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Nonalcoholic Fatty Liver Disease Risk Loci Emerge From Multi-Ancestry GWAS

NEW YORK — Researchers have identified more than six dozen genetic loci associated with chronic elevation of alanine aminotransferase, an indicator of nonalcoholic fatty liver disease (NAFLD).

NAFLD, which can develop into chronic liver disease, is on the rise globally, and both genetic and environmental factors play a role in the disease. Heritability of NAFLD is thought to be between 20 percent and 50 percent, while factors such as obesity, insulin resistance, and metabolic syndrome also contribute to disease risk.

To search for genetic variants that might explain NAFLD disease risk, researchers from the University of Pennsylvania conducted a genome-wide association study of chronic elevation of alanine aminotransferase (cALT), as a stand-in for the disease, using the diverse Million Veteran Program cohort. As they reported in Nature Genetics on Thursday, they homed in on genetic variants that implicated genes involved in both metabolic and inflammatory traits.

"This study constitutes a much-needed large-scale, multi-ancestry genetic resource that can be used to build genetic prediction models, identify causal mechanisms, and understand biological pathways contributing to NAFLD initiation and disease progression," co-senior author Kyong-Mi Chang from UPenn and the Corporal Michael J. Crescenz VA Medical Center and colleagues wrote in their paper.

For their GWAS, the researchers drew upon more than 90,400 cALT cases and more than 128,000 controls of European American, African American, and Hispanic American ancestry. Most of the cases, more than 92 percent, were male. In a multi-ancestry GWAS meta-analysis, they uncovered 77 independent SNPs that exceeded genome-wide significance.

Of those, 52 SNPs had been previously linked to ALT levels and nine were also associated with NAFLD. The team additionally uncovered one locus among only European Americans and two that were specific to African Americans.

As cALT is a proxy measure, the researchers further studied the 77 SNPs in two separate cohorts, in which the cases had histologically confirmed nonalcoholic fatty liver disease and hepatic fat. In one cohort, 66 of the 77 SNPs showed directional concordance, and in the other, 49 of the 77 SNPs did. A polygenic risk score based on 17 SNPs that were replicated in both cohorts could further strongly predict NAFLD. This, the researchers said, supports their use of cALT as a proxy for the disease.

Nine of the 17 replicated SNPs — implicating TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH, and IFI30 — had not been previously reported, they noted.

Through pleiotropy analyses, the researchers found that 61 of the 77 originally identified SNPs and all 17 of the replicated SNPs were associated with metabolic or inflammatory traits. The 77 loci could be broken down into seven gene clusters based on their association with various cardiometabolic traits. For instance, for one cluster, the loci were associated with increased LDL and total cholesterol, as well as increased apolipoprotein B1 and inflammation markers, while for another, the loci were associated with increased rates of type 2 diabetes, but decreased levels of triglycerides, LDL cholesterol, HDL cholesterol, and other factors. These findings indicate a complex model of genetic architecture underlying nonalcoholic fatty liver disease, according to the authors.

"Our approach integrating cALT, histology, and imaging reveals new insights into genetic liability to NAFLD," they added.