Genome-wide analysis of hepatic lipid content in extreme obesity

Individuals with type 2 diabetes have an increased risk of developing non-alcoholic fatty liver disease (NAFLD), and NAFLD patients are also at greater risk for developing type 2 diabetes. Although the relationship between type 2 diabetes and NAFLD is highly interconnected, the pathogenic mechanisms linking the two diseases are poorly understood. The goal of this study was to identify genetic determinants of hepatic lipid accumulation through association analysis using histological phenotypes in obese individuals. Using the Illumina HumanOmniExpress BeadChip assay, we genotyped 2,300 individuals on whom liver biopsy data were available. We analyzed total bilirubin levels, which are linked to fatty liver in severe obesity, and observed the strongest evidence for association with rs4148325 in UGT1A (P < 5.0 x 10(-93)), replicating previous findings. We assessed hepatic fat level and found strong evidence for association with rs4823173, rs2896019, and rs2281135, all located in PNPLA3 and rs10401969 in SUGP1. Analysis of liver transcript levels of 20 genes residing at the SUGP1/NCAN locus identified a 1.6-fold change in the expression of the LPAR2 gene in fatty liver. We also observed suggestive evidence for association between low-grade fat accumulation and rs10859525 and rs1294908, located upstream from SOCS2 and RAMP3, respectively. SOCS2 was differentially expressed between fatty and normal liver. These results replicate findings for several hepatic phenotypes in the setting of extreme obesity and implicate new loci that may play a role in the pathophysiology of hepatic lipid accumulation.