Genome-wide analysis identifies gallstone-susceptibility loci including genes regulating gastrointestinal motility.
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
revised:
28
09
2021
received:
23
08
2021
accepted:
29
09
2021
pubmed:
16
10
2021
medline:
27
4
2022
entrez:
15
10
2021
Statut:
ppublish
Résumé
Genome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely that many genetic determinants are undiscovered. The aim of this study was to identify genetic variants that represent new targets for gallstone research and treatment. We performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1089 cases, 5228 controls), and conducted a GWA meta-analysis (43,639 cases, 506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene-based then gene-set analysis and tissue expression of identified genes in Genotype-Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy-five risk loci were identified (p < 5 × 10 This GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. We implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.
Sections du résumé
BACKGROUND AND AIMS
Genome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely that many genetic determinants are undiscovered. The aim of this study was to identify genetic variants that represent new targets for gallstone research and treatment.
APPROACH AND RESULTS
We performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1089 cases, 5228 controls), and conducted a GWA meta-analysis (43,639 cases, 506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene-based then gene-set analysis and tissue expression of identified genes in Genotype-Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy-five risk loci were identified (p < 5 × 10
CONCLUSIONS
This GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. We implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.
Identifiants
pubmed: 34651315
doi: 10.1002/hep.32199
pii: 01515467-202205000-00005
doi:
Types de publication
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1081-1094Subventions
Organisme : Chief Scientist Office
ID : CZD/16/6
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 216767/Z/19/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 204979/Z/16/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 210752/Z/18/Z
Pays : United Kingdom
Organisme : British Heart Foundation
ID : FS/16/14/32023
Pays : United Kingdom
Organisme : British Heart Foundation
ID : CH/F/21/90010
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N008340/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 104036/Z/14/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RE/18/5/34216
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/W015919/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00007/10
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/T008008/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 219542/Z/19/Z
Pays : United Kingdom
Informations de copyright
© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
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