Abstract
Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%–27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10−8) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT–assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.
Highlights
Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of disease ranging from fatty infiltration of the liver to histologic evidence of inflammation, to fibrosis or cirrhosis, without a history of excessive alcohol ingestion [1,2]
We found that the heritability of computed tomography (CT) hepatic steatosis was 0.27, 0.27 (SE = 0.04), and 0.26 (SE 0.04) in the Amish, Family Heart Study (FamHS), and Framingham Heart Study (FRAM) cohorts respectively (n = 880–3,070) (See Materials and Methods and Table 1)
We have identified variants in three novel loci (NCAN, GCKR, and LYPLAL1) and one previously reported locus (PNPLA3) that are associated with both increasing CT hepatic steatosis and histologic NAFLD
Summary
NAFLD includes a spectrum of disease ranging from fatty infiltration of the liver (steatosis) to histologic evidence of inflammation (nonalcoholic steatohepatitis or NASH), to fibrosis or cirrhosis, without a history of excessive alcohol ingestion [1,2]. Liver attenuation measured using computed tomography (CT) is a quantitative measure that is inversely related to the amount of fat in the liver [10,11,12] It is highly correlated (r = 0.92) with the macrovesicular hepatic steatosis and is a non invasive measure of NAFLD [12]. The purpose of the present study was to determine the heritability of CT measured hepatic steatosis and to search for associated genetic variants in a meta-analysis of 7,176 individuals of European descent from the Framingham Heart Study (FRAM), the Old Order Amish Study (Amish), the Family Heart Study (FamHS), and the Age, Gene/Environment Susceptibility-Reykjavik study (AGES), which together comprise the GOLD (Genetics of Obesity-related Liver Disease) consortium (See Table S1). We report the association of these SNPs with other metabolic traits using data from the Global Lipids Genetics [13], GIANT [14], DIAGRAM [15], and MAGIC [16] Consortia, as well as investigate cis gene expression variation (eQTLs) in liver, subcutaneous and visceral fat from bariatric surgery patients from Massachusetts General Hospital [17](Figure 1)
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