A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

Marijana, Vujkovic, Corporal Michael J Crescenz VA Med Ctr; Shweta, Ramdas, University of Pennsylvania; Kim M, Lorenz, Corporal Michael J. Crescenz VA Medical Center; Xiuqing, Guo, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center; Rebecca, Darlay, Newcastle University; Heather J, Cordell, Newcastle University; Jing, He, Vanderbilt University; Yevgeniy, Gindin, Gilead Sciences, Inc.; Chuhan, Chung, Gilead Sciences, Inc.; Robert P, Myers, Gilead Sciences, Inc.; Carolin V, Schneider, University of Pennsylvania; Joseph, Park, University of Pennsylvania; Kyung Min, Lee, VA Salt Lake City Health Care System; Marina, Serper, Corporal Michael J Crescenz VA Med Ctr; Rotonya M, Carr, University of Washington; David E, Kaplan, Corporal Michael J Crescenz VA Med Ctr; Mary E, Haas, Broad Inst MIT & Harvard; Matthew T, MacLean, University of Pennsylvania; Walter R, Witschey, University of Pennsylvania; Xiang, Zhu, VA Palo Alto Health Care System, Palo Alto; Catherine, Tcheandjieu, VA Palo Alto Health Care System, Palo Alto; Rachel L, Kember, Corporal Michael J Crescenz VA Med Ctr; Henry R, Kranzler, Corporal Michael J Crescenz VA Med Ctr; Anurag, Verma, Corporal Michael J Crescenz VA Med Ctr; Ayush, Giri, Vanderbilt University; Derek M, Klarin, VA Palo Alto Health Care System, Palo Alto; Yan, Sun, Emory University; Jie, Huang, Southern University of Science & Technology; Jennifer E, Huffman, VA Boston Healthcare System; Kate, Townsend Creasy, University of Pennsylvania; Nicholas J, Hand, University of Pennsylvania; Ching-Ti, Liu, Boston University; Michelle T, Long, Boston University; Jie, Yao, Harbor-UCLA Medical Centera; Matthew, Budoff, Harbor-UCLA Medical Centera; Jingyi, Tan, Harbor-UCLA Medical Centera; Xiaohui, Li, Harbor-UCLA Medical Centera; Henry J, Lin, Harbor-UCLA Medical Centera; Yii-Der Ida, Chen, Harbor-UCLA Medical Centera; Kent D, Taylor, Harbor-UCLA Medical Centera; Ruey-Kang, Chang, Harbor-UCLA Medical Centera; Ronald M, Krauss, University of California San Francisco; Silvia, Vilarinho, Yale School of Medicine; Joseph, Brancale, Yale School of Medicine; Jonas B, Nielsen, Regeneron Genetics Center; Adam E, Locke, Regeneron Genetics Center; Marus B, Jones, Regeneron Genetics Center; Niek, Verweij, Regeneron Genetics Center; Aris, Baras, Regeneron Genetics Center; Rajender K, Reddy, University of Pennsylvania; Brent A, Neuschwander-Tetri, St Louis University; Jeffrey B, Schwimmer, University of California San Diego; Arun J, Sanyal, Virginia Commonwealth University; Naga, Chalasani, Indiana University; Kathleen A, Ryan, University of Maryland; Braxton D, Mitchell, University of Maryland; Dipender, Gill, Imperial College London; Andrew D, Wells, University of Pennsylvania; Elisabeta, Manduchi, University of Pennsylvania; Yedidya, Saiman, Temple University; Nadim, Mahmud, University of Pennsylvania; Donald R, Miller, Bedford VA Healthcare System; Peter D, Reaven, Phoenix VA Health Care System; Lawrence, Phillips, Emory University; Sumitra, Muralidhar, Veterans Health Administration, Washington; Scott L, DuVall, VA Salt Lake City Health Care System; Jennifer S, Lee, VA Palo Alto Health Care System; Themistocles L, Assimes, VA Palo Alto Health Care System; Saiju, Pyarajan, VA Boston Healthcare System; Kelly, Cho, VA Boston Healthcare System; Todd L, Edwards, Nashville VA Medical Center; Scott M, Damrauer, Corporal Michael J. Crescenz VA Medical Center; Peter, Wilson, Emory University; Michael J, Gaziano, VA Boston Healthcare System; Christopher J, O'Donnell, VA Boston Healthcare System; Amit V, Khera, Broad Institute of MIT and Harvard; Struan FA, Grant, University of Pennsylvania; Christopher D, Brown, University of Pennsylvania; Philip S, Tsao, VA Palo Alto Health Care System; Danish, Saleheen, Columbia University; Luca A, Lotta, Regeneron Genetics Center; Lisa, Bastarache, Vanderbilt University; Quentin M, Anstee, Newcastle University; Ann K, Daly, Newcastle NIHR Biomedical Research Centre; James B, Meigs, Broad Institute of MIT and Harvard; Jerome I, Rotter, Harbor-UCLA Medical Center; Julie A, Lynch, VA Salt Lake City Hlth Care Syst; Daniel J, Rader, University of Pennsylvania; Benjamin F, Voight, Corporal Michael J. Crescenz VA Medical Center; Kyong-Mi, Chang, Corporal Michael J. Crescenz VA Medical Center

