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Cited by 205Liver Disease Diagnosis and TreatmentGenetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and Animals

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

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Vujkovic, Marijana, Ramdas, Shweta, Lorenz, Kim M., Guo, Xiuqing, Darlay, Rebecca, Cordell, Heather J., He, Jing, Gindin, Yevgeniy +86 more·2022·Nature Genetics
DOI 10.1038/s41588-022-01078-zPMC PMC10024253

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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.

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  • GWAS have identified numerous variants that pose a risk for MASLD; these variants influence a number of metabolic processes such as intestinal lipid absorption, insulin sensitivity, hepatic lipogenesis and mitochondrial respiration.

    “To date, GWAS have identified numerous variants that pose a risk for MASLD; although these variants influence a number of metabolic processes such as intestinal lipid absorption, insulin sensitivity, hepatic lipogenesis and mitochondrial respiration (9, 10), the two variants with the highest significance in nearly all GWAS — PNPLA3 (patatin-like phospholipase domain-containing protein 3) and TM6SF”

    From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [9]

    The Discussion (page not provided) reports 77 loci associated with chronic ALT elevation as a proxy for NAFLD, with 17 SNP associations replicated against biopsy- or imaging-defined disease. It also links implicated genes to hepatic lipogenesis and broader metabolic pathways. The passages do not establish the claimed effects on intestinal lipid absorption, insulin sensitivity, or mitochondrial respiration. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Variants in TM6SF2 as well as microsomal triglyceride transfer protein (MTTP) and APOB have already been identified as MASLD risk factors having direct influence over VLDL secretion.

    “Indeed, variants in TM6SF2 as well as microsomal triglyceride transfer protein (MTTP) and APOB have already been identified as MASLD risk factors having direct influence over VLDL secretion (7–10), and the current experiments add Hdlbp to this list.”

    From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [9]

    The Results and Discussion (pages not provided) identify TM6SF2 and MTTP as NAFLD-related loci, and the Discussion says MTTP facilitates VLDL secretion. The paper mentions apolipoprotein B lipidation but does not identify APOB variants as risk factors; it also does not establish a direct effect of TM6SF2 variants on VLDL secretion. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • A single nucleotide polymorphism in transmembrane-6 superfamily member 2 (TM6SF2) is strongly associated with MASLD risk.

    “Noteworthy among these is a single nucleotide polymorphism in transmembrane-6 superfamily member 2 (TM6SF2), which is strongly associated with MASLD risk (7–10).”

    From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [9]

  • Few genetic variants have been mechanistically linked to MASH pathogenesis, and each has only a modest population-level effect, suggesting environmental determinants are more important in driving disease.

    “Although these findings provide valuable insights into the mechanisms underlying MASH, overall, few genetic variants have been mechanistically linked to MASH pathogenesis (145), and each exerts only a modest effect on disease outcome at the population level, suggesting that environmental determinants play a more important role in driving the disease.”

    From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [145]

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References 176 · Cited by 205

