Genome-wide association study for alcohol-related cirrhosis identifies risk loci in MARC1 and HNRNPUL1

Hamish Innes*, Stephan Buch, Sharon Hutchinson, Indra Neil Guha, Joanne R. Morling, Elleanor Barnes, Will Irving, Ewan Forrest, Vincent Pedergnan, David Goldberg, Esther Aspinall, Stephan Barclay, Peter Hayes, John Dillon, Hans Dieter Nischalke, Philipp Lutz, Ulrich Spengler, Janett Fischer, Thomas Berg, Mario BroschFlorian Eyer, Christian Datz, Sebastian Mueller, Teresa Peccerella, Pierre Deltenre, Astrid Marot, Michael Soyka, Andrew McQuillin, Marsha Y. Morgan, Jochen Hampe, Felix Stickel

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

BACKGROUND & 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.
Original languageEnglish
JournalGastroenterology
Early online date16 Jun 2020
DOIs
Publication statusE-pub ahead of print - 16 Jun 2020

Keywords

  • biomarker
  • prognostic factor
  • SNP
  • hepatic fibrogenesis

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    Innes, H., Buch, S., Hutchinson, S., Guha, I. N., Morling, J. R., Barnes, E., Irving, W., Forrest, E., Pedergnan, V., Goldberg, D., Aspinall, E., Barclay, S., Hayes, P., Dillon, J., Nischalke, H. D., Lutz, P., Spengler, U., Fischer, J., Berg, T., ... Stickel, F. (2020). Genome-wide association study for alcohol-related cirrhosis identifies risk loci in MARC1 and HNRNPUL1. Gastroenterology. https://doi.org/10.1053/j.gastro.2020.06.014