ArticleNature genetics2014
Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk.
Registry-linked trialOpen access · greenAbstract read
In one paragraph
Article in Nature genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT06289387 (Combining Gene Variants to Improve Risk Prediction for Metabolic), which is not on this map. Cited by 159 papers, 12 of them syntheses that pooled it.
0numbers the graph read from it
0cells of the map it votes in
159citing papers in PubMed, 12 pooled it
28.9field-weighted citation impact, top 1% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Combining Gene Variants to Improve Risk Prediction for Metabolic (Dysfunction)- Associated Fatty Liver Disease and Its Progression to Cirrhosis in Indian Individuals With Type 2 Diabetes: a Cross-sectional Study
Who cites it
159 citing papers in PubMed, 12 syntheses or guidelines pooled it, 310 citations in OpenAlex.
- Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.Genome biology · 2022Pooled it
- Meta-GWAS of PCSK9 levels detects two novel loci at APOB and TM6SF2.Human molecular genetics · 2022Pooled it
- TM6SF2 rs58542926 is related to hepatic steatosis, fibrosis and serum lipids both in adults and children: A meta-analysis.Frontiers in endocrinology · 2022Pooled it
- Pooled it
- Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study.PLoS genetics · 2020Pooled it
- Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease.Nature genetics · 2017Pooled it
- The effect of the TM6SF2 E167K variant on liver steatosis and fibrosis in patients with chronic hepatitis C: a meta-analysis.Scientific reports · 2017Pooled it
- Genetic factors that affect nonalcoholic fatty liver disease: A systematic clinical review.World journal of gastroenterology · 2016Pooled it
- Meta-analysis of the influence of TM6SF2 E167K variant on Plasma Concentration of Aminotransferases across different Populations and Diverse Liver Phenotypes.Scientific reports · 2016Pooled it
- Definitions of Normal Liver Fat and the Association of Insulin Sensitivity with Acquired and Genetic NAFLD-A Systematic Review.International journal of molecular sciences · 2016Pooled it
- Methods for association analysis and meta-analysis of rare variants in families.Genetic epidemiology · 2015Pooled it
- Association of Nonalcoholic Fatty Liver Disease with Subclinical Cardiovascular Changes: A Systematic Review and Meta-Analysis.BioMed research international · 2015Pooled it
- The PNPLA3 I148M variant is associated with transaminase elevations in type 2 diabetes patients treated with basal insulin peglispro.The pharmacogenomics journal · 2018Trial
- Molecular mechanisms and pathogenesis of MASH.Nature · 2026Review
- TM6SF2 overexpression suppresses the proliferation and promotes apoptosis of human hepatocellular carcinoma cells.Oncology reports · 2026Article
- Deviations from genetic additivity driven by rare variants at biobank scale.Nature communications · 2026Article
- Hepatic Lipoprotein Production, Cardiometabolic Phenotypes, and Subtypes of Steatotic Liver Disease.Circulation research · 2026Review
- Therapeutic targets for metabolic dysfunction-associated steatohepatitis: a personalized approach to disease management.Nature reviews. Gastroenterology & hepatology · 2026Review
- A deep ensemble encoder network method for improved polygenic risk score prediction.BioData mining · 2026Article
- Biomarkers for early identification of metabolic dysfunction-associated steatotic liver disease (MASLD): a narrative review.Archives of medical science : AMS · 2026Article
99 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
26 authors at 5 institutions in 2 countries.
Oddgeir L Holmen1] HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway. [2] St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway. [3].
He Zhang1] Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA. [2].
Yanbo Fan1] Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA. [2].
Daniel H Hovelson1] Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
Ellen M Schmidt1] Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
Wei ZhouDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Yanhong GuoDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Ji ZhangDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Arnulf LanghammerHUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway.
Maja-Lisa LøchenEpidemiology of Chronic Diseases Research Group, Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
Santhi K Ganesh1] Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
Lars VattenDepartment of Public Health, Norwegian University of Science and Technology, Trondheim, Norway.
Frank SkorpenDepartment of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.
Håvard Dalen1] Department of Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway. [2] Medical Imaging Laboratory for Innovative Future Healthcare, Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway.
Jifeng ZhangDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Subramaniam PennathurDepartment of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA.
