中文版 | English
Title

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

Author
Vujkovic,Marijana1,2; Ramdas,Shweta3; Lorenz,Kim M.1,3,4; Guo,Xiuqing5; Darlay,Rebecca6; Cordell,Heather J.6; He,Jing7; Gindin,Yevgeniy8; Chung,Chuhan8; Myers,Robert P.8,9; Schneider,Carolin V.3; Park,Joseph2,3; Lee,Kyung Min10; Serper,Marina1,2; Carr,Rotonya M.11; Kaplan,David E.1,2; Haas,Mary E.12; MacLean,Matthew T.3; Witschey,Walter R.13; Zhu,Xiang14,15,16,17; Tcheandjieu,Catherine14,18; Kember,Rachel L.19,20; Kranzler,Henry R.19,20; Verma,Anurag1,3; Giri,Ayush21; Klarin,Derek M.14,22,23; Sun,Yan V.24,25; Huang,Jie26; Huffman,Jennifer E.27; Townsend Creasy,Kate3; Hand,Nicholas J.3; Liu,Ching Ti28; Long,Michelle T.29; Yao,Jie5; Budoff,Matthew30; Tan,Jingyi5; Li,Xiaohui5; Lin,Henry J.5; Chen,Yii Der Ida5; Taylor,Kent D.5; Chang,Ruey Kang5; Krauss,Ronald M.31; Vilarinho,Silvia32; Brancale,Joseph32; Nielsen,Jonas B.33; Locke,Adam E.33; Jones,Marcus B.33; Verweij,Niek33; Baras,Aris33; Reddy,K. Rajender2; Neuschwander-Tetri,Brent A.34; Schwimmer,Jeffrey B.35; Sanyal,Arun J.36; Chalasani,Naga37; Ryan,Kathleen A.38; Mitchell,Braxton D.38; Gill,Dipender39; Wells,Andrew D.40,41; Manduchi,Elisabetta3; Saiman,Yedidya42; Mahmud,Nadim43; Miller,Donald R.44,45; Reaven,Peter D.46,47; Phillips,Lawrence S.24,48; Muralidhar,Sumitra49; DuVall,Scott L.10,50; Lee,Jennifer S.14,18; Assimes,Themistocles L.14,18,51; Pyarajan,Saiju27,52,53; Cho,Kelly27,52,53; Edwards,Todd L.54,55; Damrauer,Scott M.1,3,56; Wilson,Peter W.24,57; Gaziano,J. Michael27,52; O’Donnell,Christopher J.27,52,53; Khera,Amit V.23,53,58; Grant,Struan F.A.3,59,60; Brown,Christopher D.3; Tsao,Philip S.14,18,51; Saleheen,Danish61,62,63; Lotta,Luca A.33; Bastarache,Lisa7; Anstee,Quentin M.64,65; Daly,Ann K.65; Meigs,James B.23,53,66; Rotter,Jerome I.5; Lynch,Julie A.10,50,67; Rader,Daniel J.2,3; Voight,Benjamin F.1,3,4,68; Chang,Kyong Mi1,2
Corresponding AuthorVoight,Benjamin F.
Publication Years
2022
DOI
Source Title
ISSN
1061-4036
EISSN
1546-1718
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). 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), 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.

