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

Abstract

See Covering the Cover synopsis on page 1435. 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 Â 10 -8 ) and the replication studies (P < .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 individuals, high polygenic score--defined as the top quintile of the distribution-was associated with significantly increased risk of cirrhosis (odds ratio, 2.26; P < .001) and related comorbidities compared with the lowest quintile. Risk was even more pronounced among those with extreme polygenic risk (top 1% of the distribution, odds ratio, 3.16; P < .001). The impact of extreme polygenic risk was substantially more pronounced in those with elevated alcohol consumption or body mass index. Modeled as risk by age 75 years, probability of cirrhosis with extreme polygenic risk was 13.7%, 20.1%, and 48.2% among individuals with no or modest, moderate, and increased alcohol consumption, respectively (P interaction < .001). Similarly, probability among those with extreme polygenic risk was 6.5%, 10.3%, and 19.5% among individuals with normal weight, overweight, and obesity, respectively (P interaction < .001). 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.

Emerging Role of Genomic Analysis in Clinical Evaluation of Lean Individuals With NAFLD

“…( 22 ) These lean patients with NAFLD likely have a higher prevalence of common variants associated with NAFLD prevalence and severity. ( 23 ) The most well‐characterized common variant associated with NAFLD is the nonsynonymous variant p.I148M in the patatin‐like phospholipase domain containing 3 ( PNPLA3 ) gene, which has increased prevalence in Hispanics ( 24 ) and is associated with an increased risk of hepatic steatosis, ( 24 ) NASH, ( 25,26 ) cirrhosis, ( 27 ) and HCC. ( 28 ) Stender et al demonstrated that adiposity, assessed by BMI, amplifies the effect of this PNPLA3 polymorphism on fatty liver disease and its progression to cirrhosis; however, this finding was in a population of European ancestry.…”

“…( 48 ) Recently, a polygenic risk score for cirrhosis incorporating 12 independent genetic variants was derived and validated. ( 27 ) Future efforts should evaluate whether lean patients with NAFLD have high polygenic risk score.…”

Insights into Nonalcoholic Fatty-Liver Disease Heterogeneity

“…[30][31][32][33] We are therefore presently moving to a model where, across the continuum of the distribution of the inherited predisposition to NAFLD in the population, the development of polygenic risk scores (PRS) can stratify the risk of this condition and of liver-related complications. 30,31,[34][35][36] For example, "high" PRS can predict the evolution to cirrhosis and HCC independently of classical risk factors in individuals with dysmetabolism and/or NAFLD, potentially being able to aid in the clinical management and in the design of referral pathways. 35 On the other hand, it has become clear that the main common risk variant and PRS cannot discriminate accurately between "metabolic" and "genetic" NAFLD.…”

Risk of sudden coronary death based on genetic background in Chinese Han population

“…The sudden cardiac arrest-related gene variations were selected from GWAS results. To determine whether the polymorphisms of these SNPs are prone to induce SCD in the Chinese Han population, 21 SNPs with P<1x10 -7 were selected from GWAS, based solely on previous studies (22)(23)(24)(25). The results revealed that the 21 SNPs were independent and did not exhibit any linkage disequilibrium cluster.…”