Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative

被引：36

作者：

Butler-Laporte, Guillaume ^{[1
,2
]}

Povysil, Gundula ^{[3
]}

Kosmicki, Jack A. ^{[4
]}

Cirulli, Elizabeth T. ^{[5
]}

Drivas, Theodore ^{[6
,7
,8
]}

Furini, Simone ^{[9
,10
]}

Saad, Chadi ^{[11
]}

Schmidt, Axel ^{[12
,13
]}

Olszewski, Pawel ^{[14
]}

Korotko, Urszula ^{[14
,15
]}

Quinodoz, Mathieu ^{[16
,17
,18
]}

Celik, Elifnaz ^{[16
,18
]}

Kundu, Kousik ^{[19
,20
]}

Walter, Klaudia ^{[20
]}

Jung, Junghyun ^{[21
,22
]}

Stockwell, Amy D. ^{[23
]}

Sloofman, Laura G. ^{[24
]}

Jordan, Daniel M. ^{[25
]}

Thompson, Ryan C. ^{[26
]}

Del Valle, Diane ^{[27
]}

Simons, Nicole ^{[27
]}

Cheng, Esther ^{[27
]}

Sebra, Robert ^{[28
]}

Schadt, Eric E. ^{[28
]}

Kim-Schulze, Seunghee ^{[29
]}

Gnjatic, Sacha ^{[27
]}

Merad, Miriam ^{[30
]}

Buxbaum, Joseph D. ^{[24
]}

Beckmann, Noam D. ^{[30
]}

Charney, Alexander W. ^{[31
]}

Przychodzen, Bartlomiej ^{[32
]}

Chang, Timothy ^{[33
]}

Pottinger, Tess D. ^{[3
]}

Shang, Ning ^{[34
]}

Brand, Fabian ^{[13
,35
]}

Fava, Francesca ^{[9
,10
,36
,37
]}

Mari, Francesca ^{[9
,10
,36
,37
]}

Chwialkowska, Karolina ^{[14
,15
]}

Niemira, Magdalena ^{[38
]}

Pula, Szymon ^{[14
]}

Baillie, J. Kenneth ^{[39
,40
,41
,42
]}

Stuckey, Alex ^{[43
]}

Salas, Antonio ^{[44
,45
,46
]}

Bello, Xabier ^{[44
,45
,46
]}

Pardo-Seco, Jacobo ^{[44
,45
,46
]}

Gomez-Carballa, Alberto ^{[44
,45
,46
]}

Rivero-Calle, Irene ^{[45
,46
,47
]}

Martinon-Torres, Federico ^{[45
,46
,47
]}

Ganna, Andrea ^{[48
,49
]}

Karczewski, Konrad J. ^{[50
,51
]}

机构：

[1] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada

[2] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ, Canada

[3] Columbia Univ, Inst Genom Med, New York, NY USA

[4] Regeneron Genet Ctr, Tarrytown, NY USA

[5] Helix, San Mateo, CA USA

[6] Childrens Hosp Philadelphia, Dept Pediat, Div Human Genet, Philadelphia, PA 19104 USA

[7] Univ Penn, Dept Med, Perelman Sch Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA

[8] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA

[9] Univ Siena, Med Biotech Hub, Dept Med Biotechnol, Siena, Italy

[10] Univ Siena, Competence Ctr, Siena, Italy

[11] Qatar Fdn, Qatar Fdn Res Dev & Innovat, Qatar Genome Program, Doha, Qatar

[12] Univ Bonn, Sch Med, Inst Human Genet, Bonn, Germany

[13] Univ Bonn, Univ Hosp Bonn, Bonn, Germany

[14] IMAGENEME SA, Bialystok, Poland

[15] Med Univ Bialystok, Ctr Bioinformat & Data Anal, Bialystok, Poland

[16] Inst Mol & Clin Ophthalmol Basel IOB, Basel, Switzerland

[17] Univ Leicester, Dept Genet & Genome Biol, Leicester, Leics, England

[18] Univ Hosp Basel, Dept Ophthalmol, Basel, Switzerland

[19] Univ Cambridge, Dept Haematol, Cambridge, England

[20] Wellcome Sanger Inst, Dept Human Genet, Hinxton, England

[21] Univ Southern Calif, Sch Pharm, Dept Clin Pharm, Los Angeles, CA USA

[22] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA

[23] Genentech Inc, San Francisco, CA 94080 USA

[24] Icahn Sch Med Mt Sinai, Seaver Autism Ctr Res & Treatment, Dept Psychiat, New York, NY 10029 USA

