| Title: | Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1 |
| Journal: | Gastroenterology |
| Published: | 16 Jun 2020 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/32561361/ |
| DOI: | https://doi.org/10.1053/j.gastro.2020.06.014 |
| URL: | https://discovery.dundee.ac.uk/ws/files/49901431/Innes_et_al_main_manuscript_rev1_FINAL_CLEAN_AND_UNMARKED_1_.pdf |
Publication 5024
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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.</p>
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).</p>
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).</p>
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.</p>
21 Keywords
- Adult
- Aged
- Europe
- Female
- Gene Frequency
- Genetic Loci
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Heterogeneous-Nuclear Ribonucleoproteins
- Humans
- Liver Cirrhosis, Alcoholic
- Male
- Middle Aged
- Mitochondrial Proteins
- Nuclear Proteins
- Oxidoreductases
- Phenotype
- Polymorphism, Single Nucleotide
- Risk Assessment
- Risk Factors
- Transcription Factors
31 Authors
- Hamish Innes
- Stephan Buch
- Sharon Hutchinson
- Indra Neil Guha
- Joanne R Morling
- Eleanor Barnes
- Will Irving
- Ewan Forrest
- Vincent Pedergnana
- David Goldberg
- Esther Aspinall
- Stephan Barclay
- Peter C Hayes
- John Dillon
- Hans Dieter Nischalke
- Philipp Lutz
- Ulrich Spengler
- Janett Fischer
- Thomas Berg
- Mario Brosch
- Florian Eyer
- Christian Datz
- Sebastian Mueller
- Teresa Peccerella
- Pierre Deltenre
- Astrid Marot
- Michael Soyka
- Andrew McQuillin
- Marsha Y Morgan
- Jochen Hampe
- Felix Stickel
1 Application
| Application ID | Title |
|---|---|
| 8764 | The epidemiology of liver disease in a population-based cohort. |
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