Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Butler-Laporte G

PROVIDER: S-EPMC9632827 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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

Butler-Laporte Guillaume G Povysil Gundula G Kosmicki Jack A JA Cirulli Elizabeth T ET Drivas Theodore T Furini Simone S Saad Chadi C Schmidt Axel A Olszewski Pawel P Korotko Urszula U Quinodoz Mathieu M Çelik Elifnaz E Kundu Kousik K Walter Klaudia K Jung Junghyun J Stockwell Amy D AD Sloofman Laura G LG Jordan Daniel M DM Thompson Ryan C RC Del Valle Diane D Simons Nicole N Cheng Esther E Sebra Robert R Schadt Eric E EE Kim-Schulze Seunghee S Gnjatic Sacha S Merad Miriam M Buxbaum Joseph D JD Beckmann Noam D ND Charney Alexander W AW Przychodzen Bartlomiej B Chang Timothy T Pottinger Tess D TD Shang Ning N Brand Fabian F Fava Francesca F Mari Francesca F Chwialkowska Karolina K Niemira Magdalena M Pula Szymon S Baillie J Kenneth JK Stuckey Alex A Salas Antonio A Bello Xabier X Pardo-Seco Jacobo J Gómez-Carballa Alberto A Rivero-Calle Irene I Martinón-Torres Federico F Ganna Andrea A Karczewski Konrad J KJ Veerapen Kumar K Bourgey Mathieu M Bourque Guillaume G Eveleigh Robert Jm RJ Forgetta Vincenzo V Morrison David D Langlais David D Lathrop Mark M Mooser Vincent V Nakanishi Tomoko T Frithiof Robert R Hultström Michael M Lipcsey Miklos M Marincevic-Zuniga Yanara Y Nordlund Jessica J Schiabor Barrett Kelly M KM Lee William W Bolze Alexandre A White Simon S Riffle Stephen S Tanudjaja Francisco F Sandoval Efren E Neveux Iva I Dabe Shaun S Casadei Nicolas N Motameny Susanne S Alaamery Manal M Massadeh Salam S Aljawini Nora N Almutairi Mansour S MS Arabi Yaseen M YM Alqahtani Saleh A SA Al Harthi Fawz S FS Almutairi Amal A Alqubaishi Fatima F Alotaibi Sarah S Binowayn Albandari A Alsolm Ebtehal A EA El Bardisy Hadeel H Fawzy Mohammad M Cai Fang F Soranzo Nicole N Butterworth Adam A Geschwind Daniel H DH Arteaga Stephanie S Stephens Alexis A Butte Manish J MJ Boutros Paul C PC Yamaguchi Takafumi N TN Tao Shu S Eng Stefan S Sanders Timothy T Tung Paul J PJ Broudy Michael E ME Pan Yu Y Gonzalez Alfredo A Chavan Nikhil N Johnson Ruth R Pasaniuc Bogdan B Yaspan Brian B Smieszek Sandra S Rivolta Carlo C Bibert Stephanie S Bochud Pierre-Yves PY Dabrowski Maciej M Zawadzki Pawel P Sypniewski Mateusz M Kaja Elżbieta E Chariyavilaskul Pajaree P Nilaratanakul Voraphoj V Hirankarn Nattiya N Shotelersuk Vorasuk V Pongpanich Monnat M Phokaew Chureerat C Chetruengchai Wanna W Tokunaga Katsushi K Sugiyama Masaya M Kawai Yosuke Y Hasegawa Takanori T Naito Tatsuhiko T Namkoong Ho H Edahiro Ryuya R Kimura Akinori A Ogawa Seishi S Kanai Takanori T Fukunaga Koichi K Okada Yukinori Y Imoto Seiya S Miyano Satoru S Mangul Serghei S Abedalthagafi Malak S MS Zeberg Hugo H Grzymski Joseph J JJ Washington Nicole L NL Ossowski Stephan S Ludwig Kerstin U KU Schulte Eva C EC Riess Olaf O Moniuszko Marcin M Kwasniewski Miroslaw M Mbarek Hamdi H Ismail Said I SI Verma Anurag A Goldstein David B DB Kiryluk Krzysztof K Renieri Alessandra A Ferreira Manuel A R MAR Richards J Brent JB

PLoS genetics 20221103 11

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 ...[more]

