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 Brosch; Florian Eyer; Christian Datz; Sebastian Mueller; Teresa Peccerella; Pierre Deltenre; Astrid Marot; Michael Soyka; Andrew McQuillin; Marsha Y. Morgan; Jochen Hampe; Felix Stickel

doi:10.1053/j.gastro.2020.06.014

Genome-wide Association Study for Alcohol-related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1

Hamish Innes (Lead / Corresponding author), 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

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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 language	English
Pages (from-to)	1276-1298.e7
Number of pages	21
Journal	Gastroenterology
Volume	159
Issue number	4
Early online date	16 Jun 2020
DOIs	https://doi.org/10.1053/j.gastro.2020.06.014
Publication status	Published - Oct 2020

Keywords

SNP
biomarker
hepatic fibrogenesis
prognostic factor

ASJC Scopus subject areas

Hepatology
Gastroenterology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1053/j.gastro.2020.06.014

Author Accepted ManuscriptAccepted author manuscript, 314 KBLicence: CC BY-NC-ND

Cite this

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, 159(4), 1276-1298.e7. https://doi.org/10.1053/j.gastro.2020.06.014

@article{a8424e384b5043558a316f91e8216bd9,

title = "Genome-wide Association Study for Alcohol-related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1",

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.",

keywords = "SNP, biomarker, hepatic fibrogenesis, prognostic factor",

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

note = "FUNDING: This work was supported by grants from the Swiss National Funds (SNF no. 310030_169196) and the Swiss Foundation for Alcohol Research (SSA) to FS, and the Liver Systems Medicine (LiSyM) Network funded by the German Federal Ministry for Education and Research (BmBF) to JH. HI{\textquoteright}s time was supported by: (i) core research funding monies from Glasgow Caledonian University, and (ii) the STOPHCV study, which is led by EB and is supported by a grant from the UK Medical Research Council ((MR/K01532X/1: STOP-HCV). The STOPHCV study funded access to the Archie West high performance computer platform.",

year = "2020",

month = oct,

doi = "10.1053/j.gastro.2020.06.014",

language = "English",

volume = "159",

pages = "1276--1298.e7",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders",

number = "4",

}

Innes, H, Buch, S, Hutchinson, S, Guha, IN, Morling, JR, Barnes, E, Irving, W, Forrest, E, Pedergnan, V, Goldberg, D, Aspinall, E, Barclay, S, Hayes, P, Dillon, J, Nischalke, HD, Lutz, P, Spengler, U, Fischer, J, Berg, T, Brosch, M, Eyer, F, Datz, C, Mueller, S, Peccerella, T, Deltenre, P, Marot, A, Soyka, M, McQuillin, A, Morgan, MY, Hampe, J & Stickel, F 2020, 'Genome-wide Association Study for Alcohol-related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1', Gastroenterology, vol. 159, no. 4, pp. 1276-1298.e7. https://doi.org/10.1053/j.gastro.2020.06.014

TY - JOUR

T1 - Genome-wide Association Study for Alcohol-related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1

AU - Innes, Hamish

AU - Buch, Stephan

AU - Hutchinson, Sharon

AU - Guha, Indra Neil

AU - Morling, Joanne R.

AU - Barnes, Elleanor

AU - Irving, Will

AU - Forrest, Ewan

AU - Pedergnan, Vincent

AU - Goldberg, David

AU - Aspinall, Esther

AU - Barclay, Stephan

AU - Hayes, Peter

AU - Dillon, John

AU - Nischalke, Hans Dieter

AU - Lutz, Philipp

AU - Spengler, Ulrich

AU - Fischer, Janett

AU - Berg, Thomas

AU - Brosch, Mario

AU - Eyer, Florian

AU - Datz, Christian

AU - Mueller, Sebastian

AU - Peccerella, Teresa

AU - Deltenre, Pierre

AU - Marot, Astrid

AU - Soyka, Michael

AU - McQuillin, Andrew

AU - Morgan, Marsha Y.

AU - Hampe, Jochen

AU - Stickel, Felix

N1 - FUNDING: This work was supported by grants from the Swiss National Funds (SNF no. 310030_169196) and the Swiss Foundation for Alcohol Research (SSA) to FS, and the Liver Systems Medicine (LiSyM) Network funded by the German Federal Ministry for Education and Research (BmBF) to JH. HI’s time was supported by: (i) core research funding monies from Glasgow Caledonian University, and (ii) the STOPHCV study, which is led by EB and is supported by a grant from the UK Medical Research Council ((MR/K01532X/1: STOP-HCV). The STOPHCV study funded access to the Archie West high performance computer platform.

PY - 2020/10

Y1 - 2020/10

N2 - 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.

AB - 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.

KW - SNP

KW - biomarker

KW - hepatic fibrogenesis

KW - prognostic factor

UR - http://www.scopus.com/inward/record.url?scp=85086784288&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2020.06.014

DO - 10.1053/j.gastro.2020.06.014

M3 - Article

C2 - 32561361

SN - 0016-5085

VL - 159

SP - 1276-1298.e7

JO - Gastroenterology

JF - Gastroenterology

IS - 4

ER -

Genome-wide Association Study for Alcohol-related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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Stratified Medicine to Optimise the Treatment of Patients with Hepatitis c Virus Infection (STOP-HCV) (Joint with Universities of Oxford, Bristol, Glasgow, Edinburgh, Southampton, Birmingham, Nottingham, London & LHTM)

Dillon, John

Cite this

Genome-wide Association Study for Alcohol-related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Stratified Medicine to Optimise the Treatment of Patients with Hepatitis c Virus Infection (STOP-HCV) (Joint with Universities of Oxford, Bristol, Glasgow, Edinburgh, Southampton, Birmingham, Nottingham, London & LHTM)

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Dillon, John

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