ArticleNature genetics2014
Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
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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. Cited by 297 papers, 3 of them syntheses that pooled it.
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297citing papers in PubMed, 3 pooled it
63.9field-weighted citation impact, top 1% of its field
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Who cites it
297 citing papers in PubMed, 3 syntheses or guidelines pooled it, 491 citations in OpenAlex.
- Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles.Nature genetics · 2022Pooled it
- Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.Nature genetics · 2018Pooled it
- Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.Nature genetics · 2017Pooled it
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- Iron, Copper, and Zinc Dyshomeostasis in Cardiovascular and Cerebrovascular Diseases: Redox Mechanisms, Evidence Levels, and Translational Prospects.International journal of molecular sciences · 2026Review
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- Individuals who deviate from polygenic expectation are enriched for damaging variants in genes linked to rare disease.American journal of human genetics · 2026Article
- Type 2 diabetes genetics in 125,000 admixed adults from Mexico City.medRxiv : the preprint server for health sciences · 2026Article
- Metal-dependent regulated cell death: Molecular architecture and translational frontiers.iMeta · 2026Review
- Zinc accumulation-induced integrated stress response triggers β-cell identity loss.Cell research · 2026Article
- To β or not to β: think zinc (again)!Cell research · 2026Article
- A loss of function variant inmedRxiv : the preprint server for health sciences · 2026Article
- African-enriched SLC39A10 (ZIP10) missense variants differentially affect cellular zinc homeostasis and associate with health-related traits.Genes & nutrition · 2026Article
- Functional insights into dispensable genes using genome-wide loss-of-function burden tests in Arabidopsis.The Plant cell · 2026Article
- A resource of "bottom-line" variant associations for 1,281 complex traits by integrating data across published genome-wide association studies.Research square · 2026Article
- Beneficial Role of Zinc in Metabolic Syndrome: Understanding the Underlying Pathophysiological Mechanisms.Current medicinal chemistry · 2026Review
- Individuals whose phenotype deviates from genetic expectation defined by common variation are enriched for rare damaging variants in genes that cause rare disease.medRxiv : the preprint server for health sciences · 2025Article
- Severity of effect considerations regarding the use of mutation as a toxicological endpoint for risk assessment: A report from the 8th International Workshop on Genotoxicity Testing (IWGT).Environmental and molecular mutagenesis · 2025Review
237 more citing papers are in PubMed but not listed here.
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Authors and funding
82 authors at 20 institutions in 13 countries.
Jason Flannick1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
Gudmar ThorleifssondeCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Nicola L Beer1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
Suzanne B R JacobsProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.ORCID 0000000281031700
Niels GrarupNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Noël P BurttProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Anubha MahajanWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Christian FuchsbergerCenter for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
Gil Atzmon1] Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA.
Rafn BenediktssonDepartment of Endocrinology and Metabolism, Landspitali University Hospital, Reykjavik, Iceland.
John BlangeroDepartment of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, USA.
Don W Bowden1] Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. [2] Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. [3] Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. [4] Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
Ivan Brandslund1] Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark. [2] Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.
Julia BrosnanCardiovascular & Metabolic Diseases Research Unit, Pfizer, Inc., Cambridge, Massachusetts, USA.
Frank BurslemCardiovascular and Metabolic Diseases Practice, Prescient Life Sciences, London, UK.
John Chambers1] Department of Epidemiology and Biostatistics, Imperial College London, London, UK. [2] Imperial College Healthcare National Health Service (NHS) Trust, London, UK. [3] Ealing Hospital NHS Trust, Middlesex, UK.
Yoon Shin ChoDepartment of Biomedical Science, Hallym University, Chuncheon, Korea.
Cramer ChristensenDepartment of Internal Medicine and Endocrinology, Vejle Hospital, Vejle, Denmark.
Desirée A DouglasUnit of Diabetes and Celiac Diseases, Department of Clinical Sciences, Lund University, Malmö, Sweden.
Ravindranath DuggiralaDepartment of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, USA.
Zachary DymekProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Yossi FarjounProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Timothy FennellProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Pierre FontanillasProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Tom Forsén1] Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland. [2] Diabetes Care Unit, Vaasa Health Care Centre, Vaasa, Finland.
Stacey GabrielProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Benjamin Glaser1] Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. [2] Israel Diabetes Research Group (IDRG), Holon, Israel.
Daniel F GudbjartssondeCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Craig HanisHuman Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.
Torben Hansen1] Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [2] Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
Astradur B HreidarssonDepartment of Endocrinology and Metabolism, Landspitali University Hospital, Reykjavik, Iceland.
Kristian HveemDepartment of Public Health, Faculty of Medicine, Norwegian University of Science and Technology, Levanger, Norway.
