A trans-ancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a prevalent, heritable trait that can progress to cancer and liver failure. Using our recently developed proxy definition for NAFLD based on chronic liver enzyme elevation without other causes of liver disease or alcohol misuse, we performed a multi-ancestry genome-wide association study in the Million Veteran Program with 90,408 NAFLD cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance of which 70 were novel, with an additional European-American specific and two African-American specific loci. Twelve of these loci were also significantly associated with quantitative hepatic fat on radiological imaging (n=44,289). Gene prioritization based on coding annotations, gene expression from GTEx, and functional genomic annotation identified candidate genes at 97% of loci. At eight loci, the allele associated with lower gene expression in liver was also associated with reduced risk of NAFLD, suggesting potential therapeutic relevance. Functional genomic annotation and gene-set enrichment demonstrated that associated loci were relevant to liver biology. We expand the catalog of genes influencing NAFLD, and provide a novel resource to understand its disease initiation, progression and therapy.

Integration of genetic colocalizations with physiological and pharmacological perturbations identifies cardiometabolic disease genes

“…Our approach also points at novel, shared genetic architecture of traits. For example, two genes previously associated with non-alcoholic fatty liver disease, or NAFLD (COBLL1 and PNPLA3) [40,41], show colocalization in liver (Fig. 6), the former with fasting insulin and BMI and the latter with T2D, HDL, and TG, implicating them as shared genetic associations for IR/T2D and NAFLD.…”

“…For 30 of our candidate causal genes, we observed a response to atorvastatin, metformin, or rosiglitazone, three drugs used for the treatment of cardiometabolic diseases. For instance, COBLL1, a gene with liverspecific colocalization for fasting insulin and BMI and previously associated with non-alcoholic fatty liver disease [40,41], showed decreased expression under both atorvastatin and metformin in liver. Another gene, GPAM, which colocalized with HDL and TG also in liver, showed reduced expression under all three of these treatments (atorvastatin and metformin in liver, rosiglitazone in fat cells).…”

Leveraging Health Systems Data to Characterize a Large Effect Variant Conferring Risk for Liver Disease in Puerto Ricans

“…The range of Mendelian ABCB4 associated phenotypes has been noted to follow both autosomal dominant and recessive modes of inheritance. Furthermore, in large-scale population-based studies, variation in ABCB4 has been statistically associated with elevated risk for a number of liver-related phenotypes, including risk for non-alcoholic fatty liver disease[45], elevated serum liver enzyme levels[46,47], and risk for hepatobiliary carcinoma[48], suggesting that common variation in this gene may play a broader role in liver disease risk in the human population.…”

Epigenetics of Hepatic Insulin Resistance

“…Hepatic lipid accumulation is highly associated with IR (50) and, for this reason, a number of candidate gene analyses have focused on hepatic lipid metabolism genes, particularly on those pinpointed by genetic association studies. A number of GWAS have implicated FADS2 in IR-related diseases (51)(52)(53). FADS2 (delta-6 desaturase) is a rate-limiting enzyme in long-chain polyunsaturated fatty acids Comparison of obese T2D and non-T2D revealed that the IRS2 locus, which encodes a core mediator of insulin signalling in the liver, is differentially methylated in the livers of T2D patients (41).…”