Genome-wide association study of serum liver enzymes implicates diverse metabolic and liver pathology

Abstract

Serum liver enzyme concentrations are the most frequently-used laboratory markers of liver disease, a major cause of mortality. We conduct a meta-analysis of genome-wide association studies of liver enzymes from UK BioBank and BioBank Japan. We identified 160 previously-unreported independent alanine aminotransferase, 190 aspartate aminotransferase, and 199 alkaline phosphatase genome-wide significant associations, with some affecting multiple different enzymes. Associated variants implicate genes that demonstrate diverse liver cell type expression and promote a range of metabolic and liver diseases. These findings provide insight into the pathophysiology of liver and other metabolic diseases that are associated with serum liver enzyme concentrations.

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

“…15,22,23 Recent studies identified APOE, TR1B1, and FTO as potential new loci for liver enzymes. 24,25 Our study extends the results of these studies by linking variation at these loci with a clinical diagnosis of NAFLD and identifies LPL as a potential new susceptibility locus for NAFLD. Interestingly, the minor allele (C) at rs13702 associated here with protection against NAFLD has been predicted to disrupt a microRNA recognition element seed site for human microRNA miR-410, resulting in higher LPL expression.…”

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

“…viral hepatitis, alcoholic liver disease, hemochromatosis), based on previous validation within VA population 21,31 . In this regard, several GWAS studies of liver enzyme levels have been reported, particularly of serum ALT 10,11,16,34,35 , but not all studies systematically excluded other causes of ALT elevation. For example, Pazoki et al recently reported 230 locis related to ALT, of which 52 were also included in our panel of 77 (67.5%) lead cALT loci 34,35 .…”

“…In this regard, several GWAS studies of liver enzyme levels have been reported, particularly of serum ALT 10,11,16,34,35 , but not all studies systematically excluded other causes of ALT elevation. For example, Pazoki et al recently reported 230 locis related to ALT, of which 52 were also included in our panel of 77 (67.5%) lead cALT loci 34,35 . While our cALT approach was designed to enhance the specifity of non-invasive NAFLD diagnosis 21,31 , this overlap is not surprising given the high prevalence of NAFLD in the general population.…”

Integrated omics analysis reveals sirtuin signaling is central to hepatic response to a high fructose diet

“…GWAS of genes and proteins in sirtuin signaling and the four activated networks we identified show a single gene, FABP1, that has been reported to be associated with alanine aminotransferase levels, a marker of liver disease [ 59 ]. Twelve additional genes were associated with lipoprotein-, insulin-, and BMI-related traits.…”