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; 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

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, 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 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 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 × 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)	1276-1289.e7
Journal	Gastroenterology
Volume	159
Issue number	4
DOIs	https://doi.org/10.1053/j.gastro.2020.06.014
State	Published - Oct 2020
Externally published	Yes

Keywords

Biomarker
Hepatic Fibrogenesis
Prognostic Factor
SNP

UN SDGs

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

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10.1053/j.gastro.2020.06.014

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Innes, H., Buch, S., Hutchinson, S., Guha, I. N., Morling, J. R., Barnes, E., Irving, W., Forrest, E., Pedergnana, V., Goldberg, D., Aspinall, E., Barclay, S., Hayes, P. C., 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), 1276-1289.e7. https://doi.org/10.1053/j.gastro.2020.06.014

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

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. 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 × 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 = "Biomarker, Hepatic Fibrogenesis, Prognostic Factor, SNP",

author = "Hamish Innes and Stephan Buch and Sharon Hutchinson and Guha, {Indra Neil} and Morling, {Joanne R.} and Eleanor Barnes and Will Irving and Ewan Forrest and Vincent Pedergnana and David Goldberg and Esther Aspinall and Stephan Barclay and Hayes, {Peter C.} 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 = "Publisher Copyright: {\textcopyright} 2020 AGA Institute",

year = "2020",

month = oct,

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

language = "English",

volume = "159",

pages = "1276--1289.e7",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "4",

}

Innes, H, Buch, S, Hutchinson, S, Guha, IN, Morling, JR, Barnes, E, Irving, W, Forrest, E, Pedergnana, V, Goldberg, D, Aspinall, E, Barclay, S, Hayes, PC, 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. 1276-1289.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, Eleanor

AU - Irving, Will

AU - Forrest, Ewan

AU - Pedergnana, Vincent

AU - Goldberg, David

AU - Aspinall, Esther

AU - Barclay, Stephan

AU - Hayes, Peter C.

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

PY - 2020/10

Y1 - 2020/10

N2 - 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 × 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 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 × 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 - Biomarker

KW - Hepatic Fibrogenesis

KW - Prognostic Factor

KW - SNP

UR - http://www.scopus.com/inward/record.url?scp=85092604154&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2020.06.014

DO - 10.1053/j.gastro.2020.06.014

M3 - Article

C2 - 32561361

AN - SCOPUS:85092604154

SN - 0016-5085

VL - 159

SP - 1276-1289.e7

JO - Gastroenterology

JF - Gastroenterology

IS - 4

ER -

Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1

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Keywords

UN SDGs

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