PMID: 36327219

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Project description:Genome-wide association studies (GWASs) have identified loci contributing to total serum bilirubin level. However, no exome-wide approaches have been performed to address this question. Using exome-wide approach, we assessed the influence of protein-coding variants on unconjugated, conjugated, and total serum bilirubin levels in a well-characterized cohort of 773 ambulatory elderly subjects from Italy. Coding variants were replicated in 227 elderly subjects from the same area. We identified 4 missense rare (minor allele frequency, MAF < 0.5%) and low-frequency (MAF, 0.5%-5%) coding variants located in the first exon of the UGT1A1 gene, which encodes for the substrate-binding domain (rs4148323 [MAF = 0.06%; p.Gly71Arg], rs144398951 [MAF = 0.06%; p.Ile215Val], rs35003977 [MAF = 0.78%; p.Val225Gly], and rs57307513 [MAF = 0.06%; p.Ser250Pro]). These variants were in strong linkage disequilibrium with 3 intronic UGT1A1 variants (rs887829, rs4148325, rs6742078), which were significantly associated with total bilirubin level (P = 2.34 × 10(-34), P = 7.02 × 10(-34), and P = 8.27 × 10(-34)), as well as unconjugated, and conjugated bilirubin levels. We also identified UGT1A6 variants in association with total (rs6759892, p.Ser7Ala, P = 1.98 × 10(-26); rs2070959, p.Thr181Ala, P = 2.87 × 10(-27); and rs1105879, p.Arg184Ser, P = 3.27 × 10(-29)), unconjugated, and conjugated bilirubin levels. All UGT1A1 intronic variants (rs887829, rs6742078, and rs4148325) and UGT1A6 coding variants (rs6759892, rs2070959, and rs1105879) were significantly associated with gallstone-related cholecystectomy risk. The UGT1A6 variant rs2070959 (p.Thr181Ala) was associated with the highest risk of gallstone-related cholecystectomy (OR, 4.58; 95% CI, 1.58-13.28; P = 3.21 × 10(-3)). Using an exome-wide approach we identified coding variants on UGT1A1 and UGT1A6 genes in association with serum bilirubin level and hyperbilirubinemia risk in elderly subjects. UGT1A1 intronic single-nucleotide polymorphisms (SNPs) (rs6742078, rs887829, rs4148324) serve as proxy markers for the low-frequency and rare UGT1A1 variants, thereby providing mechanistic explanation to the relationship between UGT1A1 intronic SNPs and the UGT1A1 enzyme activity. UGT1A1 and UGT1A6 variants might be potentially associated with gallstone-related cholecystectomy risk.

Project description:Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P < 5.0 × 10 - 7). One of the most significant signals (Pall histologies = 1.01 × 10 - 13;Pserous = 3.54 × 10 - 14) occurred at 3q25.31 for rs62273959, a missense variant mapping to the LEKR1 gene that is in LD (r2 = 0.90) with a previously identified 'best hit' (rs7651446) mapping to an intron of TIPARP. Suggestive associations (5.0 × 10 - 5 > P≥5.0 ×10 - 7) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (PAML = 3.23 × 10 - 5; PSKAT-o = 9.23 × 10 - 4) and KRT13 (PAML = 1.67 × 10 - 4; PSKAT-o = 1.07 × 10 - 5), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed to further unravel the unexplained heritability and biology of this disease.

Project description:BackgroundAlcohol use disorder (AUD) runs in families and is accompanied by genetic variation. Some families exhibit an extreme susceptibility in which multiple cases are found and often with an early onset of the disorder. Large scale genome-wide association studies have identified several genes with impressive statistical probabilities. Most of these genes are common variants. Our goal was to perform exome sequencing in families characterized by multiple cases (multiplex families) to determine if rare variants might be segregating with disease status.MethodsA case-control approach was used to leverage the power of a large control sample of unrelated individuals (N = 8,983) with exome sequencing [Institute for Genomic Medicine (IGM)], for comparison with probands with AUD (N = 53) from families selected for AUD multiplex status. The probands were sequenced at IGM using similar protocols to those used for the archival controls. Specifically, the presence of a same-sex pair of adult siblings with AUD was the minimal criteria for inclusion. Using a gene-based collapsing analysis strategy, a search for qualifying variants within the sequence data was undertaken to identify ultra-rare non-synonymous variants.ResultsWe searched 18,666 protein coding genes to identify an excess of rare deleterious genetic variation using whole exome sequence data in the 53 AUD individuals from a total of 282 family members. To complete a case/control analysis of unrelated individuals, probands were compared to unrelated controls. Case enrichment for 16 genes with significance at 10-4 and one at 10-5 are plausible candidates for follow-up studies. Six genes were ultra rare [minor allele frequency (MAF) of 0.0005]: CDSN, CHRNA9, IFT43, TLR6, SELENBP1, and GMPPB. Eight genes with MAF of 0.001: ZNF514, OXGR1, DIEXF, TMX4, MTBP, PON2, CRHBP, and ANKRD46 were identified along with three protein-truncating variants associated with loss-of-function: AGTRAP, ANKRD46, and PPA1. Using an ancestry filtered control group (N = 2,814), nine genes were found; three were also significant in the comparison to the larger control group including CHRNA9 previously implicated in alcohol and nicotine dependence.ConclusionThis study implicates ultra-rare loss-of-function genes in AUD cases. Among the genes identified include those previously reported for nicotine and alcohol dependence (CHRNA9 and CRHBP).

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

Publications

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

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