Quentin M Anstee1, Rebecca Darlay2, Simon Cockell3, Marica Meroni4, Olivier Govaere5, Dina Tiniakos6, Alastair D Burt7, Pierre Bedossa5, Jeremy Palmer5, Yang-Lin Liu5, Guruprasad P Aithal8, Michael Allison9, Hannele Yki-Järvinen10, Michele Vacca11, Jean-Francois Dufour12, Pietro Invernizzi13, Daniele Prati4, Mattias Ekstedt14, Stergios Kechagias14, Sven Francque15, Salvatore Petta16, Elisabetta Bugianesi17, Karine Clement18, Vlad Ratziu19, Jörn M Schattenberg20, Luca Valenti4, Christopher P Day5, Heather J Cordell2, Ann K Daly21. 1. Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom. Electronic address: quentin.anstee@ncl.ac.uk. 2. Population & Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. 3. Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. 4. Department of Pathophysiology and Transplantation, University of Milan, Translational Medicine - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 5. Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. 6. Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Department of Pathology, Aretaieio Hospital, National & Kapodistrian University of Athens, Greece. 7. Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia. 8. NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK. 9. Liver Unit, Department of Medicine, Cambridge Biomedical Research Centre, Cambridge University NHS Foundation Trust, United Kingdom. 10. Department of Medicine, University of Helsinki, Helsinki, Finland & Helsinki University Hospital, Helsinki, Finland. 11. Liver Unit, Department of Medicine, Cambridge Biomedical Research Centre, Cambridge University NHS Foundation Trust, United Kingdom; Department of Biochemistry and Wellcome Trust/MRC Institute of Metabolic Science, MRC Metabolic Diseases Unit, Metabolic Research Laboratories, University of Cambridge, UK. 12. University Clinic for Visceral Surgery and Medicine, University of Berne, Freiburgstrasse, Berne 3010, Switzerland. 13. Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy. 14. Division of Gastroenterology and Hepatology, Department of Medicine and Health Sciences, Linköping University, Linkoping, Sweden. 15. Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium. 16. Sezione di Gastroenterologia, Dipartimento Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro", Università di Palermo, Palermo, Italy. 17. Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy. 18. Sorbonne University, Inserm, Nutrition and obesity: Systemic approaches, Nutrition department, Pitié-Salpêtrière hospital, Assistance Publique-Hôpitaux de Paris, 75013 Paris, France. 19. Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France. 20. NAFLD Research Center, Department of Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany. 21. Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. Electronic address: a.k.daly@ncl.ac.uk.
Abstract
BACKGROUND & AIMS: Genetic factors associated with non-alcoholic 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 ≤5 × 10-8 at 4 locations (chromosome [chr] 2 GCKR/C2ORF16; chr4 HSD17B13; chr19 TM6SF2; chr22 PNPLA3) together with 2 other signals with p <1 × 10-7 (chr1 near LEPR and chr8 near IDO2/TC1). Case-only analysis of quantitative traits showed that the PNPLA3 signal (rs738409) had genome-wide significance for steatosis, fibrosis and NAFLD activity score and a new signal (PYGO1 rs62021874) had close to genome-wide significance for steatosis (p = 8.2 × 10-8). Subgroup case-control analysis for NASH confirmed the PNPLA3 signal. The chr1 LEPR single nucleotide polymorphism also showed genome-wide significance for this phenotype. Considering the subgroup with advanced fibrosis (≥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 individual's risk of developing advanced disease. Some genes where these sequences are located may also be good targets for future drug treatments.
BACKGROUND & AIMS: Genetic factors associated with non-alcoholic 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 ≤5 × 10-8 at 4 locations (chromosome [chr] 2 GCKR/C2ORF16; chr4 HSD17B13; chr19 TM6SF2; chr22 PNPLA3) together with 2 other signals with p <1 × 10-7 (chr1 near LEPR and chr8 near IDO2/TC1). Case-only analysis of quantitative traits showed that the PNPLA3 signal (rs738409) had genome-wide significance for steatosis, fibrosis and NAFLD activity score and a new signal (PYGO1rs62021874) had close to genome-wide significance for steatosis (p = 8.2 × 10-8). Subgroup case-control analysis for NASH confirmed the PNPLA3 signal. The chr1 LEPR single nucleotide polymorphism also showed genome-wide significance for this phenotype. Considering the subgroup with advanced fibrosis (≥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 individual's risk of developing advanced disease. Some genes where these sequences are located may also be good targets for future drug treatments.
Authors: Mary E Haas; James P Pirruccello; Samuel N Friedman; Minxian Wang; Connor A Emdin; Veeral H Ajmera; Tracey G Simon; Julian R Homburger; Xiuqing Guo; Matthew Budoff; Kathleen E Corey; Alicia Y Zhou; Anthony Philippakis; Patrick T Ellinor; Rohit Loomba; Puneet Batra; Amit V Khera Journal: Cell Genom Date: 2021-12-08
Authors: Carolin V Schneider; Kai Markus Schneider; Donna M Conlon; Joseph Park; Marijana Vujkovic; Inuk Zandvakili; Yi-An Ko; Christian Trautwein; Regerneron Center; Rotonya M Carr; Pavel Strnad; Christoph A Thaiss; Daniel J Rader Journal: Med (N Y) Date: 2021-07-09