Jin ChenDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Carl PlatouDepartment of Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway.
Ellisiv B Mathiesen1] Brain and Circulation Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway. [2] Brain and Circulation Research Group, University Hospital of North Norway, Tromsø, Norway.
Tom WilsgaardEpidemiology of Chronic Diseases Research Group, Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
Inger NjølstadEpidemiology of Chronic Diseases Research Group, Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
Michael BoehnkeDepartment of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
Y Eugene ChenDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Gonçalo R AbecasisDepartment of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
Kristian Hveem1] HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway. [2] Department of Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway.
Cristen J Willer1] Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA. [3] Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
Michigan Medicine · USNorwegian University of Science and Technology · NOUiT The Arctic University of Norway · NOUniversity of Michigan–Ann Arbor · USLevanger Hospital · NO
Funding
Identifying Genes for Type 2 Diabetes: FUSIONU01DK062370 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI BOEHNKE, MICHAEL L, SCOTT, LAURA J. · 2009 to 2021
$11.6MUsing genetics to discover mechanisms of myocardial infarctionR01HL109946 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI YUQING Eugene CHEN, Ida Liisa Surakka · 2011 to 2026
$8.9MThe Role of PPAR-gamma in Vascular Lesion FormationR01HL068878 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CHEN, YUQING EUGENE · 2002 to 2019
$7.6MIdentifying Genes for Type 2 Diabetes:FUSIONR01DK062370 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI BOEHNKE, MICHAEL L, SCOTT, LAURA J. · 2003 to 2025
$6.7MTraining Program in BioinformaticsT32GM070449 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ATHEY, BRIAN DAVID, BURMEISTER, MARGIT · 2005 to 2020
$3.6MCETP and HDL Function in Cardiovascular DiseasesR01HL117491 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CHEN, YUQING EUGENE · 2013 to 2016
$2.4MGenetic Variants Associated with HDL and LDL Cholesterol, and Triglyceride LevelsR00HL094535 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI WILLER, CRISTEN J · 2011 to 2013
$724kIdentifying Genes for Type 2 Diabetes: FUSIONR56DK062370 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI BOEHNKE, MICHAEL L · 2008 to 2008
$500kGenetic Variants Associated with HDL and LDL Cholesterol, and Triglyceride LevelsK99HL094535 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI WILLER, CRISTEN J · 2009 to 2010
$180kNHLBI NIH HHS K99 HL094535NHLBI NIH HHS R00 HL094535NHLBI NIH HHS R01 HL068878NHLBI NIH HHS R01 HL109946NHLBI NIH HHS R01 HL117491NIDDK NIH HHS R01 DK062370NIDDK NIH HHS R56 DK062370NIDDK NIH HHS U01 DK062370NIGMS NIH HHS T32 GM070449
Abstract
Blood lipid levels are heritable, treatable risk factors for cardiovascular disease. We systematically assessed genome-wide coding variation to identify new genes influencing lipid traits, fine map known lipid loci and evaluate whether low-frequency variants with large effects exist for these traits. Using an exome array, we genotyped 80,137 coding variants in 5,643 Norwegians. We followed up 18 variants in 4,666 Norwegians and identified ten loci with coding variants associated with a lipid trait (P < 5 × 10(-8)). One variant in TM6SF2 (encoding p.Glu167Lys), residing in a known genome-wide association study locus for lipid traits, influences total cholesterol levels and is associated with myocardial infarction. Transient TM6SF2 overexpression or knockdown of Tm6sf2 in mice alters serum lipid profiles, consistent with the association observed in humans, identifying TM6SF2 as a functional gene within a locus previously known as NCAN-CILP2-PBX4 or 19p13. This study demonstrates that systematic assessment of coding variation can quickly point to a candidate causal gene.
Indexed as
Genetic VariationAnimalsCholesterol, LDLExomeGene Knockdown TechniquesGenome-Wide Association StudyGenotypeHumansLipidsMembrane ProteinsMiceMice, Inbred C57BLMutation, MissenseMyocardial InfarctionNorwayRisk FactorsCholesterol, LDLLipidsMembrane ProteinsTM6SF2 protein, human
Identifiers
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Registered trials
NCT06289387ClinicalTrials.gov
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.