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Meta-Analysis
. 2021 Nov 3;2(11):100437.
doi: 10.1016/j.xcrm.2021.100437. eCollection 2021 Nov 16.

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

Nooshin Ghodsian  1 , Erik Abner  2 , Connor A Emdin  3   4 , Émilie Gobeil  1 , Nele Taba  2   5 , Mary E Haas  3   6 , Nicolas Perrot  1 , Hasanga D Manikpurage  1 , Éloi Gagnon  1 , Jérôme Bourgault  1 , Alexis St-Amand  1 , Christian Couture  1 , Patricia L Mitchell  1 , 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 Esko  2 , Benoit J Arsenault  1   13
Affiliations
Meta-Analysis

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

Nooshin Ghodsian et al. Cell Rep Med. .

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.

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Conflict of interest statement

A.T. receives research funding from Johnson & Johnson Medical Companies, Medtronic, Bodynov, and GI Windows for studies on bariatric surgery and has received consulting fees from Novo Nordisk and Bausch Health. A.V.K. has served as a scientific advisor to Sanofi, Amgen, Maze Therapeutics, Navitor Pharmaceuticals, Sarepta Therapeutics, Novartis, Verve Therapeutics, Silence Therapeutics, Veritas International, Color Health, Third Rock Ventures, and Columbia University (NIH); has received speaking fees from Illumina, MedGenome, Amgen, and the Novartis Institute for Biomedical Research; and has received sponsored research agreements from the Novartis Institute for Biomedical Research and IBM Research. B.J.A. is a consultant for Novartis and Silence Therapeutics and has received research contracts from Pfizer, Ionis Pharmaceuticals, and Silence Therapeutics.

Figures

None
Graphical abstract
Figure 1
Figure 1
Main results of the meta-analysis of genome-wide association studies (GWASs) (A) Manhattan plot depicting single-nucleotide polymorphisms (SNPs) associated with non-alcoholic fatty liver disease in the GWAS meta-analysis of the eMERGE, FinnGen, UK Biobank, and Estonian Biobank cohorts. Identification of genetic variants linked with NAFLD via a risk factor-informed Bayesian GWAS based on (B) Bayes Factors (BFs), (C) direct effects, and (D) posterior effects. Genetic loci harboring SNPs associated with NAFLD (p < 5.0e−8) are shown.
Figure 2
Figure 2
Shared genetic etiology at the LPL locus LocusCompare plot depicting colocalization of the top SNPs associated with subcutaneous adipose tissue LPL expression and NAFLD. Each dot represents a SNP at the LPL locus. In the left panel, these SNPs are plotted to represent their effect on LPL expression (top right) against their effect on NAFLD (bottom right).
Figure 3
Figure 3
Results of the LD regression analysis between NAFLD and other human diseases and traits LD regression analyses were performed in LD Hub to test the genetic correlation of NAFLD with 240 human diseases and traits. Statistically significant (p < 0.05) genetic correlation coefficients (Rg) and their 95% confidence intervals are presented. adjBMI, adjusted for body mass index; FEV1/FVC, forced expiratory volume in 1 s/forced vital capacity; HOMA-IR, homeostatic model of insulin resistance; VLDL, very-low-density lipoproteins.
See this image and copyright information in PMC

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