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GWAS and enrichment analyses of non-alcoholic fatty liver disease identify new trait-associated genes and pathways across eMERGE Network

dc.contributor.authorNiu, Xinnan
dc.contributor.authorWei, Wei-Qi
dc.contributor.authorCarroll, Robert J.
dc.identifier.citationNamjou, B., Lingren, T., Huang, Y. et al. GWAS and enrichment analyses of non-alcoholic fatty liver disease identify new trait-associated genes and pathways across eMERGE Network. BMC Med 17, 135 (2019).
dc.descriptionOnly Vanderbilt University affiliated authors are listed on VUIR. For a full list of authors, access the version of record at
dc.description.abstractBackgroundNon-alcoholic fatty liver disease (NAFLD) is a common chronic liver illness with a genetically heterogeneous background that can be accompanied by considerable morbidity and attendant health care costs. The pathogenesis and progression of NAFLD is complex with many unanswered questions. We conducted genome-wide association studies (GWASs) using both adult and pediatric participants from the Electronic Medical Records and Genomics (eMERGE) Network to identify novel genetic contributors to this condition.MethodsFirst, a natural language processing (NLP) algorithm was developed, tested, and deployed at each site to identify 1106 NAFLD cases and 8571 controls and histological data from liver tissue in 235 available participants. These include 1242 pediatric participants (396 cases, 846 controls). The algorithm included billing codes, text queries, laboratory values, and medication records. Next, GWASs were performed on NAFLD cases and controls and case-only analyses using histologic scores and liver function tests adjusting for age, sex, site, ancestry, PC, and body mass index (BMI).ResultsConsistent with previous results, a robust association was detected for the PNPLA3 gene cluster in participants with European ancestry. At the PNPLA3-SAMM50 region, three SNPs, rs738409, rs738408, and rs3747207, showed strongest association (best SNP rs738409 p=1.70x10(-20)). This effect was consistent in both pediatric (p=9.92x10(-6)) and adult (p=9.73x10(-15)) cohorts. Additionally, this variant was also associated with disease severity and NAFLD Activity Score (NAS) (p=3.94x10(-8), beta=0.85). PheWAS analysis link this locus to a spectrum of liver diseases beyond NAFLD with a novel negative correlation with gout (p=1.09x10(-4)). We also identified novel loci for NAFLD disease severity, including one novel locus for NAS score near IL17RA (rs5748926, p=3.80x10(-8)), and another near ZFP90-CDH1 for fibrosis (rs698718, p=2.74x10(-11)). Post-GWAS and gene-based analyses identified more than 300 genes that were used for functional and pathway enrichment analyses.ConclusionsIn summary, this study demonstrates clear confirmation of a previously described NAFLD risk locus and several novel associations. Further collaborative studies including an ethnically diverse population with well-characterized liver histologic features of NAFLD are needed to further validate the novel findings.en_US
dc.description.sponsorshipIn eMERGE Network (Phase 3 ascertainment), this phase of the eMERGE Network was initiated and funded by the NHGRI through the following grants: U01HG008666 (Cincinnati Children's Hospital Medical Center); U01HG008657 (Kaiser Washington/University of Washington); U01HG008685 (Brigham and Women's Hospital); U01H00G8672 (Vanderbilt University Medical Center); U01HG006379 (Mayo Clinic); U01HG008679 (Geisinger Clinic); U01HG008680 (Columbia University Health Sciences); U01HG008684 (Children's Hospital of Philadelphia); U01HG008673 (Northwestern University); U01HG008701 (Vanderbilt University Medical Center serving as the Coordinating Center); U01HG00676 (Partners Health-care/Broad Institute); and U01HG008664 (Baylor College of Medicine). In eMERGE Network (Phase 1 and 2 ascertainment), the eMERGE Network was initiated and funded by NHGRI through the following grants: U01HG006828 (Cincinnati Children s Hospital Medical Center/Boston Children's Hospital); U01HG006830 (Children's Hospital of Philadelphia); U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation and Pennsylvania State University); U01HG006382 (Geisinger Clinic); U01HG006375 (Group Health (now Kaiser Permanente Washington Health Research Institute)/University of Washington; U01HG006379 (Mayo Clinic); U01HG006380 (Icahn School of Medicine at Mount Sinai); U01HG006388 (Northwestern University); U01HG006378 (Vanderbilt University Medical Center); and U01HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center) with U01HG004438 (CIDR) and U01HG004424 (the Broad Institute) serving as Genotyping Centers. This project was also supported by NIH R01DK099222 (SD), and U01AI130830, P30AR070549, R01AI024717, the US Department of Veterans Affairs (I01BX001834) (JBH).en_US
dc.publisherBMC Medicineen_US
dc.rightsOpen Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.
dc.subjectFatty liveren_US
dc.subjectGenetic polymorphismen_US
dc.subjectPolygenic risk scoreen_US
dc.titleGWAS and enrichment analyses of non-alcoholic fatty liver disease identify new trait-associated genes and pathways across eMERGE Networken_US

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