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; Shweta Ramdas; Kim M Lorenz; Xiuqing Guo; Rebecca Darlay; Heather J Cordell; Jing He; Yevgeniy Gindin; Chuhan Chung; Robert P Myers; Carolin V Schneider; Joseph Park; Kyung Min Lee; Marina Serper; Rotonya M Carr; David E Kaplan; Mary E Haas; Matthew T MacLean; Walter R Witschey; Xiang Zhu; Catherine Tcheandjieu; Rachel L Kember; Henry R Kranzler; Anurag Verma; Ayush Giri; Derek M Klarin; Yan V Sun; Jie Huang; Jennifer E Huffman; Kate Townsend Creasy; Nicholas J Hand; Ching-Ti Liu; Michelle T Long; Jie Yao; Matthew Budoff; Jingyi Tan; Xiaohui Li; Henry J Lin; Yii-Der Ida Chen; Kent D Taylor; Ruey-Kang Chang; Ronald M Krauss; Silvia Vilarinho; Joseph Brancale; Jonas B Nielsen; Adam E Locke; Marcus B Jones; Niek Verweij; Aris Baras; K Rajender Reddy; Brent A Neuschwander-Tetri; Jeffrey B Schwimmer; Arun J Sanyal; Naga Chalasani; Kathleen A Ryan; Braxton D Mitchell; Dipender Gill; Andrew D Wells; Elisabetta Manduchi; Yedidya Saiman; Nadim Mahmud; Donald R Miller; Peter D Reaven; Lawrence S Phillips; Sumitra Muralidhar; Scott L DuVall; Jennifer S Lee; Themistocles L Assimes; Saiju Pyarajan; Kelly Cho; Todd L Edwards; Scott M Damrauer; Peter W Wilson; J Michael Gaziano; Christopher J O'Donnell; Amit V Khera; Struan F A Grant; Christopher D Brown; Philip S Tsao; Danish Saleheen; Luca A Lotta; Lisa Bastarache; Quentin M Anstee; Ann K Daly; James B Meigs; Jerome I Rotter; Julie A Lynch; Regeneron Genetics Center; Geisinger-Regeneron DiscovEHR Collaboration; EPoS Consortium; VA Million Veteran Program; Daniel J Rader; Benjamin F Voight; Kyong-Mi Chang

doi:10.1038/s41588-022-01078-z

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

Nat Genet. 2022 Jun;54(6):761-771. doi: 10.1038/s41588-022-01078-z. Epub 2022 Jun 2.

Authors

Marijana Vujkovic^#^{1

2}, Shweta Ramdas^#³, Kim M Lorenz^{1

3

4}, Xiuqing Guo⁵, Rebecca Darlay⁶, Heather J Cordell⁶, Jing He⁷, Yevgeniy Gindin⁸, Chuhan Chung⁸, Robert P Myers^{8

9}, Carolin V Schneider³, Joseph Park^{2

3}, Kyung Min Lee¹⁰, Marina Serper^{1

2}, Rotonya M Carr¹¹, David E Kaplan^{1

2}, Mary E Haas¹², Matthew T MacLean³, Walter R Witschey¹³, Xiang Zhu^{14

15

16

17}, Catherine Tcheandjieu^{14

18}, Rachel L Kember^{19

20}, Henry R Kranzler^{19

20}, Anurag Verma^{1

3}, Ayush Giri²¹, Derek M Klarin^{14

22

23}, Yan V Sun^{24

25}, Jie Huang²⁶, Jennifer E Huffman²⁷, Kate Townsend Creasy³, Nicholas J Hand³, Ching-Ti Liu²⁸, Michelle T Long²⁹, Jie Yao⁵, Matthew Budoff³⁰, Jingyi Tan⁵, Xiaohui Li⁵, Henry J Lin⁵, Yii-Der Ida Chen⁵, Kent D Taylor⁵, Ruey-Kang Chang⁵, Ronald M Krauss³¹, Silvia Vilarinho³², Joseph Brancale³², Jonas B Nielsen³³, Adam E Locke³³, Marcus B Jones³³, Niek Verweij³³, Aris Baras³³, K Rajender Reddy², Brent A Neuschwander-Tetri³⁴, Jeffrey B Schwimmer³⁵, Arun J Sanyal³⁶, Naga Chalasani³⁷, Kathleen A Ryan³⁸, Braxton D Mitchell³⁸, Dipender Gill³⁹, Andrew D Wells^{40

