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

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 < 5 × 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.

Keywords: Chronic Liver Disease; Cirrhosis; Genetics; Genome-Wide Association Study.

Figure 1.

Study design. ARIC, Atherosclerosis Risk in Communities

Figure 2.

Discovery analysis of 4,829 cirrhosis cases, 72,705 controls free of cirrhosis and 362,539 individuals with ALT level measurements. A total of 3.1 million snps are considered in this analysis. The red red horizontal line indicates the threshold for genome-wide significance (P = 5 × 10−8).

Figure 3.

Association of polygenic risk for cirrhosis with liver disease and death in the Partners HealthCare Biobank. Estimates were derived using logistic regression with adjustment for age, sex and five principal components of ancestry. Low polygenic risk was defined as the 0th to 19th percentile of the polygenic score. Intermediate polygenic risk was defined as the 20th to 79th percentile. High polygenic risk was defined as the 80th to 100th percentile.

Figure 4.

Association of extreme polygenic risk or rare large-effect mutations with cirrhosis. HFE, SERPINA1 or ATP7B refer to HFE p.Cys282Tyr, SERPINA1 p.Glu366Lys (Z/Z genotype) and ATP7B loss-of-function mutations in the homozygous state. Estimates were derived using logistic regression with adjustment for age, sex and five principal components of ancestry. OR, odds ratio

Figure 5.

Association of alcohol consumption and body weight with cumulative risk of cirrhosis among individuals at extreme and non-extreme polygenic risk of cirrhosis. A. Cumulative risk of cirrhosis by body mass index. B. Cumulative risk of cirrhosis by alcohol consumption. C. Cumulative risk of cirrhosis by body-mass index and alcohol consumption. Extreme polygenic risk was defined as the top percentile of the polygenic score. BMI, body-mass index. PRS, polygenic risk score.