Erik Ingelsson1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [2] Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Bo Isomaa1] Folkhalsan Research Centre, Helsinki, Finland. [2] Department of Social Services and Health Care, Jakobstad, Finland.
Stefan Johansson1] KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway. [2] Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. [3] Department of Biomedicine, University of Bergen, Bergen, Norway.
Torben Jørgensen1] Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark. [2] Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [3] Faculty of Medicine, University of Aalborg, Aalborg, Denmark.
Marit Eika JørgensenSteno Diabetes Center, Gentofte, Denmark.
Sekar Kathiresan1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA. [4] Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Augustine KongdeCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Jaspal Kooner1] Imperial College Healthcare National Health Service (NHS) Trust, London, UK. [2] Ealing Hospital NHS Trust, Middlesex, UK. [3] National Heart and Lung Institute (NHLI), Imperial College London, Hammersmith Hospital, London, UK.
Jasmina KravicDepartment of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
Markku LaaksoDepartment of Medicine, University of Eastern Finland, Kuopio Campus and Kuopio University Hospital, Kuopio, Finland.
Jong-Young LeeCenter for Genome Science, Korea National Institute of Health, Osong Health Technology, Chungcheongbuk-do, Korea.
Lars LindDepartment of Medical Sciences, Uppsala University, Uppsala, Sweden.
Cecilia M Lindgren1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Allan Linneberg1] Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark. [2] Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [3] Department of Clinical Experimental Research, Glostrup University Hospital, Glostrup, Denmark.ORCID 0000000209940184
Gisli MassondeCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Thomas MeitingerInstitute of Human Genetics, Technical University Munich, Munich, Germany.
Karen L MohlkeDepartment of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
Anders Molven1] KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway. [2] Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway. [3] Department of Pathology, Haukeland University Hospital, Bergen, Norway.
Andrew P Morris1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [2] Department of Biostatistics, University of Liverpool, Liverpool, UK.
Shobha PotluriApplied Quantitative Genotherapeutics, Pfizer, Inc., South San Francisco, California, USA.
Rainer Rauramaa1] Kuopio Research Institute of Exercise Medicine, Kuopio, Finland. [2] Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
Rasmus Ribel-MadsenNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Ann-Marie RichardCardiovascular & Metabolic Diseases Research Unit, Pfizer, Inc., Cambridge, Massachusetts, USA.
Tim RolphCardiovascular & Metabolic Diseases Research Unit, Pfizer, Inc., Cambridge, Massachusetts, USA.
Veikko SalomaaNational Institute for Health and Welfare (THL), Helsinki, Finland.
Ayellet V Segrè1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
Hanna SkärstrandUnit of Diabetes and Celiac Diseases, Department of Clinical Sciences, Lund University, Malmö, Sweden.
Valgerdur SteinthorsdottirdeCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Heather M StringhamCenter for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
Patrick SulemdeCODE Genetics/Amgen, Inc., Reykjavik, Iceland.ORCID 0000000171236123
E Shyong Tai1] Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore. [2] Department of Medicine, National University of Singapore, National University Health System, Singapore. [3] Duke-National University of Singapore Graduate Medical School, Singapore.
Yik Ying Teo1] Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore. [2] Centre for Molecular Epidemiology, National University of Singapore, Singapore. [3] Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore. [4] Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore. [5] Department of Statistics and Applied Probability, National University of Singapore, Singapore.
Tanya TeslovichCenter for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
Unnur Thorsteinsdottir1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
Jeff K TrimmerCardiovascular & Metabolic Diseases Research Unit, Pfizer, Inc., Cambridge, Massachusetts, USA.
Tiinamaija Tuomi1] Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland. [2] Folkhalsan Research Centre, Helsinki, Finland.
Jaakko Tuomilehto1] Centre for Vascular Prevention, Danube-University Krems, Krems, Austria. [2] Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland. [3] Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
Fariba Vaziri-SaniUnit of Diabetes and Celiac Diseases, Department of Clinical Sciences, Lund University, Malmö, Sweden.
Benjamin F Voight1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. [3] Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
James G WilsonDepartment of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Michael BoehnkeCenter for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
Mark I McCarthy1] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK. [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [3] Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Churchill Hospital, Oxford, UK.
Pål R Njølstad1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway. [3] Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
Oluf PedersenNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Go-T2D Consortium
T2D-GENES Consortium
Leif Groop1] Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden. [2] Finnish Institute for Molecular Medicine (FIMM), Helsinki University, Helsinki, Finland.
David R CoxApplied Quantitative Genotherapeutics, Pfizer, Inc., South San Francisco, California, USA.
