Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis

DBDS Genomic Consortium; Jonas Ghouse; Ole B Pedersen; Stefan Stender

doi:10.1038/s41588-024-01720-y

Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis

DBDS Genomic Consortium, Jonas Ghouse^*, Ole B Pedersen, Stefan Stender^*

^*Corresponding author af dette arbejde

Klinisk Immunologisk Afdeling

Publikation: Bidrag til tidsskrift › Artikel › Forskning › peer review

Abstract

We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.

Originalsprog	Engelsk
Sider (fra-til)	827-837
Antal sider	11
Tidsskrift	Nature Genetics
Vol/bind	56
Udgave nummer	5
Tidlig onlinedato	17 apr. 2024
DOI	https://doi.org/10.1038/s41588-024-01720-y
Status	Udgivet - maj 2024

Finansiering

Bevillingsgivere	Bevillingsgivernummer
Beckett-Fonden	43247
Novo Nordisk Foundation	NNF20SA0064340
Beckett-Fonden	23-2-10636
Danmarks Frie Forskningsfond	9060-00012B, NNF22OC0075038, NNF17OC0031204
John and Birthe Meyer Foundation
Innovationsfonden
NordForsk
Villadsen Family Foundation
Arvid Nilssons Fond	MVP000
Department of Veterans Affairs	I01 BX003362
Novo Nordisk Foundation	NNF17OC0027594, NNF14CC0001
National Institutes of Health	1 OT2 OD026549, 1 OT2 OD026554, 1 OT2 OD026557, 1 OT2 OD026556, 1 OT2 OD026550, 1 OT2 OD 026552, 1 OT2 OD026553, 1 OT2 OD026548, 1 OT2 OD026551, 1 OT2 OD026555, AOD 16037
Doris Duke Foundation	2019081
European Regional Development Fund	(2014-2020.4.01.15-0012 GENTRANSMED)
Estonian Research Council	PRG1911
University of Copenhagen	PI Søren Brunak

Adgang til dokumentet

10.1038/s41588-024-01720-y

Citationsformater

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title = "Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis",

abstract = "We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.",

keywords = "Alanine Transaminase/blood, Carcinoma, Hepatocellular/genetics, Case-Control Studies, Cohort Studies, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Lipase/genetics, Liver Cirrhosis/genetics, Liver Neoplasms/genetics, Male, Membrane Proteins/genetics, Multifactorial Inheritance/genetics, Polymorphism, Single Nucleotide, Risk Factors, gamma-Glutamyltransferase/genetics, Disease, Risk, Genome-wide association",

author = "\{DBDS Genomic Consortium\} and Jonas Ghouse and Gardar Sveinbj{\"o}rnsson and Marijana Vujkovic and Anne-Sofie Seidelin and Helene Gellert-Kristensen and Gustav Ahlberg and Vinicius Tragante and Rand, \{S{\o}ren A\} and Joseph Brancale and Silvia Vilarinho and Lundegaard, \{Pia Rengtved\} and Erik S{\o}rensen and Christian Erikstrup and Bruun, \{Mie Topholm\} and Jensen, \{Bitten Aagaard\} and S{\o}ren Brunak and Karina Banasik and Henrik Ullum and Niek Verweij and Luca Lotta and Aris Baras and Tooraj Mirshahi and Carey, \{David J\} and Kaplan, \{David E\} and Julie Lynch and Timothy Morgan and Tae-Hwi Schwantes-An and Dochtermann, \{Daniel R\} and Saiju Pyarajan and Tsao, \{Philip S\} and Triin Laisk and Reedik M{\"a}gi and Julia Kozlitina and Anne Tybj{\ae}rg-Hansen and David Jones and Knowlton, \{Kirk U\} and Lincoln Nadauld and Egil Ferkingstad and Bj{\"o}rnsson, \{Einar S\} and Ulfarsson, \{Magnus O\} and {\'A}rni Sturluson and Patrick Sulem and Pedersen, \{Ole B\} and Ostrowski, \{Sisse R\} and Gudbjartsson, \{Daniel F\} and Kari Stefansson and Olesen, \{Morten Salling\} and Kyong-Mi Chang and Hilma Holm and Henning Bundgaard and Stefan Stender",

note = "{\textcopyright} 2024. The Author(s).",

year = "2024",

month = may,

doi = "10.1038/s41588-024-01720-y",

language = "English",

volume = "56",

pages = "827--837",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "5",

}

TY - JOUR

T1 - Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis

AU - DBDS Genomic Consortium

AU - Ghouse, Jonas

AU - Sveinbjörnsson, Gardar

AU - Vujkovic, Marijana

AU - Seidelin, Anne-Sofie

AU - Gellert-Kristensen, Helene

AU - Ahlberg, Gustav

AU - Tragante, Vinicius

AU - Rand, Søren A

AU - Brancale, Joseph

AU - Vilarinho, Silvia

AU - Lundegaard, Pia Rengtved

AU - Sørensen, Erik

AU - Erikstrup, Christian

AU - Bruun, Mie Topholm

AU - Jensen, Bitten Aagaard

AU - Brunak, Søren

AU - Banasik, Karina

AU - Ullum, Henrik

AU - Verweij, Niek

AU - Lotta, Luca

AU - Baras, Aris

AU - Mirshahi, Tooraj

AU - Carey, David J

AU - Kaplan, David E

AU - Lynch, Julie

AU - Morgan, Timothy

AU - Schwantes-An, Tae-Hwi

AU - Dochtermann, Daniel R

AU - Pyarajan, Saiju

AU - Tsao, Philip S

AU - Laisk, Triin

AU - Mägi, Reedik

AU - Kozlitina, Julia

AU - Tybjærg-Hansen, Anne

AU - Jones, David

AU - Knowlton, Kirk U

AU - Nadauld, Lincoln

AU - Ferkingstad, Egil

AU - Björnsson, Einar S

AU - Ulfarsson, Magnus O

AU - Sturluson, Árni

AU - Sulem, Patrick

AU - Pedersen, Ole B

AU - Ostrowski, Sisse R

AU - Gudbjartsson, Daniel F

AU - Stefansson, Kari

AU - Olesen, Morten Salling

AU - Chang, Kyong-Mi

AU - Holm, Hilma

AU - Bundgaard, Henning

AU - Stender, Stefan

PY - 2024/5

Y1 - 2024/5

N2 - We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.

AB - We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.

KW - Alanine Transaminase/blood

KW - Carcinoma, Hepatocellular/genetics

KW - Case-Control Studies

KW - Cohort Studies

KW - Female

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Humans

KW - Lipase/genetics

KW - Liver Cirrhosis/genetics

KW - Liver Neoplasms/genetics

KW - Male

KW - Membrane Proteins/genetics

KW - Multifactorial Inheritance/genetics

KW - Polymorphism, Single Nucleotide

KW - Risk Factors

KW - gamma-Glutamyltransferase/genetics

KW - Disease

KW - Risk

KW - Genome-wide association

U2 - 10.1038/s41588-024-01720-y

DO - 10.1038/s41588-024-01720-y

M3 - Article

C2 - 38632349

SN - 1061-4036

VL - 56

SP - 827

EP - 837

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis

Abstract

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