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Multi-SNP Analysis of GWAS Data Identifies Pathways Associated With Washington University School of Medicine Digital Commons@Becker Open Access Publications 2013 Multi-SNP analysis of GWAS data identifies pathways associated with nonalcoholic fatty liver disease Qing-Rong Chen National Cancer Institute, National Institutes of Health, Bethesda Rosemary Braun National Cancer Institute, National Institutes of Health, Bethesda Ying Hu National Cancer Institute, National Institutes of Health, Bethesda Chunhua Yan National Cancer Institute, National Institutes of Health, Bethesda Elizabeth M. Brunt Washington University School of Medicine in St. Louis See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Chen, Qing-Rong; Braun, Rosemary; Hu, Ying; Yan, Chunhua; Brunt, Elizabeth M.; Meerzaman, Daoud; Sanyal, Arun J.; and Buetow, Kenneth, ,"Multi-SNP analysis of GWAS data identifies pathways associated with nonalcoholic fatty liver disease." PLoS One.8,7. e65982. (2013). https://digitalcommons.wustl.edu/open_access_pubs/1598 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Qing-Rong Chen, Rosemary Braun, Ying Hu, Chunhua Yan, Elizabeth M. Brunt, Daoud Meerzaman, Arun J. Sanyal, and Kenneth Buetow This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/open_access_pubs/1598 Multi-SNP Analysis of GWAS Data Identifies Pathways Associated with Nonalcoholic Fatty Liver Disease Qing-Rong Chen1*, Rosemary Braun1,2, Ying Hu1, Chunhua Yan1, Elizabeth M. Brunt3, Daoud Meerzaman1, Arun J. Sanyal4., Kenneth Buetow1,5. 1 Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America, 2 Biostatistics Division, Department of Preventive Medicine and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, Illinois, United States of America, 3 Department of Pathology & Immunology, School of Medicine, Washington University, St Louis, Missouri, United States of America, 4 Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, Virginia, United States of America, 5 Computational Science and Informatics Program, Complex Adaptive Systems Initiative, Arizona State University, Phoenix, Arizona, United States of America 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. Citation: Chen Q-R, Braun R, Hu Y, Yan C, Brunt EM, et al. (2013) Multi-SNP Analysis of GWAS Data Identifies Pathways Associated with Nonalcoholic Fatty Liver Disease. PLoS ONE 8(7): e65982. doi:10.1371/journal.pone.0065982 Editor: Silvia C. Sookoian, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Argentina Received March 15, 2013; Accepted April 30, 2013; Published July 19, 2013 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, U01DK061713), and the National Institute of Child Health and Human Development (NICHD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] . These authors contributed equally to this work. Introduction inflammation and fibrosis [6–7]. Since the discovery of the association between the PNPLA3 mutation and steatosis and Nonalcoholic fatty liver disease (NAFLD) affects almost a third steatohepatitis, several additional single nucleotide polymorphisms of the adult population in North America [1]. The clinical- (SNPs) have been identified to be associated with NASH [7]. histologic spectrum of NAFLD ranges from nonalcoholic fatty However, despite these individual SNP associations, the biologic liver (NAFL) to nonalcoholic steatohepatitis (NASH) [2]. While mechanisms that distinguish alternative clinical outcomes or NAFL progresses to cirrhosis in less than 5% of cases, NASH can disease progression are largely unknown. progress to cirrhosis in 15–20% of cases [3–4]. NAFLD is also a Genetic analysis of biologic processes as opposed to analysis of risk factor for the development of hepatocellular cancer which can individual SNPs may provide more insight into pathogenesis. The develop with or without cirrhosis [5]. It is therefore a public health pathway of distinction analysis (PoDA) is a recently developed priority to better understand the pathogenesis of the disease as well computational technique which tests for the association of as factors that drive disease progression. variation within multiple genes involved in a defined biologic Recently, a single variant in PNPLA (rs738409; I148M) has been pathway with a given phenotype [8]. This method may thus be shown to be strongly associated with increased hepatic fat levels, PLOS ONE | www.plosone.org 1 July 2013 | Volume 8 | Issue 7 | e65982 Pathways Associated with NAFLD used to investigate whether collections of constitutional genome Data Analysis variability within biologic processes determine the predisposition The Pathway of Distinction Analysis (PoDA) [8] was applied to to develop steatohepatitis vs. steatosis or drive the progression to the NAFLD genotype data for the following histologic phenotypes: cirrhosis and hepatocellular cancer. Importantly, it identifies steatohepatitis, NAFLD activity score (NAS) and its histologic interactions between SNPs in driving a specific phenotype even components (steatosis, cytologic ballooning and lobular inflamma- when individually the SNPs may not be significantly related to the tion), fibrosis stage, and cirrhosis. Each of these phenotypes were phenotype. analyzed as qualitative binary traits as described below: (1) In this analysis, PoDA was performed on a genome wide Steatohepatitis: definite steatohepatitis (n = 56) vs. controls (stea- association study dataset obtained from the NIDDK NASH tohepatitis absent, n = 131). (2) NAS: high score (NAS $5, Clinical Research Network (CRN) on 250 highly characterized n = 114) vs. low scores (NAS ,5, n = 124), Steatosis: moderate to adult female subjects with varying phenotypes of NAFLD [9]. The severe (grades 2–3, n = 102) vs. mild to none (grades ,2, n = 93), specific objectives of the study were to determine whether biologic Lobular inflammation: moderate to severe (grades 2–3, n = 96) vs. process variation measured through genomic variation of genes mild to none (grades 0–1, n = 99), Ballooning: many ballooned within these networks was related to the development of cells (grade 2, n = 111) vs. controls with
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