[25] Icahn Sch Med Mt Sinai, Mt Sinai Cln Intelligence Ctr, Charles Bronfman Inst Personalized Med, Dept Genet & Genom Sci, New York, NY 10029 USA

[26] Icahn Inst Data Sci & Genom Technol, New York, NY USA

[27] Icahn Sch Med Mt Sinai, New York, NY 10029 USA

[28] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[29] Icahn Sch Med Mt Sinai, Human Immune Monitoring Ctr, Precis Immunol Inst, Dept Oncol Sci, New York, NY 10029 USA

[30] Icahn Sch Med Mt Sinai, Tisch Canc Inst, Precis Immunol Inst, New York, NY 10029 USA

[31] Icahn Sch Med Mt Sinai, Mt Sinai Clin Intelligence Ctr, Dept Genet & Genom Sci, New York, NY 10029 USA

[32] Vanda Pharmaceut, Washington, DC USA

[33] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA

[34] Columbia Univ, Vagelos Coll Phys & Surg, Dept Med, Div Nephrol, New York, NY USA

[35] Univ Bonn, Sch Med, Inst Genom Stat & Bioinformat, Bonn, Germany

[36] Azienda Osped Univ Senese, Genet Med, Siena, Italy

[37] Univ Siena, Med Genet, Siena, Italy

[38] Med Univ Bialystok, Ctr Clin Res, Bialystok, Poland

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

[40] Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland

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

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

[43] Genom England, London, England

[44] Univ Santiago de Compostela, Hosp Clin Univ Santiago SERGAS, Fac Med, Inst Ciencias Forenses INCIFOR, Santiago De Compostela, Spain

[45] Inst Invest Sanitaria Santiago, Genet Vaccines & Infect Res Grp GENVIP, Santiago De Compostela, Spain

[46] Ctr Invest Biomed Red Enfermedades Resp CIBER ES, Madrid, Spain

[47] Hosp Clin Univ Santiago de Compostela, Dept Pediat, Translat Pediat & Infect Dis, Santiago De Compostela, Spain

[48] Univ Helsinki, Inst Mol Med Finland, Helsinki Inst Life Sci, Helsinki, Finland

[49] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02115 USA

[50] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Genet, Cambridge, MA USA

来源：

PLOS GENETICS | 2022年 / 18卷 / 11期

基金：

英国医学研究理事会; 瑞典研究理事会; 美国国家卫生研究院; 加拿大健康研究院; 瑞士国家科学基金会; 英国生物技术与生命科学研究理事会; 日本科学技术振兴机构;

关键词：

PROTEINS;

D O I：

10.1371/journal.pgen.1010367

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10(-7)). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights. Author summary COVID-19 clinical outcomes vary immensely, but a patient's genetic make-up is an important determinant of how they will fare against the virus. While many genetic variants commonly found in the populations were previously found to be contributing to more severe disease by the COVID-19 Host Genetics Initiative, it isn't clear if more rare variants found in less individuals could also play a role. This is important because genetic variants with the largest impact on COVID-19 severity are expected to be rarely found in the population, and these rare variants require different technologies to be studies (usually whole-exome or whole-genome sequencing). Here, we combined sequencing results from 21 cohorts across 12 countries to perform a rare variant association study. In an analysis comprising 5,085 participants with severe COVID-19 and 571,737 controls, we found that the gene for toll-like receptor 7 (TLR7) on chromosome X was an important determinant of severe COVID-19. Importantly, despite being found on a sex chromosome, this observation was consistent across both sexes.

引用

页数：26

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