Multi-SNP analysis of GWAS data identifies pathways associated with nonalcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a common liver disease; the histological spectrum of which ranges from steatosis to steatohepatitis. Nonalcoholic steatohepatitis (NASH) often leads to cirrhosis and development of hepatocellular carcinoma. To better understand pathogenesis of NAFLD, we performed the pathway of distinction analysis (PoDA) on a genome-wide association study dataset of 250 non-Hispanic white female adult patients with NAFLD, who were enrolled in the NASH Clinical Research Network (CRN) Database Study, to investigate whether biologic process variation measured through genomic variation of genes within these pathways was related to the development of steatohepatitis or cirrhosis. Pathways such as Recycling of eIF2:GDP, biosynthesis of steroids, Terpenoid biosynthesis and Cholesterol biosynthesis were found to be significantly associated with NASH. SNP variants in Terpenoid synthesis, Cholesterol biosynthesis and biosynthesis of steroids were associated with lobular inflammation and cytologic ballooning while those in Terpenoid synthesis were also associated with fibrosis and cirrhosis. These were also related to the NAFLD activity score (NAS) which is derived from the histological severity of steatosis, inflammation and ballooning degeneration. Eukaryotic protein translation and recycling of eIF2:GDP related SNP variants were associated with ballooning, steatohepatitis and cirrhosis. Il2 signaling events mediated by PI3K, Mitotic metaphase/anaphase transition, and Prostanoid ligand receptors were also significantly associated with cirrhosis. Taken together, the results provide evidence for additional ways, beyond the effects of single SNPs, by which genetic factors might contribute to the susceptibility to develop a particular phenotype of NAFLD and then progress to cirrhosis. Further studies are warranted to explain potential important genetic roles of these biological processes in NAFLD.

Figure 1. Two representative significant pathways in steatohepatitis.

Scatter plots of distance score S for each pathway and overlayed with boxplots are given in the left panel; higher values of S indicate the sample is closer to other cases than it is to other controls. Distribution of S for cases (red) and controls (black) are given to the right. A. “Viral messenger RNA synthesis” – Reactome. B. “mRNA splicing – Major pathway” – Reactome.

Figure 2. Two representative significant pathways in cirrhosis.

Scatter plots of distance score S for each pathway and overlayed with boxplots are given in the left panel; higher values of S indicate the sample is close to other cases than it is to other controls. Distribution of S for cases (red) and controls (black) are given to the right. A. “IL2 signaling events mediated by PI3K” – NCI-Nature. B. “Lectin induced complement pathway” – BioCarta.