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Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically-characterised cohort


Quentin M. Anstee

Rebecca Darlay

Simon Cockell

Marica Meroni

Olivier Govaere

Dina Tiniakos

Alastair D. Burt

Pierre Bedossa

Jeremy Palmer

Yang-Lin Liu

Michael Allison


Michele Vacca

Jean-Francois Dufour

Pietro Invernizzi

Daniele Prati

Mattias Ekstedt

Stergios Kechagias

Sven Francque

Salvatore Petta

Elisabetta Bugianesi

Karine Clement

Vlad Ratziu


Luca Valenti

Christopher P. Day

Heather J. Cordell

Ann K. Daly


Background and Aims

Genetic factors associated with non-alcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most GWAS studies have adopted radiologically assessed hepatic triglyceride content as reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a genome-wide association study (GWAS) encompassing the full spectrum of histologically characterized NAFLD.


The GWAS involved 1483 European NAFLD cases and 17781 genetically-matched population controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance.


Case-control analysis identified signals showing p-values ? 5 x 10-8 at four locations (chromosome (chr) 2 GCKR/C2ORF16; chr4 HSD17B13; chr19 TM6SF2; chr22 PNPLA3) together with two other signals with p[less than]1 x10-7 (chr1 near LEPR and chr8 near IDO2/TC1). Case-only analysis of quantitative traits steatosis, disease activity score, NAS and fibrosis showed that the PNPLA3 signal (rs738409) was genome-wide significantly associated with steatosis, fibrosis and NAS score and identified a new signal (PYGO1 rs62021874) with close to genome-wide significance for steatosis (p=8.2 x 10-8). Subgroup case-control analysis for NASH confirmed the PNPLA3 signal. The chr1 LEPR SNP also showed genome-wide significance for this phenotype. Considering the subgroup with advanced fibrosis (?F3), the signals on chromosomes 2, 19 and 22 remained genome-wide significant. With the exception of GCKR/C2ORF16, the genome-wide significant signals replicated.


This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome-wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting relevance of Wnt signalling pathways in NAFLD pathogenesis.


Anstee, Q. M., Darlay, R., Cockell, S., Meroni, M., Govaere, O., Tiniakos, D., …Daly, A. K. (2020). Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically-characterised cohort. Journal of Hepatology, 73(3), 505-515.

Journal Article Type Article
Acceptance Date Apr 2, 2020
Online Publication Date Apr 13, 2020
Publication Date 2020-09
Deposit Date Apr 16, 2020
Publicly Available Date Apr 14, 2021
Journal Journal of Hepatology
Print ISSN 0168-8278
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 73
Issue 3
Pages 505-515
Keywords NAFLD, NASH, Fibrosis, GWAS, PNPLA3, TM6SF2, GCKR, HSD17B13, SNP, Hepatology
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