Genome-Wide Association Study of Liver Fat: The Multiethnic Cohort Adiposity Phenotype Study.

The global rise in fatty liver is a major public health problem. Thus, it is critical to identify both global and population-specific genetic variants associated with liver fat. We conducted a genome-wide association study (GWAS) of percent liver fat and nonalcoholic fatty liver disease (NAFLD) assessed by magnetic resonance imaging in 1,709 participants from the population-based Multiethnic Cohort Adiposity Phenotype Study. Our participants comprised older adults of five U.S. racial/ethnic groups: African Americans (n = 277), Japanese Americans (n = 424), Latinos (n = 348), Native Hawaiians (n = 274), and European Americans (n = 386). The established missense risk variant rs738409 located in patatin-like phospholipase domain containing 3 () at 22q13 was confirmed to be associated with percent liver fat ( = 3.52 × 10) but more strongly in women than men ( heterogeneity = 0.002). Its frequency correlated with the prevalence of NAFLD across the five ethnic/racial groups. Rs738409 was also associated with homeostasis model assessment of insulin resistance (HOMA-IR) (beta = 0.028;  = 0.009) and circulating levels of insulin (beta = 0.022;  = 0.020) and alanine aminotransferase (beta = 0.016;  = 0.030). A novel association of percent liver fat with rs77249491 (located at 6q13 between limb region 1 domain containing 1 [] and collagen type XIX alpha 1 chain [] ( = 1.42 × 10) was also observed. Rs7724941 was associated with HOMA-IR (beta = 0.12;  = 0.0005), insulin (beta = 0.11;  = 0.0003), triglycerides (beta = 0.059;  = 0.01), high-density lipoprotein (beta = -0.046;  = 0.04), and sex hormone binding globulin (beta = -0.084;  = 0.0012). This variant was present in Japanese Americans (minor allele frequency [MAF], 8%) and Native Hawaiians (MAF, 2%). : We replicated the rs738409 association in a multiethnic population and identified a novel liver fat risk variant in Japanese Americans and Native Hawaiians. GWASes of percent liver fat in East Asian and Oceanic populations are needed to replicate the rs77249491 association.