Association of Genetic Variation With Cirrhosis: A Multi-Trait Genome-Wide Association and Gene-Environment Interaction Study.

TitleAssociation of Genetic Variation With Cirrhosis: A Multi-Trait Genome-Wide Association and Gene-Environment Interaction Study.
Publication TypeJournal Article
Year of Publication2021
AuthorsEmdin, CA, Haas, M, Ajmera, V, Simon, TG, Homburger, J, Neben, C, Jiang, L, Wei, W-Q, Feng, Q, Zhou, A, Denny, J, Corey, K, Loomba, R, Kathiresan, S, Khera, AV
JournalGastroenterology
Volume160
Issue5
Pagination1620-1633.e13
Date Published2021 Apr
ISSN1528-0012
Abstract

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

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.

DOI10.1053/j.gastro.2020.12.011
Alternate JournalGastroenterology
PubMed ID33310085
PubMed Central IDPMC8035329
Grant ListK08 HG010155 / HG / NHGRI NIH HHS / United States
K23 DK119460 / DK / NIDDK NIH HHS / United States
UM1 HG008895 / HG / NHGRI NIH HHS / United States