Kari Stefansson1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
David Altshuler1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. [4] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. [5] Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA. [6] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. [7] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Broad Institute · USdeCODE Genetics (Iceland) · ISPfizer (United States) · USLund University · SECentre for Human Genetics · GBUniversity of Copenhagen · DKUniversity of Michigan · USHaukeland University Hospital · NOGlostrup Hospital · DKNational University of Singapore · SGReykjavík University · ISTexas Biomedical Research Institute · USUniversity of Eastern Finland · FIUniversity of Helsinki · FIAlbert Einstein College of Medicine · USDepartment of Social Services · AUFinnish Institute for Health and Welfare · FIHadassah Medical Center · ILHallym University · KRImperial College Healthcare NHS Trust · GB
Funding
Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6MLow-Pass Sequencing and High-Density SNP Genotyping for Type 2 DiabetesRC2DK088389 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ALTSHULER, DAVID, BOEHNKE, MICHAEL L · 2009 to 2010
$17.9MUniversity of Michigan Training Program in Genomic ScienceT32HG000040 · NHGRI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Sebastian Zoellner · 1995 to 2026
$16.4MMultiethnic Study of Type 2 Diabetes GenesU01DK085526 · NIDDK · BROAD INSTITUTE, INC. · PI ALTSHULER, DAVID, JABLONSKI, KATHLEEN ANN · 2009 to 2014
$15.7MTRAINING GRANT IN GENETICST32GM007748 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI Anne O'Donnell-Luria, Louise Wilkins-Haug · 1985 to 2026
$12.0MIdentifying Genes for Type 2 Diabetes: FUSIONU01DK062370 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI BOEHNKE, MICHAEL L, SCOTT, LAURA J. · 2009 to 2021
$11.6MTargeted Genetic Analysis of T2D and Quantitative TraitsR01DK072193 · NIDDK · UNIV OF NORTH CAROLINA CHAPEL HILL · PI KAREN L. MOHLKE · 2005 to 2026
$11.3MGenetic epidemiology of rare and regulatory variants for metabolic traitsR01DK093757 · NIDDK · UNIV OF NORTH CAROLINA CHAPEL HILL · PI KAREN L. MOHLKE · 2011 to 2026
$8.2MIdentifying Genes for Type 2 Diabetes:FUSIONR01DK062370 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI BOEHNKE, MICHAEL L, SCOTT, LAURA J. · 2003 to 2025
$6.7MGENETIC ANALYSIS OF TYPE II DIABETES IN FINNISH POPULATIONZ01HG000024 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI COLLINS, FRANCIS S. · 1995 to 2008
$6.2MDiscovery of Functional Variants in Type 2 Diabetes Genes in Mexican AmericansU01DK085524 · NIDDK · UNIVERSITY OF TEXAS RIO GRANDE VALLEY · PI BLANGERO, JOHN, DEFRONZO, RALPH A · 2009 to 2019
$5.9MJACKSON HEART STUDY--EXAM CENTERN01HC095171 · HC · UNIVERSITY OF MISSISSIPPI MEDICAL CENTER · PI JONES, DANIEL W · 1999 to 2001
$4.6MIntramural NIH HHS Z01 HG000024NCI NIH HHS R13 CA124293NHGRI NIH HHS T32 HG000040NHGRI NIH HHS U54 HG003067NHGRI NIH HHS U54HG003067NHLBI NIH HHS N01 HC095170NHLBI NIH HHS N01 HC095171NHLBI NIH HHS N01 HC095172NIDDK NIH HHS 5U01DK085526NIDDK NIH HHS DK088389NIDDK NIH HHS R01 DK062370NIDDK NIH HHS R01 DK072193NIDDK NIH HHS R01 DK093757NIDDK NIH HHS R01 DK098032NIDDK NIH HHS RC2 DK088389NIDDK NIH HHS U01 DK062370NIDDK NIH HHS U01 DK085501NIDDK NIH HHS U01 DK085524NIDDK NIH HHS U01 DK085526NIDDK NIH HHS U01 DK085545NIDDK NIH HHS U01 DK085584NIGMS NIH HHS T32 GM007748Wellcome Trust 090532Wellcome Trust 098017Wellcome Trust 098381
Abstract
Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
Indexed as
AnimalsBase SequenceBlood GlucoseCation Transport ProteinsDiabetes Mellitus, Type 2Genetic Association StudiesGenotypeHumansIon TransportMiceMice, KnockoutMolecular Sequence DataMutation, MissenseProinsulinSequence Analysis, DNAZinc Transporter 8Blood GlucoseCation Transport ProteinsProinsulinSLC30A8 protein, humanZinc Transporter 8
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