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

BACKGROUND: 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 interact with polygenic predisposition. METHODS: A multi-trait genome-wide association study (GWAS) combining cirrhosis and alanine aminotransferase (ALT) levels, performed in five discovery studies (UK Biobank, Vanderbilt BioVU, the Atherosclerosis Risk in Communities study, and two case-control studies containing 4,829 individuals with cirrhosis and 72,705 controls and 362,539 individuals with ALT levels). Identified variants were replicated in three studies (Partners HealthCare Biobank, FinnGen and Biobank Japan containing 3,554 individuals with cirrhosis and 343,826 controls). A polygenic score was tested in Partners HealthCare Biobank RESULTS: Five previously-reported and seven newly-identified genetic variants were associated with cirrhosis in both the discovery studies multi-trait GWAS (p< 5×10(−8)) and the replication studies (p< 0.05), including a missense variant in the APOE gene and a noncoding variant near EFN1A. These 12 variants were used to generate a polygenic score. Among Partners HealthCare Biobank participants, high polygenic score -- defined as the top quintile of the distribution -- was associated with significantly increased risk of cirrhosis (OR 2.26, p