41}, Elisabetta Manduchi³, Yedidya Saiman⁴², Nadim Mahmud⁴³, Donald R Miller^{44

45}, Peter D Reaven^{46

47}, Lawrence S Phillips^{24

48}, Sumitra Muralidhar⁴⁹, Scott L DuVall^{10

50}, Jennifer S Lee^{14

18}, Themistocles L Assimes^{14

18

51}, Saiju Pyarajan^{27

52

53}, Kelly Cho^{27

52

53}, Todd L Edwards^{54

55}, Scott M Damrauer^{1

3

56}, Peter W Wilson^{24

57}, J Michael Gaziano^{27

52}, Christopher J O'Donnell^{27

52

53}, Amit V Khera^{23

53

58}, Struan F A Grant^{3

59

60}, Christopher D Brown³, Philip S Tsao^{14

18

51}, Danish Saleheen^{61

62

63}, Luca A Lotta³³, Lisa Bastarache⁷, Quentin M Anstee^{64

65}, Ann K Daly⁶⁵, James B Meigs^{23

53

66}, Jerome I Rotter⁵, Julie A Lynch^{10

50

67}; Regeneron Genetics Center; Geisinger-Regeneron DiscovEHR Collaboration; EPoS Consortium; VA Million Veteran Program; Daniel J Rader^#^{2

3}, Benjamin F Voight^#^{68

69

70

71}, Kyong-Mi Chang^#^{72

73}

Affiliations

¹ Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
² Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
³ Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁴ Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁵ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁶ Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK.
⁷ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ Gilead Sciences, Inc., Foster City, CA, USA.
⁹ The Liver Company, Palo Alto, CA, USA.
¹⁰ VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
¹¹ Division of Gastroenterology, University of Washington, Seattle, WA, USA.
¹² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹³ Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁴ VA Palo Alto Health Care System, Palo Alto, CA, USA.
¹⁵ Department of Statistics, The Pennsylvania State University, University Park, PA, USA.
¹⁶ Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, USA.
¹⁷ Department of Statistics, Stanford University, Stanford, CA, USA.
¹⁸ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁹ Mental Illness Research Education and Clinical Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
²⁰ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
²¹ Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA.
²² Division of Vascular Surgery, Stanford University School of Medicine, Palo Alto, CA, USA.
²³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁴ Atlanta VA Medical Center, Decatur, GA, USA.
²⁵ Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA.
²⁶ School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen, Guangdong, China.
²⁷ VA Boston Healthcare System, Boston, MA, USA.
²⁸ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
²⁹ Department of Medicine, Section of Gastroenterology, Boston University School of Medicine, Boston, MA, USA.
³⁰ Department of Cardiology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
³¹ Departments of Pediatrics and Medicine, University of California, San Francisco, San Francisco, CA, USA.
³² Section of Digestive Diseases, Department of Internal Medicine, and Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
³³ Regeneron Genetics Center, Tarrytown, NY, USA.
³⁴ Department of Internal Medicine, Saint Louis University, St. Louis, MO, USA.
³⁵ Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
³⁶ Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
³⁷ Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
³⁸ Program for Personalized and Genomic Medicine, Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
³⁹ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
⁴⁰ Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁴¹ Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁴² Department of Medicine, Section of Hepatology, Lewis Katz School of Medicine at Temple University, Temple University Hospital, Philadelphia, PA, USA.
⁴³ Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁴⁴ Center for Healthcare Organization and Implementation Research, Bedford VA Healthcare System, Bedford, MA, USA.
⁴⁵ Center for Population Health, Department of Biomedical and Nutritional Sciences, University of Massachusetts, Lowell, MA, USA.
⁴⁶ Phoenix VA Health Care System, Phoenix, AZ, USA.
⁴⁷ College of Medicine, University of Arizona, Phoenix, AZ, USA.
⁴⁸ Division of Endocrinology, Emory University School of Medicine, Atlanta, GA, USA.
⁴⁹ Office of Research and Development, Veterans Health Administration, Washington, DC, USA.
⁵⁰ Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁵¹ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁵² Department of Medicine, Brigham Women's Hospital, Boston, MA, USA.
⁵³ Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁵⁴ Nashville VA Medical Center, Nashville, TN, USA.
⁵⁵ Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵⁶ Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁵⁷ Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA.
⁵⁸ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁵⁹ Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁶⁰ Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁶¹ Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
⁶² Department of Cardiology, Columbia University Irving Medical Center, New York, NY, USA.
⁶³ Center for Non-Communicable Diseases, Karachi, Sindh, Pakistan.
⁶⁴ Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
⁶⁵ Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
⁶⁶ Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁶⁷ College of Nursing and Health Sciences, University of Massachusetts, Lowell, MA, USA.
⁶⁸ Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA. [email protected].
⁶⁹ Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. [email protected].
⁷⁰ Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. [email protected].
⁷¹ Institute of Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. [email protected].
⁷² Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA. [email protected].
⁷³ Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alanine Transaminase
Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics
Genome-Wide Association Study*
Humans
Intracellular Signaling Peptides and Proteins / genetics
Lipase / genetics
Membrane Proteins / genetics
Non-alcoholic Fatty Liver Disease* / genetics
Polymorphism, Single Nucleotide / genetics
Protein Serine-Threonine Kinases / antagonists & inhibitors

Substances

Intracellular Signaling Peptides and Proteins
Membrane Proteins
TRIB1 protein, human
Alpha-Ketoglutarate-Dependent Dioxygenase FTO
FTO protein, human
Alanine Transaminase
Protein Serine-Threonine Kinases
Lipase

Abstract

Publication types

MeSH terms

Substances

Grants and funding