Oveis Jamialahmadi1, Rosellina Margherita Mancina1, Ester Ciociola1, Federica Tavaglione2, Panu K Luukkonen3, Guido Baselli4, Francesco Malvestiti5, Dorothée Thuillier6, Violeta Raverdy7, Ville Männistö8, Rosaria Maria Pipitone9, Grazia Pennisi9, Daniele Prati4, Rocco Spagnuolo10, Salvatore Petta9, Jussi Pihlajamäki11, François Pattou7, Hannele Yki-Järvinen12, Luca Valenti13, Stefano Romeo14. 1. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden. 2. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden; Clinical Medicine and Hepatology Unit, Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy. 3. Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Internal Medicine, Yale University, New Haven, Connecticut. 4. Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy. 5. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy. 6. Univ Lille, Inserm, Lille Pasteur Institute, Centre Hospitalier Universitaire de Lille, European Genomic Institute for Diabetes, U1190 Translational Research in Diabetes, Lille University, Lille, France. 7. Univ Lille, Inserm, Lille Pasteur Institute, Centre Hospitalier Universitaire de Lille, European Genomic Institute for Diabetes, U1190 Translational Research in Diabetes, Lille University, Lille, France; Centre Hospitalier Universitaire de Lille, Department of General and Endocrine Surgery, Integrated Center for Obesity, Lille, France. 8. Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Finland; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland; Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, Finland. 9. Section of Gastroenterology and Hepatology, Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro," University of Palermo, Palermo, Italy. 10. Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy. 11. Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland; Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, Finland. 12. Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland. 13. Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy. Electronic address: luca.valenti@unimi.it. 14. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy; Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address: stefano.romeo@wlab.gu.se.
Abstract
BACKGROUND & AIMS: Fatty liver disease (FLD) is a growing epidemic that is expected to be the leading cause of end-stage liver disease within the next decade. Both environmental and genetic factors contribute to the susceptibility of FLD. Several genetic variants contributing to FLD have been identified in exome-wide association studies. However, there is still a missing hereditability indicating that other genetic variants are yet to be discovered. METHODS: To find genes involved in FLD, we first examined the association of missense and nonsense variants with alanine aminotransferase at an exome-wide level in 425,671 participants from the UK Biobank. We then validated genetic variants with liver fat content in 8930 participants in whom liver fat measurement was available, and replicated 2 genetic variants in 3 independent cohorts comprising 2621 individuals with available liver biopsy. RESULTS: We identified 190 genetic variants independently associated with alanine aminotransferase after correcting for multiple testing with Bonferroni method. The majority of these variants were not previously associated with this trait. Among those associated, there was a striking enrichment of genetic variants influencing lipid metabolism. We identified the variants rs2792751 in GPAM/GPAT1, the gene encoding glycerol-3-phosphate acyltransferase, mitochondrial, and rs429358 in APOE, the gene encoding apolipoprotein E, as robustly associated with liver fat content and liver disease after adjusting for multiple testing. Both genes affect lipid metabolism in the liver. CONCLUSIONS: We identified 2 novel genetic variants in GPAM and APOE that are robustly associated with steatosis and liver damage. These findings may help to better elucidate the genetic susceptibility to FLD onset and progression.
BACKGROUND & AIMS:Fatty liver disease (FLD) is a growing epidemic that is expected to be the leading cause of end-stage liver disease within the next decade. Both environmental and genetic factors contribute to the susceptibility of FLD. Several genetic variants contributing to FLD have been identified in exome-wide association studies. However, there is still a missing hereditability indicating that other genetic variants are yet to be discovered. METHODS: To find genes involved in FLD, we first examined the association of missense and nonsense variants with alanine aminotransferase at an exome-wide level in 425,671 participants from the UK Biobank. We then validated genetic variants with liver fat content in 8930 participants in whom liver fat measurement was available, and replicated 2 genetic variants in 3 independent cohorts comprising 2621 individuals with available liver biopsy. RESULTS: We identified 190 genetic variants independently associated with alanine aminotransferase after correcting for multiple testing with Bonferroni method. The majority of these variants were not previously associated with this trait. Among those associated, there was a striking enrichment of genetic variants influencing lipid metabolism. We identified the variants rs2792751 in GPAM/GPAT1, the gene encoding glycerol-3-phosphate acyltransferase, mitochondrial, and rs429358 in APOE, the gene encoding apolipoprotein E, as robustly associated with liver fat content and liver disease after adjusting for multiple testing. Both genes affect lipid metabolism in the liver. CONCLUSIONS: We identified 2 novel genetic variants in GPAM and APOE that are robustly associated with steatosis and liver damage. These findings may help to better elucidate the genetic susceptibility to FLD onset and progression.