Research works printed but not linked: 92

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Authors
Vujkovic, M., Ramdas, S., Lorenz, K. M., Guo, X., Darlay, R., Cordell, H. J., He, J., Gindin, Y., Chung, C., Myers, R. P., Schneider, C. V., Park, J., Lee, K. M., Serper, M., Carr, R. M., Kaplan, D. E., Haas, M. E., MacLean, M. T., Witschey, W. R., Zhu, X., Tcheandjieu, C., Kember, R. L., Kranzler, H. R., Verma, A., Giri, A., Klarin, D. M., Sun, Y. V., Huang, J., Huffman, J. E., Creasy, K. T., Hand, N. J., Liu, C.-T., Long, M. T., Yao, J., Budoff, M., Tan, J., Li, X., Lin, H. J., Chen, Y.-D. I., Taylor, K. D., Chang, R.-K., Krauss, R. M., Vilarinho, S., Brancale, J., Nielsen, J. B., Locke, A. E., Jones, M. B., Verweij, N., Baras, A., Reddy, K. R., Neuschwander-Tetri, B. A., Schwimmer, J. B., Sanyal, A. J., Chalasani, N., Ryan, K. A., Mitchell, B. D., Gill, D., Wells, A. D., Manduchi, E., Saiman, Y., Mahmud, N., Miller, D. R., Reaven, P. D., Phillips, L. S., Muralidhar, S., DuVall, S. L., Lee, J. S., Assimes, T. L., Pyarajan, S., Cho, K., Edwards, T. L., Damrauer, S. M., Wilson, P. W., Gaziano, J. M., O’Donnell, C. J., Khera, A. V., Grant, S. F. A., Brown, C. D., Tsao, P. S., Saleheen, D., Lotta, L. A., Bastarache, L., Anstee, Q. M., Daly, A. K., Meigs, J. B., Rotter, J. I., Lynch, J. A., Regeneron Genetics Center, Geisinger-Regeneron DiscovEHR Collaboration, EPoS Consortium, Program, V. M. V., Rader, D. J., Voight, B. F., & Chang, K.-M.
Affiliations
  • University of Pennsylvania (US)
  • The Lundquist Institute (US)
  • Newcastle University (GB)
  • Vanderbilt University Medical Center (US)
  • Gilead Sciences (United States) (US)
  • VA Salt Lake City Healthcare System (US)
  • Philadelphia VA Medical Center (US)
  • University of Washington (US)
  • Broad Institute (US)
  • Pennsylvania State University (US)
  • VA Palo Alto Health Care System (US)
  • Emory University (US)
  • Southern University of Science and Technology (CN)
  • VA Boston Healthcare System (US)
  • Boston University (US)
  • University of California, San Francisco (US)
  • Yale University (US)
  • Regeneron (United States) (US)
  • University of California San Diego (US)
  • Virginia Commonwealth University (US)
  • Indiana University School of Medicine (US)
  • University of Maryland, Baltimore (US)
  • Imperial College London (GB)
  • Children's Hospital of Philadelphia (US)
  • Temple University Hospital (US)
  • University of Massachusetts Lowell (US)
  • University of Arizona (US)
  • Veterans Health Administration (US)
  • University of Utah (US)
  • Brigham and Women's Hospital (US)
  • Vanderbilt University (US)
  • Columbia University Irving Medical Center (US)
  • Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
Corresponding author
  • Voight, Benjamin F.
  • Chang, Kyong-Mi
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2022-06
Volume
54
Issue
6
Pages
761-771
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-022-01078-z
PMC
PMC10024253
OpenAlex
W4281771922
Cited by
205
References
176
Citations by year
2026: 31 · 2025: 48 · 2024: 59 · 2023: 46 · 2022: 16 · 2021: 5
FWCI
30.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • medRxiv (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01-CX001737, IK2-CX001780, I01BX003341, CX001899, UL1 TR002378, I01-BX003362, I01 BX005831, MVP000, R01 DK127083, R03 AI133172, I01 CX001899, U01 DK098246, R21 AI156161)
  • Amgen
  • Bristol-Myers Squibb
  • Pfizer
  • AstraZeneca
  • GlaxoSmithKline
  • Gilead Sciences
  • Office of Research and Development (MVP#000)
  • University of Pennsylvania (UL1 TR001878)
  • Institute for Translational Medicine and Therapeutics
  • Regeneron Pharmaceuticals
  • Indivior
  • European Federation of Pharmaceutical Industries and Associations
  • Arbor Pharmaceuticals
  • American Society of Clinical Psychopharmacology
  • Intercept Pharmaceuticals
  • Novo Nordisk
  • H. Lundbeck A/S
  • National Institutes of Health (I01 CX001737, 5t32hl007734-30, HL0-07734, DK078616, DK127083, DK114291-01A1, EB029460, DK101478, U01-DK091958, AI133172, AI156161, T32-HL007734, DK114291, DK115897, UL1TR001878, UL1TR002378)
  • Allergan
  • Novartis Pharma
  • National Institute on Alcohol Abuse and Alcoholism (R01AA026302)
  • National Heart, Lung, and Blood Institute (R01HL151855, R01HL134853, T-32HL007734, R01HL105756, HL007734, R01HL137984)
  • National Human Genome Research Institute (K08HG010155, U01HG011719)
  • National Institute of Allergy and Infectious Diseases (R03AI133172, R01AI123539, R21AI156161)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK114291, DK101478, DK078616, U01 DK091958, K23DK115897, R01DK122586, K23DK113252, R56DK101478, R21DK099716, R01DK101478, U01DK098246, DK126194, U01DK078616, AI133172, R01DK114291, UM1DK126194, DK115897, DK122586, UM1DK078616, K08DK124577, U24DK061730, R01DK131033, U01DK061732, R01DK127083, U01DK061738, P30DK111024)
  • National Institute of Biomedical Imaging and Bioengineering (P41EB029460)
  • U.S. National Library of Medicine (R01LM010685)
  • National Center for Advancing Translational Sciences
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD056465)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
non-alcoholic fatty liver disease, genetic susceptibility loci, pleiotropy, metabolic phenotypes, TRIB1, PPARγ, microsomal triglyceride transfer protein, SERPINA1, FTO, interleukin-1 receptor antagonist, beta2-glycoprotein I, IFI30
MeSH terms
Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Alanine Transaminase, Humans, Lipase, Membrane Proteins, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Intracellular Signaling Peptides and Proteins, Genome-Wide Association Study, Non-alcoholic Fatty Liver Disease

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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