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Innes, Hamish; Buch, Stephan; Hutchinson, Sharon; Guha, Indra Neil; Morling, Joanne R.; Barnes, Eleanor; Irving, Will; Forrest, Ewan; Pedergnana, Vincent; Goldberg, David; Aspinall, Esther; Barclay, Stephan; Hayes, Peter C.; Dillon, John; Nischalke, Hans Dieter; Lutz, Philipp; Spengler, Ulrich; Fischer, Janett; Berg, Thomas; Brosch, Mario; Eyer, Florian; Datz, Christian; Müller, Sebastian; Peccerella, Teresa; Deltenre, Pierre; Marot, Astrid; Soyka, Michael; McQuillin, Andrew; Morgan, Marsha Y.; Hampe, Jochen and Stickel, Felix (2020): Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1. In: Gastroenterology, Vol. 159, No. 4: pp. 1276-1289

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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 x 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.

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