Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits
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Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.
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The liver/lipid cluster includes loci GCKR, PNPLA3, and TM6SF2, which functional experiments have shown to relate to liver lipid metabolism.
“The liver/lipid cluster includes loci GCKR, PNPLA3, and TM6SF2, which have been shown through functional experiments to relate to liver lipid metabolism (24–31).”
From Increased genetic risk for β-cell failure is associated with β-cell function decline in people with prediabetes (2024) · cites this paper as [26]
The Discussion links GCKR to substrates for liver lipogenesis and PNPLA3 to triglyceride breakdown, citing prior functional work. It does not include TM6SF2 among the loci it identifies or establish the stated three-locus cluster; its own analysis is primarily genetic association rather than functional experiments (Discussion; Results, page not provided). (LLM, conf=0.88)
Experimental — accuracy not yet measuredCausal common variants associated with continuous endophenotypes have been associated with disease in many cases.
“In many cases, causal common variants associated with a continuous endophenotype have been associated with disease [eg80–82]”
From Rare and common variants: twenty arguments (2012) · cites this paper as [82]
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- Authors
- Speliotes, E. K., Yerges-Armstrong, L. M., Wu, J., Hernaez, R., Kim, L. J., Palmer, C. D., Gudnason, V., Eiriksdottir, G., Garcia, M. E., Launer, L. J., Nalls, M. A., Clark, J. M., Mitchell, B. D., Shuldiner, A. R., Butler, J. L., Tomas, M., Hoffmann, U., Hwang, S.-J., Massaro, J. M., O'Donnell, C. J., Sahani, D. V., Salomaa, V., Schadt, E. E., Schwartz, S. M., Siscovick, D. S., CRN, N., GIANT Consortium, MAGIC Investigators, Voight, B. F., Carr, J. J., Feitosa, M. F., Harris, T. B., Fox, C. S., Smith, A. V., Kao, W. H. L., Hirschhorn, J. N., Borecki, I. B., & GOLD Consortium
- Affiliations
- Broad Institute (US)
- Washington University in St. Louis (US)
- National Institutes of Health (US)
- Boston Children's Hospital (US)
- University of Iceland (IS)
- Johns Hopkins University (US)
- University of Maryland, Baltimore (US)
- Centro de Investigación Biomédica en Red (ES)
- Massachusetts General Hospital (US)
- National Heart, Lung, and Blood Institute (US)
- Boston University (US)
- Pacific Biosciences (United States) (US)
- University of Washington (US)
- Wake Forest University Health Sciences (US)
- Corresponding author
- Speliotes, Elizabeth K.
- Borecki, Ingrid B.
- ORCID
- Speliotes, Elizabeth K.
- Wu, Jun
- Palmer, Cameron D.
- Gudnason, Vilmundur
- Launer, Lenore J.
- Clark, Jeanne M.
- Mitchell, Braxton D.
- Shuldiner, Alan R.
- Hoffmann, Udo
- Hwang, Shih-Jen
- Massaro, Joseph M.
- Salomaa, Veikko
- Siscovick, David S.
- Voight, Benjamin F.
- Carr, J. Jeffrey
- Feitosa, Mary F.
- Harris, Tamara B.
- Fox, Caroline S.
- Smith, Albert V.
- Kao, W. H. Linda
- Hirschhorn, Joel N.
- Borecki, Ingrid B.
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-03-10
- Volume
- 7
- Issue
- 3
- Pages
- e1001324
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3053321
- OpenAlex
- W2156760391
- Cited by
- 984
- References
- 56
- Citations by year
- 2026: 33 · 2025: 39 · 2024: 70 · 2023: 63 · 2022: 61 · 2021: 74 · 2020: 103 · 2019: 72 · 2018: 67 · 2017: 51 · 2016: 69 · 2015: 74 · 2014: 66 · 2013: 69 · 2012: 48
- FWCI
- 7.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Genetics (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- UWA Profiles and Research Repository (UWA) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- VU Research Portal (publishedVersion, other-oa)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- QUT ePrints (Queensland University of Technology) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion, public-domain)
- Research Explorer (The University of Manchester) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, public-domain)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HAL (submittedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Leiden Repository (Leiden University) (submittedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, public-domain)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Työväentutkimus Vuosikirja (submittedVersion)
- UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
- UnissResearch (Università degli Studi di Sassari) (submittedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- OPUS (Augsburg University) (submittedVersion, public-domain)
- Open Research (University of Surrey) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Apollo (public-domain)
- Funders
- American Diabetes Association
- School of Medicine, Boston University (N01-HC25195)
- Wellcome Trust (095515, 095515/Z/11/Z, 090532)
- National Institute for Health and Care Research (NF-SI-0508-10212, NF-SI-0508-10082)
- British Heart Foundation (PG/09/002/26056, RG/07/008/23674)
- Generalitat de Catalunya
- Novo Nordisk Fonden (#NNF10OC1013354)
- Hjartavernd (N01-AG-1-2100)
- National Institutes of Health (n01ag12100-57-0-2, 5p60dk079637-02, N01-AG-1-2100, 5r01hl087700-03, n01hc25195-41-0-1, P60-DK079637, N01-HC 25195, DK-079637, U01-DK061730)
- U.S. Public Health Service (ULRR02413101)
- Instituto de Salud Carlos III (RD 06/0009)
- National Institute on Aging (R01-AG-18728, N01-AG12100, N01-AG012100, R01AG018728, N02-HL-6-4278, N01-HC-25195, AG-18728, T32AG000262)
- National Heart, Lung, and Blood Institute (HL72515, U01HL72515, HC25195, N01‐HC25195, U01HL084756, R01-HL087700, N01-HC, N02- HL-64278, N01-HC-025195, U01HL072515, R01HL088119)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01DK061730, T32-DK07191, DK07191, P60 DK-079637, DK079637, N01-HC-25195, R01DK075681, T32 DK07191-32, DK07191-32, F32DK079466, U01DK061718, U01DK061728, U01DK061731, U01DK061732, K23DK080145, K01DK067207, DK079466, grants U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, U01DK061713, P30DK072488, K24DK002957, R01DK075787, U01DK061731, U01DK061713, U01DK061728, U01DK061737, U01DK061732, U01DK061734, U01DK061718, U01DK061738, T32DK007191)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (F32AR059469)
- National Center for Research Resources (UL1RR024989, M01RR000750, UL1RR025014, M01RR020359, M01RR000065, M01RR000188, M01 RR-00188, M01RR000827)
- 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 › Nutrition, Genetics, and Disease
- Keywords
- non-alcoholic fatty liver disease, hepatic steatosis, genetic susceptibility, PNPLA3, neurocan, PPP1R3B, GCKR, LYPLAL1, serum lipids, glycemic traits, anthropometric traits, heritability, metabolic phenotypes, genetic heterogeneity, NASH
- MeSH terms
- Acyltransferases, Adult, Aged, Aged, 80 and over, Blood Glucose, Fatty Liver, Humans, Insulin, Lipase, Male, Membrane Proteins, Middle Aged, Nerve Tissue Proteins, Chondroitin Sulfate Proteoglycans, Tomography, X-Ray Computed, Cohort Studies, Case-Control Studies, Mutation, Missense, Polymorphism, Single Nucleotide, Lectins, C-Type, Quantitative Trait Loci, Adaptor Proteins, Signal Transducing, Phospholipases A2, Calcium-Independent, Genome-Wide Association Study, Neurocan, Non-alcoholic Fatty Liver Disease
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