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Background and aimsLittle 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.MethodsWe 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).ResultsIn 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).ConclusionsIn 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.

Original publication

DOI

10.1053/j.gastro.2020.06.014

Type

Journal article

Journal

Gastroenterology

Publication Date

10/2020

Volume

159

Pages

1276 - 1289.e7

Addresses

School of Health and Life Sciences, Glasgow Caledonian University, Glasgow United Kingdom; Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom; Health Protection Scotland, Glasgow, United Kingdom. Electronic address: Hamish.Innes@gcu.ac.uk.

Keywords

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