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

Butler-Laporte G, Povysil G, Kosmicki JA, Cirulli ET, Drivas T, Furini S, Saad C, Schmidt A, Olszewski P, Korotko U, Quinodoz M, Çelik E, Kundu K, Walter K, Jung J, Stockwell AD, Sloofman LG, Jordan DM, Thompson RC, Del Valle D, Simons N, Cheng E, Sebra R, Schadt EE, Kim-Schulze S, Gnjatic S, Merad M, Buxbaum JD, Beckmann ND, Charney AW, Przychodzen B, Chang T, Pottinger TD, Shang N, Brand F, Fava F, Mari F, Chwialkowska K, Niemira M, Pula S, Baillie JK, Stuckey A, Salas A, Bello X, Pardo-Seco J, Gómez-Carballa A, Rivero-Calle I, Martinón-Torres F, Ganna A, Karczewski KJ, Veerapen K, Bourgey M, Bourque G, Eveleigh RJ, Forgetta V, Morrison D, Langlais D, Lathrop M, Mooser V, Nakanishi T, Frithiof R, Hultström M, Lipcsey M, Marincevic-Zuniga Y, Nordlund J, Schiabor Barrett KM, Lee W, Bolze A, White S, Riffle S, Tanudjaja F, Sandoval E, Neveux I, Dabe S, Casadei N, Motameny S, Alaamery M, Massadeh S, Aljawini N, Almutairi MS, Arabi YM, Alqahtani SA, Al Harthi FS, Almutairi A, Alqubaishi F, Alotaibi S, Binowayn A, Alsolm EA, El Bardisy H, Fawzy M, Cai F, Soranzo N, Butterworth A, COVID-19 Host Genetics Initiative , DeCOI Host Genetics Group , GEN-COVID Multicenter Study (Italy) , Mount Sinai Clinical Intelligence Center , GEN-COVID consortium (Spain) , GenOMICC Consortium , Japan COVID-19 Task Force , Regeneron Genetics Center , Geschwind DH, Arteaga S, Stephens A, Butte MJ, Boutros PC, Yamaguchi TN, Tao S, Eng S, Sanders T, Tung PJ, Broudy ME, Pan Y, Gonzalez A, Chavan N, Johnson R, Pasaniuc B, Yaspan B, Smieszek S, Rivolta C, Bibert S, Bochud PY, Dabrowski M, Zawadzki P, Sypniewski M, Kaja E, Chariyavilaskul P, Nilaratanakul V, Hirankarn N, Shotelersuk V, Pongpanich M, Phokaew C, Chetruengchai W, Tokunaga K, Sugiyama M, Kawai Y, Hasegawa T, Naito T, Namkoong H, Edahiro R, Kimura A, Ogawa S, Kanai T, Fukunaga K, Okada Y, Imoto S, Miyano S, Mangul S, Abedalthagafi MS, Zeberg H, Grzymski JJ, Washington NL, Ossowski S, Ludwig KU, Schulte EC, Riess O, Moniuszko M, Kwasniewski M, Mbarek H, Ismail SI, Verma A, Goldstein DB, Kiryluk K, Renieri A, Ferreira MAR, Richards JB

PLoS Genet. 18 (11) e1010367 [2022-11-00; online 2022-11-03]

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.

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NGI Uppsala (SNP&SEQ Technology Platform) [Service]

National Genomics Infrastructure [Service]

PubMed 36327219

DOI 10.1371/journal.pgen.1010367

Crossref 10.1371/journal.pgen.1010367

pmc: PMC9632827
pii: PGENETICS-D-22-00434


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