Publication

A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

Persistent URL

https://open.library.emory.edu/purl/81937pvnh5-emory

Last modified

09/19/2025

Type of Material

Article

Authors

Marijana Vujkovic, Corporal Michael J Crescenz VA Med Ctr

Shweta Ramdas, University of Pennsylvania

Kim M Lorenz, Corporal Michael J. Crescenz VA Medical Center

Xiuqing Guo, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

Rebecca Darlay, Newcastle University

Heather J Cordell, Newcastle UniversityJing He, Vanderbilt UniversityYevgeniy Gindin, Gilead Sciences, Inc.Chuhan Chung, Gilead Sciences, Inc.Robert P Myers, Gilead Sciences, Inc.Carolin V Schneider, University of PennsylvaniaJoseph Park, University of PennsylvaniaKyung Min Lee, VA Salt Lake City Health Care SystemMarina Serper, Corporal Michael J Crescenz VA Med CtrRotonya M Carr, University of WashingtonDavid E Kaplan, Corporal Michael J Crescenz VA Med CtrMary E Haas, Broad Inst MIT & HarvardMatthew T MacLean, University of PennsylvaniaWalter R Witschey, University of PennsylvaniaXiang Zhu, VA Palo Alto Health Care System, Palo AltoCatherine Tcheandjieu, VA Palo Alto Health Care System, Palo AltoRachel L Kember, Corporal Michael J Crescenz VA Med CtrHenry R Kranzler, Corporal Michael J Crescenz VA Med CtrAnurag Verma, Corporal Michael J Crescenz VA Med CtrAyush Giri, Vanderbilt UniversityDerek M Klarin, VA Palo Alto Health Care System, Palo AltoYan Sun, Emory UniversityJie Huang, Southern University of Science & TechnologyJennifer E Huffman, VA Boston Healthcare SystemKate Townsend Creasy, University of PennsylvaniaNicholas J Hand, University of PennsylvaniaChing-Ti Liu, Boston UniversityMichelle T Long, Boston UniversityJie Yao, Harbor-UCLA Medical CenteraMatthew Budoff, Harbor-UCLA Medical CenteraJingyi Tan, Harbor-UCLA Medical CenteraXiaohui Li, Harbor-UCLA Medical CenteraHenry J Lin, Harbor-UCLA Medical CenteraYii-Der Ida Chen, Harbor-UCLA Medical CenteraKent D Taylor, Harbor-UCLA Medical CenteraRuey-Kang Chang, Harbor-UCLA Medical CenteraRonald M Krauss, University of California San FranciscoSilvia Vilarinho, Yale School of MedicineJoseph Brancale, Yale School of MedicineJonas B Nielsen, Regeneron Genetics CenterAdam E Locke, Regeneron Genetics CenterMarus B Jones, Regeneron Genetics CenterNiek Verweij, Regeneron Genetics CenterAris Baras, Regeneron Genetics CenterRajender K Reddy, University of PennsylvaniaBrent A Neuschwander-Tetri, St Louis UniversityJeffrey B Schwimmer, University of California San DiegoArun J Sanyal, Virginia Commonwealth UniversityNaga Chalasani, Indiana UniversityKathleen A Ryan, University of MarylandBraxton D Mitchell, University of MarylandDipender Gill, Imperial College LondonAndrew D Wells, University of PennsylvaniaElisabeta Manduchi, University of PennsylvaniaYedidya Saiman, Temple UniversityNadim Mahmud, University of PennsylvaniaDonald R Miller, Bedford VA Healthcare SystemPeter D Reaven, Phoenix VA Health Care SystemLawrence Phillips, Emory UniversitySumitra Muralidhar, Veterans Health Administration, WashingtonScott L DuVall, VA Salt Lake City Health Care SystemJennifer S Lee, VA Palo Alto Health Care SystemThemistocles L Assimes, VA Palo Alto Health Care SystemSaiju Pyarajan, VA Boston Healthcare SystemKelly Cho, VA Boston Healthcare SystemTodd L Edwards, Nashville VA Medical CenterScott M Damrauer, Corporal Michael J. Crescenz VA Medical CenterPeter Wilson, Emory UniversityMichael J Gaziano, VA Boston Healthcare SystemChristopher J O'Donnell, VA Boston Healthcare SystemAmit V Khera, Broad Institute of MIT and HarvardStruan FA Grant, University of PennsylvaniaChristopher D Brown, University of PennsylvaniaPhilip S Tsao, VA Palo Alto Health Care SystemDanish Saleheen, Columbia UniversityLuca A Lotta, Regeneron Genetics CenterLisa Bastarache, Vanderbilt UniversityQuentin M Anstee, Newcastle UniversityAnn K Daly, Newcastle NIHR Biomedical Research CentreJames B Meigs, Broad Institute of MIT and HarvardJerome I Rotter, Harbor-UCLA Medical CenterJulie A Lynch, VA Salt Lake City Hlth Care SystDaniel J Rader, University of PennsylvaniaBenjamin F Voight, Corporal Michael J. Crescenz VA Medical CenterKyong-Mi Chang, Corporal Michael J. Crescenz VA Medical Center

Language

English

Date

2022-06-02

Publisher

NATURE PORTFOLIO

Publication Version

Author Accepted Manuscript (After Peer Review)

Copyright Statement

© 2022, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply

Final Published Version (URL)

http://dx.doi.org/10.1038/s41588-022-01078-z

Title of Journal or Parent Work

NATURE GENETICS

Volume

Issue

Start Page

End Page

Supplemental Material (URL)

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance, including 25 without prior NAFLD or alanine aminotransferase associations, with one additional locus identified in European American-only and two in African American-only analyses (P < 5 × 10−8). External replication in histology-defined NAFLD cohorts (7,397 cases and 56,785 controls) or radiologic imaging cohorts (n = 44,289) replicated 17 single-nucleotide polymorphisms (SNPs) (P < 6.5 × 10−4), of which 9 were new (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH and IFI30). Pleiotropy analysis showed that 61 of 77 multiancestry and all 17 replicated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.

Author Notes