Electronic health record-based genome-wide meta-analysis provides insights on the genetic architecture of non-alcoholic fatty liver disease

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

doi:10.1016/j.xcrm.2021.100437

Electronic health record-based genome-wide meta-analysis provides insights on the genetic architecture of non-alcoholic fatty liver disease

Cell Rep Med. 2021 Nov 3;2(11):100437. doi: 10.1016/j.xcrm.2021.100437. eCollection 2021 Nov 16.

Authors

Nooshin Ghodsian¹, Erik Abner², Connor A Emdin^{3

4}, Émilie Gobeil¹, Nele Taba^{2

5}, Mary E Haas^{3

6}, Nicolas Perrot¹, Hasanga D Manikpurage¹, Éloi Gagnon¹, Jérôme Bourgault¹, Alexis St-Amand¹, Christian Couture¹, Patricia L Mitchell¹, Yohan Bossé^{1

7}, Patrick Mathieu^{1

8}, Marie-Claude Vohl^{9

10}, André Tchernof^{1

10}, Sébastien Thériault^{1

11}, Amit V Khera^{3

4

12}, Tõnu Esko², Benoit J Arsenault^{1

13}

Affiliations

¹ Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada.
² Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Riia 23b, 51010, Estonia.
³ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
⁴ Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
⁵ Institute of Molecular and Cell Biology, University of Tartu, Tartu, Riia 23, 51010, Estonia.
⁶ Department of Molecular Biology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁷ Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada.
⁸ Department of Surgery, Faculty of Medicine, Université Laval, Québec, QC, Canada.
⁹ Centre NUTRISS, Institut sur la Nutrition et les Aliments Fonctionnels, Université Laval, Québec, QC, Canada.
¹⁰ School of Nutrition, Université Laval, Québec, QC, Canada.
¹¹ Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Université Laval, Québec, QC, Canada.
¹² Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
¹³ Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a complex disease linked to several chronic diseases. We aimed at identifying genetic variants associated with NAFLD and evaluating their functional consequences. We performed a genome-wide meta-analysis of 4 cohorts of electronic health record-documented NAFLD in participants of European ancestry (8,434 cases and 770,180 controls). We identify 5 potential susceptibility loci for NAFLD (located at or near GCKR, TR1B1, MAU2/TM6SF2, APOE, and PNPLA3). We also report a potentially causal effect of lower LPL expression in adipose tissue on NAFLD susceptibility and an effect of the FTO genotype on NAFLD. Positive genetic correlations between NAFLD and cardiometabolic diseases and risk factors such as body fat accumulation/distribution, lipoprotein-lipid levels, insulin resistance, and coronary artery disease and negative genetic correlations with parental lifespan, socio-economic status, and acetoacetate levels are observed. This large GWAS meta-analysis reveals insights into the genetic architecture of NAFLD.

Keywords: adipose tissue; electronic health records; genetics; genome-wide association study; lipoprotein lipase; non-alcoholic fatty liver disease.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Electronic Health Records*
Genetic Predisposition to Disease*
Genetic Variation
Genome-Wide Association Study*
Humans
Linkage Disequilibrium / genetics
Lipoprotein Lipase / genetics
Non-alcoholic Fatty Liver Disease / genetics*
Obesity / genetics
Phenotype

Substances

Lipoprotein Lipase