Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease in the US. Notably, disease prevalence differs greatly by race/ethnicity, with the highest prevalence in those of Hispanic and Asian ancestry, and the lowest prevalence in those of African ancestry. To date, studies have identified common variants associated with MASLD in predominantly European or American populations. We have conducted the largest-to-date multi-ancestry whole genome sequencing (WGS) association study to identify rare variants that promote MASLD in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium.

Methods: Study- and ethnic/race-stratified association analyses were conducted in six cohorts with imaging-measured hepatic steatosis using SAIGEgds adjusted for age, sex, alcoholic drinks per week, and principal component estimates of admixture. Stratified results were meta-analyzed for Hispanic Ancestry, non-Hispanic European Ancestry, non-Hispanic African Ancestry, and non-Hispanic Chinese Ancestry individuals and for an overall analysis using a fixed-effects meta-analysis in METAL. Cochran’s Q test and the I2 metric were used to identify and quantify heterogeneity.

Results: The meta-analysis included 16,664 individuals with imaging-measured hepatic steatosis. Of these, 9,443 were of European Ancestry, 5,918 were of African Ancestry, 937 were of Hispanic Ancestry and 366 were of Chinese Ancestry. The ethnic/race-stratified meta-analysis identified six variants significantly associated (P<=5E-08) with MASLD, i.e. European Ancestry (n=2), African Ancestry (n=4), including variants in/near PNPLA3, TM6SF2, PPP1R3B, LINC01684, and SLC2A1. An additional 15 variants trended toward association (P<=5E-07) i.e. European Ancestry (n=1), African Ancestry (n=11), Hispanic Ancestry (n=2), and Chinese Ancestry (n=1) with MASLD.

Conclusion: In a large, multiethnic analysis of imaging-measured hepatic steatosis, we replicated loci previously associated with MASLD and identified possible new race-specific loci. Several variants were trending toward association and will benefit from ongoing analyses to include 6,492 additional samples.