Compostela 15706, Spain

[2] Inst Salud Carlos III, Ctr Biomed Network Res Rare Dis CIBERER, Madrid 28029, Spain

[3] Inst Invest Sanitaria Santiago IDIS, Santiago De Compostela 15706, Spain

[4] Univ Santiago de Compostela, Ctr Singular Invest Med Mol & Enfermedades Cronic, Santiago De Compostela 15782, Spain

[5] Inst Salud Carlos III ISCIII, Ctr Nacl Microbiol CNM, Unidad Infecc Viral & Inmun, Madrid 28220, Spain

[6] Spanish Natl Canc Res Ctr, Human Genotyping CEGEN Unit, Madrid 28029, Spain

[7] Inst Tecnol & Energias Renovables, Genom Div, Santa Cruz De Tenerife 38600, Spain

[8] Fdn Publ Galegade Med Xenom, Sistema Galegode Saude SERGAS, Santiago De Compostela 15706, Spain

[9] Hosp Univ La Paz IDIPAZ, Inst Genet Med & Mol INGEMM, Madrid 28046, Spain

[10] ERN, ITHACA, European Reference Network, Amsterdam, Netherlands

[11] Hosp Univ 12 Octubre, Inst Invest Sanitaria Hosp 12 Octubre imas12, Unit Infect Dis, Madrid 28041, Spain

[12] Inst Salud Carlos III, Spanish Network Res Infect Dis REIPI RD16 0016 00, Madrid 28029, Spain

[13] Univ Complutense, Sch Med, Madrid 28040, Spain

[14] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Infecciosas CI, Madrid 28029, Spain

[15] Hosp Gen Santa Barbara Soria, Soria 42005, Spain

[16] Navarra Hlth Serv Hosp, Dept Pediat, Pediat Neurol Unit, Pamplona 31008, Spain

[17] NavarraBioMed Res Grp, Navarra Hlth Serv, Pamplona 31008, Spain

[18] Hosp Univ Virgen Macarena, Neumol, Seville 41009, Spain

[19] Univ Autonoma Madrid, Fdn Jimenez Diaz Univ Hosp, Inst Invest Sanitaria, UAM,FJD,IIS,Dept Genet & Genom, Madrid 28040, Spain

[20] Hosp Gen Univ Gregorio Maranon IiSGM, Inst Psychiat & Mental Hlth, Dept Child & Adolescent Psychiat, Madrid 28007, Spain

[21] Biocruces Bizkai HRI, Baracaldo 48903, Bizkaia, Spain

[22] Cruces Univ Hosp, Osakidetza, Baracaldo 48903, Bizkaia, Spain

[23] Inst Salud Carlos III, Ctr Biomed Network Res Mental Hlth CIBERSAM, Madrid 28029, Spain

[24] Fdn Docencia I Recerca Mutua Terrassa, Terrassa 08221, Spain

[25] Spanish Natl Canc Res Ctr, CNIO Biobank, Madrid 28029, Spain

[26] Hosp Gen Occidente Seguro Social, Zapopan 45170, Jalisco, Mexico

[27] Univ Guadalajara, Ctr Univ Tonala, Tonala 45425, Jalisco, Mexico

[28] Univ Guadalajara, Ctr Invest Multidisciplinario Salud, Tonala 45425, Jalisco, Mexico

[29] Inst Murciano Invest Biosanitaria IMIB Arrixaca, Murcia, Spain

[30] Univ Catolica San Antonio Murcia UCAM, Murcia 30120, Spain

[31] Hosp Univ Salamanca IBSAL, Serv Med Interna, Unidad Enfermedades Infecciosas, Salamanca 37007, Spain

[32] Univ Salamanca, Salamanca 37007, Spain

[33] Escola Tecn Saude, Lab Vigilancia Mol Aplicada, BR-68515000 Brasilia, Para, Brazil

[34] Univ Fed Pernambuco, Genet Postgrad Program, BR-50670907 Recife, PE, Brazil

[35] Hosp Univ Mutua Terrassa, Terrassa 08221, Spain

[36] Inst Invest Sanitaria Santiago IDIS, Xenet Cardiovasc, Santiago De Compostela 15706, Spain

[37] Inst Salud Carlos III, Ctr Biomed Network Res Cardiovasc Dis CIBERCV, Madrid 28029, Spain

[38] Inst Invest Biomed Girona IDIBGI, Cardiovasc Genet Ctr, Girona 17190, Spain

[39] Univ Girona, Sch Med, Med Sci Dept, Girona 17190, Spain

[40] Hosp Josep Trueta, Cardiol Serv, Girona 17190, Spain

[41] Univ Seville, Virgen Rocio Univ Hosp, Consejo Super Invest Cient CSIC, Inst Biomed Seville IBiS, Seville 41013, Spain

[42] Univ Seville, Hosp Univ Virgen Rocio, Dept Med, Seville 41013, Spain

[43] Inst Salud Carlos III, Ctr Biomed Network Res Epidemiol & Publ Hlth CIBE, Madrid 28029, Spain

[44] Inst Biomed Sevilla, Seville 41013, Spain

[45] Hosp Univ Salamanca IBSAL, Serv Med Interna, Salamanca 37007, Spain

[46] Inst Salud Carlos III, Ctr Biomed Network Res Diabet & Metab Associated, Madrid 28029, Spain

[47] Univ Basque Country, UPV EHU, Bizkaia 48903, Spain

[48] Inst Invest Sanitaria Galicia Sur, Xerencia Xest Integrada Vigo Serv Galego Saude, Oncol & Genet Unit, Vigo 36312, Spain

[49] Hosp Univ Rio Hortega, Valladolid 47012, Spain

[50] Complejo Hosp Univ A Coruna CHUAC, Sistema Galego Saude SERGAS, Serv Med Intens, La Coruna 15009, Spain

来源：

HUMAN MOLECULAR GENETICS | 2022年

关键词：

ANDROGEN RECEPTOR; AUTOZYGOSITY; HOMOZYGOSITY; ASSOCIATION; INTERFERON; COMPLEMENT; EXPRESSION; SARS-COV-2; GENETICS; RANGE;

D O I：

10.1093/hmg/ddac132

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Here, we describe the results of a genome-wide study conducted in 11939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P<5x10(-8)) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P= 1.3x10(-22) and P= 8.1x10(-12), respectively), and for variants in 9q21.32 near TLE1 only among females (P= 4.4x10(-8)). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P= 2.7x10(-8)) and ARHGAP33 (P= 1.3x10(-8)), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P=4.1x10(-8)). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or >= 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

引用

页码：3789 / 3806

页数：18

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