Association of Genetic Variation With Cirrhosis: A Multi-Trait Genome-Wide Association and Gene-Environment Interaction Study.
Adult
Age Factors
Aged
Alcohol Drinking
/ adverse effects
Case-Control Studies
Comorbidity
Female
Gene-Environment Interaction
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Humans
Liver Cirrhosis
/ diagnosis
Male
Middle Aged
Multifactorial Inheritance
Obesity
/ epidemiology
Phenotype
Risk Assessment
Risk Factors
Chronic Liver Disease
Cirrhosis
Genetics
Genome-Wide Association Study
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
03
07
2020
revised:
28
11
2020
accepted:
05
12
2020
pubmed:
15
12
2020
medline:
31
8
2021
entrez:
14
12
2020
Statut:
ppublish
Résumé
In contrast to most other common diseases, few genetic variants have been identified that impact risk of cirrhosis. We aimed to identify new genetic variants that predispose to cirrhosis, to test whether such variants, aggregated into a polygenic score, enable genomic risk stratification, and to test whether alcohol intake or body mass index interacts with polygenic predisposition. We conducted a multi-trait genome-wide association study combining cirrhosis and alanine aminotransferase levels performed in 5 discovery studies (UK Biobank, Vanderbilt BioVU, Atherosclerosis Risk in Communities study, and 2 case-control studies including 4829 individuals with cirrhosis and 72,705 controls and 362,539 individuals with alanine aminotransferase levels). Identified variants were replicated in 3 studies (Partners HealthCare Biobank, FinnGen, and Biobank Japan including 3554 individuals with cirrhosis and 343,826 controls). A polygenic score was tested in Partners HealthCare Biobank. Five previously reported and 7 newly identified genetic variants were associated with cirrhosis in both the discovery studies multi-trait genome-wide association study (P < 5 × 10 Twelve independent genetic variants, 7 of which are newly identified in this study, conferred risk for cirrhosis. Aggregated into a polygenic score, these variants identified a subset of the population at substantially increased risk who are most susceptible to the hepatotoxic effects of excess alcohol consumption or obesity.
Sections du résumé
BACKGROUND & AIMS
In contrast to most other common diseases, few genetic variants have been identified that impact risk of cirrhosis. We aimed to identify new genetic variants that predispose to cirrhosis, to test whether such variants, aggregated into a polygenic score, enable genomic risk stratification, and to test whether alcohol intake or body mass index interacts with polygenic predisposition.
METHODS
We conducted a multi-trait genome-wide association study combining cirrhosis and alanine aminotransferase levels performed in 5 discovery studies (UK Biobank, Vanderbilt BioVU, Atherosclerosis Risk in Communities study, and 2 case-control studies including 4829 individuals with cirrhosis and 72,705 controls and 362,539 individuals with alanine aminotransferase levels). Identified variants were replicated in 3 studies (Partners HealthCare Biobank, FinnGen, and Biobank Japan including 3554 individuals with cirrhosis and 343,826 controls). A polygenic score was tested in Partners HealthCare Biobank.
RESULTS
Five previously reported and 7 newly identified genetic variants were associated with cirrhosis in both the discovery studies multi-trait genome-wide association study (P < 5 × 10
CONCLUSIONS
Twelve independent genetic variants, 7 of which are newly identified in this study, conferred risk for cirrhosis. Aggregated into a polygenic score, these variants identified a subset of the population at substantially increased risk who are most susceptible to the hepatotoxic effects of excess alcohol consumption or obesity.
Identifiants
pubmed: 33310085
pii: S0016-5085(20)35545-1
doi: 10.1053/j.gastro.2020.12.011
pmc: PMC8035329
mid: NIHMS1680867
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1620-1633.e13Subventions
Organisme : NHGRI NIH HHS
ID : K08 HG010155
Pays : United States
Organisme : NIDDK NIH HHS
ID : K23 DK119460
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL133786
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG008895
Pays : United States
Informations de copyright
Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.
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