Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort
Background & Aims: Genetic factors associated with nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most genome-wide association studies (GWASs) have adopted radiologically assessed hepatic triglyceride content as the reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a GWAS encompassing the full spectrum of histologically characterised NAFLD. Methods: The GWAS involved 1,483 European NAFLD cases and 17,781 genetically matched 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. Results: Case-control analysis identified signals showing p values = F3), the signals on chr2, chr19 and chr22 maintained their genome-wide significance. Except for GCKR/C2ORF16, the genome-wide significance signals were replicated. Conclusions: 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 that Wnt signalling pathways may be relevant in NAFLD pathogenesis. Lay summary: Non-alcoholic fatty liver disease is a common disease where excessive fat accumulates in the liver and may result in cirrhosis. To understand who is at risk of developing this disease and suffering liver damage, we undertook a genetic study to compare the genetic profiles of people suffering from fatty liver disease with genetic profiles seen in the general population. We found that particular sequences in 4 different areas of the human genome were seen at different frequencies in the fatty liver disease cases. These sequences may help predict an individuals risk of developing advanced disease. Some genes where these sequences are located may also be good targets for future drug treatments. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. ; Funding Agencies|EPoS (Elucidating Pathways of Steatohepatitis) consortium - Horizon 2020 Framework Program of the European Union [634413]; FLIP consortium(EuropeanUnion FP7 grant) [241762]; Newcastle NIHR Biomedical Research Centre