URL[Source Record]
Indexed By
Language
English
Important Publications
NI Journal Papers
SUSTech Authorship
Others
WOS Accession No
WOS:000805090300004
ESI Research Field
MOLECULAR BIOLOGY & GENETICS
Scopus EID
2-s2.0-85132074767
Data Source
Scopus
Citation statistics
Cited Times [WOS]:8
Document TypeJournal Article
Identifierhttp://kc.sustech.edu.cn/handle/2SGJ60CL/355717
DepartmentSchool of Public Health and Emergency Management
Affiliation
1.Corporal Michael J. Crescenz VA Medical Center,Philadelphia,United States
2.Department of Medicine,University of Pennsylvania Perelman School of Medicine,Philadelphia,United States
3.Department of Genetics,University of Pennsylvania Perelman School of Medicine,Philadelphia,United States
4.Department of Systems Pharmacology and Translational Therapeutics,University of Pennsylvania Perelman School of Medicine,Philadelphia,United States
5.The Institute for Translational Genomics and Population Sciences,Department of Pediatrics,The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center,Torrance,United States
6.Population Health Sciences Institute,Newcastle University,Newcastle upon Tyne,United Kingdom
7.Department of Biomedical Informatics,Vanderbilt University Medical Center,Nashville,United States
8.Gilead Sciences,Inc.,Foster City,United States
9.The Liver Company,Palo Alto,United States
10.VA Salt Lake City Health Care System,Salt Lake City,United States
11.Division of Gastroenterology,University of Washington,Seattle,United States
12.Broad Institute of MIT and Harvard,Cambridge,United States
13.Department of Radiology,University of Pennsylvania Perelman School of Medicine,Philadelphia,United States
14.VA Palo Alto Health Care System,Palo Alto,United States
15.Department of Statistics,The Pennsylvania State University,University Park,United States
16.Huck Institutes of the Life Sciences,The Pennsylvania State University,University Park,United States
17.Department of Statistics,Stanford University,Stanford,United States
18.Department of Medicine,Stanford University School of Medicine,Stanford,United States
19.Mental Illness Research Education and Clinical Center,Corporal Michael J. Crescenz VA Medical Center,Philadelphia,United States
20.Department of Psychiatry,University of Pennsylvania Perelman School of Medicine,Philadelphia,United States
21.Department of Obstetrics and Gynecology,Vanderbilt University Medical Center,Nashville,United States
22.Division of Vascular Surgery,Stanford University School of Medicine,Palo Alto,United States
23.Program in Medical and Population Genetics,Broad Institute of MIT and Harvard,Cambridge,United States
24.Atlanta VA Medical Center,Decatur,United States
25.Department of Epidemiology,Emory University Rollins School of Public Health,Atlanta,United States
26.School of Public Health and Emergency Management,Southern University of Science and Technology,Shenzhen,Guangdong,China
27.VA Boston Healthcare System,Boston,United States
28.Department of Biostatistics,Boston University School of Public Health,Boston,United States
29.Department of Medicine,Section of Gastroenterology,Boston University School of Medicine,Boston,United States
30.Department of Cardiology,The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center,Torrance,United States
31.Departments of Pediatrics and Medicine,University of California,San Francisco,San Francisco,United States
32.Section of Digestive Diseases,Department of Internal Medicine,and Department of Pathology,Yale School of Medicine,New Haven,United States
33.Regeneron Genetics Center,Tarrytown,United States
34.Department of Internal Medicine,Saint Louis University,St. Louis,United States
35.Department of Pediatrics,University of California San Diego,La Jolla,United States
36.Department of Internal Medicine,Virginia Commonwealth University School of Medicine,Richmond,United States
37.Department of Medicine,Indiana University School of Medicine,Indianapolis,United States
38.Program for Personalized and Genomic Medicine,Division of Endocrinology,Diabetes and Nutrition,Department of Medicine,University of Maryland School of Medicine,Baltimore,United States
39.Department of Epidemiology and Biostatistics,School of Public Health,Imperial College London,London,United Kingdom
40.Department of Pathology and Laboratory Medicine,University of Pennsylvania Perelman School of Medicine,Philadelphia,United States
41.Department of Pathology,Children’s Hospital of Philadelphia,Philadelphia,United States
42.Department of Medicine,Section of Hepatology,Lewis Katz School of Medicine at Temple University,Temple University Hospital,Philadelphia,United States
43.Department of Medicine,Division of Gastroenterology,University of Pennsylvania Perelman School of Medicine,Philadelphia,United States
44.Center for Healthcare Organization and Implementation Research,Bedford VA Healthcare System,Bedford,United States
45.Center for Population Health,Department of Biomedical and Nutritional Sciences,University of Massachusetts,Lowell,United States
46.Phoenix VA Health Care System,Phoenix,United States
47.College of Medicine,University of Arizona,Phoenix,United States
48.Division of Endocrinology,Emory University School of Medicine,Atlanta,United States
49.Office of Research and Development,Veterans Health Administration,Washington,United States
50.Department of Medicine,University of Utah School of Medicine,Salt Lake City,United States
51.Stanford Cardiovascular Institute,Stanford University School of Medicine,Stanford,United States
52.Department of Medicine,Brigham Women’s Hospital,Boston,United States
53.Department of Medicine,Harvard Medical School,Boston,United States
54.Nashville VA Medical Center,Nashville,United States
55.Division of Epidemiology,Department of Medicine,Vanderbilt Genetics Institute,Vanderbilt University Medical Center,Nashville,United States
56.Department of Surgery,University of Pennsylvania Perelman School of Medicine,Philadelphia,United States
57.Division of Cardiology,Emory University School of Medicine,Atlanta,United States
58.Center for Genomic Medicine,Massachusetts General Hospital,Boston,United States
59.Department of Pediatrics,University of Pennsylvania Perelman School of Medicine,Philadelphia,United States
60.Division of Human Genetics,Children’s Hospital of Philadelphia,Philadelphia,United States
61.Department of Medicine,Columbia University Irving Medical Center,New York,United States
62.Department of Cardiology,Columbia University Irving Medical Center,New York,United States
63.Center for Non-Communicable Diseases,Karachi,Sindh,Pakistan
64.Faculty of Medical Sciences,Newcastle University,Newcastle upon Tyne,United Kingdom
65.Newcastle NIHR Biomedical Research Centre,Newcastle upon Tyne Hospitals NHS Foundation Trust,Newcastle upon Tyne,United Kingdom
66.Division of General Internal Medicine,Massachusetts General Hospital,Boston,United States
67.College of Nursing and Health Sciences,University of Massachusetts,Lowell,United States
68.Institute of Translational Medicine and Therapeutics,University of Pennsylvania Perelman School of Medicine,Philadelphia,United States
Recommended Citation
GB/T 7714
Vujkovic,Marijana,Ramdas,Shweta,Lorenz,Kim M.,et al. A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation[J]. NATURE GENETICS,2022.
APA
Vujkovic,Marijana.,Ramdas,Shweta.,Lorenz,Kim M..,Guo,Xiuqing.,Darlay,Rebecca.,...&Chang,Kyong Mi.(2022).A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation.NATURE GENETICS.
MLA
Vujkovic,Marijana,et al."A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation".NATURE GENETICS (2022).
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