Insights from Genome-Wide Association Analyses of Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis, which can progress to nonalcoholic steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma in the absence of excessive alcohol consumption. Nonalcoholic fatty liver disease will become the number one cause of liver disease worldwide by 2020. Nonalcoholic fatty liver disease is correlated albeit imperfectly with obesity and other metabolic diseases such as diabetes, hyperlipidemia, and cardiovascular disease, but exactly how having one of these diseases contributes to the development of other metabolic diseases is only now being elucidated. Development of NAFLD and related metabolic diseases is genetically influenced in the population, and recent genome-wide association studies (GWASs) have discovered genetic variants that associate with these diseases. These GWAS-associated variants cannot only help us to identify individuals at high risk of developing NAFLD, but also to better understand its pathophysiology so that we can develop more effective treatments for this disease and related metabolic diseases in the future.

Relationship Between Nonalcoholic Fatty Liver Disease Susceptibility Genes and Coronary Artery Disease

“…Selection of NAFLD susceptibility genes started with recent concise overviews on this topic and was subsequently expanded by a Medline search for “NAFLD” and “gene.” Because some genetic association studies have been conducted in relatively small populations and are therefore more likely to be underpowered, a stringent selection procedure was applied. A NAFLD gene was included in the present study when one of the following criteria was fulfilled: (1) The gene was identified by genome‐wide association studies (GWASs) for NAFLD, as diagnosed by either histology or imaging; (2) the gene was identified by GWASs for a NAFLD‐related trait, e.g., liver enzymes or alcoholic fatty liver disease (AFLD), and subsequently confirmed in a NAFLD cohort; or (3) the gene was reported by multiple case‐control studies in NAFLD cohorts and subsequently confirmed by meta‐analysis.…”

Insulin Resistance Exacerbates Genetic Predisposition to Nonalcoholic Fatty Liver Disease in Individuals Without Diabetes

“…Nonalcoholic fatty liver disease (NAFLD) is a result of the excess accumulation of lipids in hepatocytes (hepatic steatosis) in the absence of heavy alcohol consumption . Hepatic steatosis is also associated with the risk of developing dyslipidemia or dysglycemia as well as cardiovascular disease, which is the number one cause of death in individuals with NAFLD .…”

“…Heritability of hepatic steatosis ranges from 22% to 38% across all ancestries, suggesting that specific genotypes may predispose individuals to NAFLD . Previously, the Genetics of Obesity‐Related Liver Disease Consortium conducted a genome‐wide association study in 7,176 individuals of European ancestry (EA), with replication in histology‐based samples .…”

“…N onalcoholic fatty liver disease (NAFLD) is a result of the excess accumulation of lipids in hepatocytes (hepatic steatosis) in the absence of heavy alcohol consumption. (1) Hepatic steatosis is also associated with the risk of developing dyslipidemia or dysglycemia (2) as well as cardiovascular Disease Consortium conducted a genome-wide association study in 7,176 individuals of European ancestry (EA), with replication in histology-based samples. (9) This study identified that rs738409 (in patatin-like phospholipase domain containing 3 [PNPLA3]), a missense single nucleotide polymorphism (SNP) first associated with hepatic fat content a decade ago (10) ; the missense variant rs2228603 (in neurocan/transmembrane 6 superfamily member 2 [NCAN/TM6SF2]); and intronic variants rs12137855 (in lysophospholipaselike 1 [LYPLAL1]) and rs780094 (in glucokinase regulatory protein [GCKR]) were significantly associated with hepatic steatosis.…”

The effect of liver enzymes on body composition: a Mendelian randomization study

“…Single nucleotide polymorphisms (SNPs) predicting plasma log transformed ALT, ALP and GGT at genome-wide significance (p-value<5 × 10 −8 ) adjusted for age and sex were obtained from the largest available genome-wide association study (GWAS) of plasma levels of liver enzymes comprising 61,089 adults (~86% European, mean age 52.8 years, 50.6% women). 15,19 For SNPs in linkage disequilibrium (R 2 >0.01), we retained SNPs with the lowest p-value using the “Clumping” function of MR-Base ( TwoSampleMR ) R package, based on the 1000 Genomes catalog. 20 Whether any of the selected SNPs were associated with potential confounders was assessed from their Bonferroni corrected associations with height, alcohol use (intake frequency and intake versus 10 years previously), smoking (current smoking and past smoking), education, financial situation, physical activity (moderate and vigorous physical activity), and age of puberty (menarche and voice breaking) in the UK Biobank.…”