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Characterization of european ancestry nonalcoholic fatty liver disease‐associated variants in individuals of african and hispanic descent

Nonalcoholic fatty liver disease (NAFLD) is an obesity‐related condition affecting over 50% of individuals in some populations and is expected to become the number one cause of liver disease worldwide by 2020. Common, robustly associated genetic variants in/near five genes were identified for hepatic steatosis, a quantifiable component of NAFLD, in European ancestry individuals. Here we tested whether these variants were associated with hepatic steatosis in African‐ and/or Hispanic‐Americans and fine‐mapped the observed association signals. We measured hepatic steatosis using computed tomography in five African American (n = 3,124) and one Hispanic American (n = 849) cohorts. All analyses controlled for variation in age, age2, gender, alcoholic drinks, and population substructure. Heritability of hepatic steatosis was estimated in three cohorts. Variants in/near PNPLA3, NCAN, LYPLAL1, GCKR, and PPP1R3B were tested for association with hepatic steatosis using a regression framework in each cohort and meta‐analyzed. Fine‐mapping across African American cohorts was conducted using meta‐analysis. African‐ and Hispanic‐American cohorts were 33.9/37.5% male, with average age of 58.6/42.6 years and body mass index of 31.8/28.9 kg/m2, respectively. Hepatic steatosis was 0.20‐0.34 heritable in African‐ and Hispanic‐American families (P < 0.02 in each cohort). Variants in or near PNPLA3, NCAN, GCKR, PPP1R3B in African Americans and PNPLA3 and PPP1R3B in Hispanic Americans were significantly associated with hepatic steatosis; however, allele frequency and effect size varied across ancestries. Fine‐mapping in African Americans highlighted missense variants at PNPLA3 and GCKR and redefined the association region at LYPLAL1. Conclusion: Multiple genetic variants are associated with hepatic steatosis across ancestries. This explains a substantial proportion of the genetic predisposition in African‐ and Hispanic‐Americans. Missense variants in PNPLA3 and GCKR are likely functional across multiple ancestries. (Hepatology 2013;53:966–975)