Abstract
SummaryNon-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.
Highlights
Genome-wide association studies (GWASs) have identified genetic variants associated with liver fat accumulation,[15,16] liver enzymes,[17] and different forms of liver diseases,[18,19] less than a handful of small genome-wide association studies (GWASs) sought to identify genetic variants associated with a clinical diagnosis of Non-alcoholic fatty liver disease (NAFLD)
Identification of genetic variants associated with NAFLD To identify genetic variants associated with NAFLD, we performed 2 new GWASes in the UK Biobank and Estonian Biobank and performed a meta-analysis of 4 cohorts (UK Biobank, Estonian Biobank, Electronic Medical Records and Genomics (eMERGE), and FinnGen), totaling 8,434 NAFLD cases, all identified through electronic health record (EHR), and 770,180 controls
We identified 4 genetic loci that harbored at least 1 SNP that passed the genome-wide significance threshold of p £ 5 3 10À8 (TRIB1, MAU2 [TM6SF2], APOE, and PNPLA3)
Summary
Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases.[1,2] According to recent estimates, $25% of the adult population worldwide may have NAFLD.[3,4] This disease has been predicted to become the most frequent indication for liver transplantation in Western countries by 2030.5 NAFLD is a progressive liver disease with potential consequences for several other chronic disorders such as cardiovascular disease (CVD) (the leading cause of death in patients with NAFLD),[6,7,8,9] type 2 diabetes (T2D),[10,11] dyslipidemia,[12] and other extrahepatic manifestations such as chronic kidney disease[13] and gastrointestinal neoplasms.[14]To better understand the etiology of complex diseases such as NAFLD and to develop therapies that may help patients with this disease living longer and healthier, the genetic architecture of NAFLD needs to be better understood. The GWAS of the Electronic Medical Records and Genomics (eMERGE) network included 1,106 NAFLD cases and 8,571 controls identified only 1 NAFLD susceptibility locus (PNPLA3). The NAFLD GWAS of the UK Biobank included 1,664 NAFLD cases and 400,055 controls identified only 2 regions robustly associated with NAFLD (PNPLA3 and PBX4/TM6SF2). The UK Biobank analysis did not exclude participants with secondary causes of NAFLD (e.g., hepatitis, alcoholism) and used a rather vague definition
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