Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1

Gastroenterology. 2020 Oct;159(4):1276-1289.e7. doi: 10.1053/j.gastro.2020.06.014. Epub 2020 Jun 16.

Abstract

Background and aims: Little is known about genetic factors that affect development of alcohol-related cirrhosis. We performed a genome-wide association study (GWAS) of samples from the United Kingdom Biobank (UKB) to identify polymorphisms associated with risk of alcohol-related liver disease.

Methods: We performed a GWAS of 35,839 participants in the UKB with high intake of alcohol against markers of hepatic fibrosis (FIB-4, APRI, and Forns index scores) and hepatocellular injury (levels of aminotransferases). Loci identified in the discovery analysis were tested for their association with alcohol-related cirrhosis in 3 separate European cohorts (phase 1 validation cohort; n=2545). Variants associated with alcohol-related cirrhosis in the validation at a false discovery rate of less than 20% were then directly genotyped in 2 additional European validation cohorts (phase 2 validation, n=2068).

Results: In the GWAS of the discovery cohort, we identified 50 independent risk loci with genome-wide significance (P < 5 × 10-8). Nine of these loci were significantly associated with alcohol-related cirrhosis in the phase 1 validation cohort; 6 of these 9 loci were significantly associated with alcohol-related cirrhosis in phase 2 validation cohort, at a false discovery rate below 5%. The loci included variants in the mitochondrial amidoxime reducing component 1 gene (MARC1) and the heterogeneous nuclear ribonucleoprotein U like 1 gene (HNRNPUL1). After we adjusted for age, sex, body mass index, and type-2 diabetes in the phase 2 validation cohort, the minor A allele of MARC1:rs2642438 was associated with reduced risk of alcohol-related cirrhosis (adjusted odds ratio, 0.76; P=.0027); conversely, the minor C allele of HNRNPUL1:rs15052 was associated with an increased risk of alcohol-related cirrhosis (adjusted odds ratio, 1.30; P=.020).

Conclusions: In a GWAS of samples from the UKB, we identified and validated (in 5 European cohorts) single-nucleotide polymorphisms that affect risk of alcohol-related cirrhosis in opposite directions: the minor A allele in MARC1:rs2642438 decreases risk, whereas the minor C allele in HNRNPUL1:rs15052 increases risk.

Keywords: Biomarker; Hepatic Fibrogenesis; Prognostic Factor; SNP.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Adult
  • Aged
  • Europe / epidemiology
  • Female
  • Gene Frequency
  • Genetic Loci*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Heterogeneous-Nuclear Ribonucleoproteins / genetics*
  • Humans
  • Liver Cirrhosis, Alcoholic / diagnosis
  • Liver Cirrhosis, Alcoholic / epidemiology
  • Liver Cirrhosis, Alcoholic / genetics*
  • Male
  • Middle Aged
  • Mitochondrial Proteins / genetics*
  • Nuclear Proteins / genetics*
  • Oxidoreductases / genetics*
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Risk Assessment
  • Risk Factors
  • Transcription Factors / genetics*

Substances

  • HNRNPUL1 protein, human
  • Heterogeneous-Nuclear Ribonucleoproteins
  • Mitochondrial Proteins
  • Nuclear Proteins
  • Transcription Factors
  • Oxidoreductases
  • mitochondrial amidoxime reducing component 1, human