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Cited by 215Liver Disease Diagnosis and TreatmentGenetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and Animals

Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease

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Chen, Yanhua, Du, Xiaomeng, Kuppa, Annapurna, Feitosa, Mary F., Bielak, Lawrence F., O’Connell, Jeffrey R., Musani, Solomon K., Guo, Xiuqing +29 more·2023·Nature Genetics
DOI 10.1038/s41588-023-01497-6PMC PMC10918428
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Abstract

Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the top 10% and 1% of genetic risk have a 2.5-fold to 6-fold increased risk of NAFLD, cirrhosis and hepatocellular carcinoma. These genetic variants identify subtypes of NAFLD, improve estimates of disease risk and can guide the development of targeted therapeutics.

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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 [10]

    The Discussion reports 17 NAFLD-associated loci and links implicated genes to intestinal lipid absorption, insulin signaling, and hepatic de novo lipogenesis. It also mentions mitochondrial processes, but does not establish that the identified variants influence mitochondrial respiration specifically. The paper uses the term NAFLD rather than MASLD; page numbers are unavailable in our copy. (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 [10]

    The Discussion (page not provided) describes NAFLD-increasing TM6SF2 variants and proposes that TM6SF2 affects VLDL lipid loading. It also says MTTP has been associated with NAFLD and transfers lipids to nascent apoB during lipoprotein assembly. Our copy does not identify APOB variants as NAFLD risk factors, and it presents the TM6SF2 mechanism as proposed rather than a demonstrated direct effect 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 [10]

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Authors
Chen, Y., Du, X., Kuppa, A., Feitosa, M. F., Bielak, L. F., O’Connell, J. R., Musani, S. K., Guo, X., Kahali, B., Chen, V. L., Smith, A. V., Ryan, K. A., Eirksdottir, G., Allison, M. A., Bowden, D. W., Budoff, M. J., Carr, J. J., Chen, Y.-D. I., Taylor, K. D., Oliveri, A., Correa, A., Crudup, B. F., Kardia, S. L. R., Mosley, T. H., Norris, J. M., Terry, J. G., Rotter, J. I., Wagenknecht, L. E., Halligan, B. D., Young, K. A., Hokanson, J. E., Washko, G. R., Gudnason, V., Province, M. A., Peyser, P. A., Palmer, N. D., & Speliotes, E. K.
Affiliations
  • The Lundquist Institute (US)
  • University of Michigan (US)
  • Washington University in St. Louis (US)
  • University of Maryland, Baltimore (US)
  • University of Mississippi Medical Center (US)
  • Icelandic Heart Association (IS)
  • University of California San Diego (US)
  • Wake Forest University Health Sciences (US)
  • University of California, Los Angeles (US)
  • Vanderbilt University (US)
  • Colorado School of Public Health (US)
  • Brigham and Women's Hospital (US)
  • University of Iceland (IS)
Corresponding author
Speliotes, Elizabeth K.
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2023-09-14
Volume
55
Issue
10
Pages
1640-1650
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-023-01497-6
PMC
PMC10918428
OpenAlex
W4386741123
Cited by
215
References
13
Citations by year
2026: 66 · 2025: 74 · 2024: 68 · 2023: 6 · 2022: 1
FWCI
43.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
U.S. Department of Health & Human Services | National Institutes of Health (R01 DK106621, RO1 DK107904)
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, PNPLA3, TM6SF2, apolipoprotein E, SREBF1, Grb14, adipose triglyceride lipase, MBOAT7, PTPRD, de novo lipogenesis, mitochondrial function, cholesterol metabolism, hepatocellular carcinoma, liver cirrhosis, phenome-wide association study, genetic risk prediction
MeSH terms
Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Acyltransferases, Humans, Liver, Liver Cirrhosis, Phospholipases, Protein Serine-Threonine Kinases, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Intracellular Signaling Peptides and Proteins, Genome-Wide Association Study, Non-alcoholic Fatty Liver Disease

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