Authors: Marijana Vujkovic; Shweta Ramdas; Daniel J Rader; Benjamin F Voight; Kyong-Mi Chang; Kim M Lorenz; Xiuqing Guo; Rebecca Darlay; Heather J Cordell; Jing He; Yevgeniy Gindin; Chuhan Chung; Robert P Myers; Carolin V Schneider; Joseph Park; Kyung Min Lee; Marina Serper; Rotonya M Carr; David E Kaplan; Mary E Haas; Matthew T MacLean; Walter R Witschey; Xiang Zhu; Catherine Tcheandjieu; Rachel L Kember; Henry R Kranzler; Anurag Verma; Ayush Giri; Derek M Klarin; Yan V Sun; Jie Huang; Jennifer E Huffman; Kate Townsend Creasy; Nicholas J Hand; Ching-Ti Liu; Michelle T Long; Jie Yao; Matthew Budoff; Jingyi Tan; Xiaohui Li; Henry J Lin; Yii-Der Ida Chen; Kent D Taylor; Ruey-Kang Chang; Ronald M Krauss; Silvia Vilarinho; Joseph Brancale; Jonas B Nielsen; Adam E Locke; Marcus B Jones; Niek Verweij; Aris Baras; K Rajender Reddy; Brent A Neuschwander-Tetri; Jeffrey B Schwimmer; Arun J Sanyal; Naga Chalasani; Kathleen A Ryan; Braxton D Mitchell; Dipender Gill; Andrew D Wells; Elisabetta Manduchi; Yedidya Saiman; Nadim Mahmud; Donald R Miller; Peter D Reaven; Lawrence S Phillips; Sumitra Muralidhar; Scott L DuVall; Jennifer S Lee; Themistocles L Assimes; Saiju Pyarajan; Kelly Cho; Todd L Edwards; Scott M Damrauer; Peter W Wilson; J Michael Gaziano; Christopher J O'Donnell; Amit V Khera; Struan F A Grant; Christopher D Brown; Philip S Tsao; Danish Saleheen; Luca A Lotta; Lisa Bastarache; Quentin M Anstee; Ann K Daly; James B Meigs; Jerome I Rotter; Julie A Lynch Journal: Nat Genet Date: 2022-06-02 Impact factor: 41.307
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: Nooshin Ghodsian; Erik Abner; Connor A Emdin; Émilie Gobeil; Nele Taba; Mary E Haas; Nicolas Perrot; Hasanga D Manikpurage; Éloi Gagnon; Jérôme Bourgault; Alexis St-Amand; Christian Couture; Patricia L Mitchell; Yohan Bossé; Patrick Mathieu; Marie-Claude Vohl; André Tchernof; Sébastien Thériault; Amit V Khera; Tõnu Esko; Benoit J Arsenault Journal: Cell Rep Med Date: 2021-11-03
Authors: Aaron Hakim; Matthew Moll; Joseph Brancale; Jiangyuan Liu; Jessica A Lasky-Su; Edwin K Silverman; Silvia Vilarinho; Z Gordon Jiang; Yered H Pita-Juárez; Ioannis S Vlachos; Xuehong Zhang; Fredrik Åberg; Nezam H Afdhal; Brian D Hobbs; Michael H Cho Journal: Hepatology Date: 2021-11-09 Impact factor: 17.298
Authors: Pierre Deltenre; Jochen Hampe; Felix Stickel; Stephan Buch; Hamish Innes; Hans Dieter Nischalke; Indra Neil Guha; Karl Heinz Weiss; Will Irving; Daniel Gotthardt; Eleanor Barnes; Janett Fischer; M Azim Ansari; Jonas Rosendahl; Shang-Kuan Lin; Astrid Marot; Vincent Pedergnana; Markus Casper; Jennifer Benselin; Frank Lammert; John McLauchlan; Philip L Lutz; Victoria Hamill; Sebastian Mueller; Joanne R Morling; Georg Semmler; Florian Eyer; Johann von Felden; Alexander Link; Arndt Vogel; Jens U Marquardt; Stefan Sulk; Jonel Trebicka; Luca Valenti; Christian Datz; Thomas Reiberger; Clemens Schafmayer; Thomas Berg Journal: Hepatol Commun Date: 2021-12-27