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Nature Genetics volume 55, pages 973–983 (2023)Cite this article

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Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10−8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.

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GWAS summary statistics will be made available on the MAGIC investigators.

Website (https://magicinvestigators.org/downloads/) and GWAS catalog (https://www.ebi.ac.uk/gwas/home): GCST90267567, GCST90267568, GCST90267569, GCST90267570, GCST90267571, GCST90267572, GCST90267573, GCST90267574, GCST90267575, GCST90267576, GCST90267577 and GCST90267578.

Data from the Fenland cohort can be requested by bona fide researchers for specified scientific purposes via the study website (https://www.mrc-epid.cam.ac.uk/research/studies/fenland/information-for-researchers/). Data will either be shared through an institutional data-sharing agreement or arrangements will be made for analyses to be conducted remotely without the necessity for data transfer.

All data used in genetic risk score association analyses are available from the UK Biobank upon application (https://www.ukbiobank.ac.uk). All analyses in the UK Biobank in this manuscript were conducted under application 44448. Further details about the RISC study and data availability can be found here: http://www.egir.org/egirrisc/. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. The data used for the analyses described in this manuscript can be obtained from the GTEx Portal (https://www.gtexportal.org/home/) and dbGaP accession number phs000424.v8.p2. Genome regulatory annotations from ENCODE (https://www.encodeproject.org/) and Roadmap Epigenomics Consortium (https://egg2.wustl.edu/roadmap/web_portal/) were explored via UCSC Genome Browser (http://genome.ucsc.edu). Published differentiated 3T3-L1 RNA-sequencing data used in this study are available from GEO accession GSE129957 (https://www.ncbi.nlm.nih.gov/geo/). Source data are provided with this paper.

No previously unreported custom code or algorithm was used to generate results. The following software and packages were used for data analysis: METAL v.2011-03-25 (http://csg.sph.umich.edu/abecasis/Metal/download/), random-metal v.2017-07-24 (https://github.com/explodecomputer/random-metal), linkage disequilibrium score regression v.1.0.1 (https://github.com/bulik/ldsc), R v.3.6.0 and v.4.0.3 (https://www.r-project.org/). R packages coloc v.5.1.0 (https://cran.r-project.org/web/packages/coloc/).

Hyprcoloc v.1.0 (https://github.com/jrs95/hyprcoloc).

GCTA 1.26.0 (https://yanglab.westlake.edu.cn/software/gcta/#Overview). EasyQC v.17.8 (https://www.uni-regensburg.de/medizin/epidemiologie-praeventivmedizin/genetische-epidemiologie/software/index.html). Associated code and scripts used in this manuscript are available on GitHub: https://github.com/MRC-Epid/GWAS_postchallenge_insulin (https://zenodo.org/record/7805583#.ZC7C_exBxhE).

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We are grateful to investigators, staff members and study participants for their contribution to all participating studies. A full list of individual and study acknowledgments appears in the Supplementary Note. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

These authors jointly supervised this work: Karen L. Mohlke, Eleanor Wheeler, Stephen O’Rahilly, Daniel J. Fazakerley,Claudia Langenberg.

MRC Epidemiology Unit Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK

Alice Williamson, Jian’an Luan, Nicholas J. Wareham, Eleanor Wheeler & Claudia Langenberg

Metabolic Research Laboratories Wellcome Trust-MRC Institute of Metabolic Science, Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK

Alice Williamson, Dougall M. Norris, Stephen O’Rahilly & Daniel J. Fazakerley

Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA

Xianyong Yin, Anne U. Jackson & Michael Boehnke

Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA

Xianyong Yin, Anne U. Jackson & Michael Boehnke

Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China

Xianyong Yin

Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

K. Alaine Broadaway, Anne H. Moxley, Swarooparani Vadlamudi, Emma P. Wilson & Karen L. Mohlke

Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

Vasudha Ahuja, Om P. Dwivedi, Liisa Hakaste, Rashmi B. Prasad, Leif Groop & Tiinamaija Tuomi

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

Mette K. Andersen, Anna Jonsson, Carsten F. Rundsten, Sara E. Stinson, Sufyan Suleman, Torben Hansen & Niels Grarup

Department of Pediatrics, Genomic Outcomes, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA

Zorayr Arzumanyan, Xiuqing Guo, Jingyi Tan & Kent D. Taylor

Center for Precision Health Research National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

Lori L. Bonnycastle, Michael R. Erdos, Narisu Narisu & Francis S. Collins

Department of Internal Medicine III, Metabolic and Vascular Medicine, Medical Faculty Carl Gustav Carus, Dresden, Germany

Stefan R. Bornstein, Maxi P. Bretschneider & Nikolaos Perakakis

Helmholtz Zentrum München Paul Langerhans Institute Dresden (PLID), University Hospital and Faculty of Medicine TU Dresden, Dresden, Germany

Stefan R. Bornstein, Maxi P. Bretschneider, Sandra Herrmann, Nikolaos Perakakis, Romy Walther & Peter E. H. Schwarz

German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany

Stefan R. Bornstein, Maxi P. Bretschneider, Christian Gieger, Nikolaos Perakakis, Annette Peters, Harald Grallert & Peter E. H. Schwarz

Department of Medicine, Division of Endocrinology and Diabetes, Keck School of Medicine USC, Los Angeles, CA, USA

Thomas A. Buchanan

Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei City, Taiwan

Yi-Cheng Chang

Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan

Yi-Cheng Chang

Institute of Biomedical Sciences, Academia Sinica, Taipei City, Taiwan

Yi-Cheng Chang

Department of Internal Medicine, Division of Endocrinology and Metabolism, National Taiwan University Hospital, Taipei City, Taiwan

Lee-Ming Chuang

Institute of Population Health Sciences, National Health Research Institutes, Toufen, Taiwan

Ren-Hua Chung

Department of Gynecology and Obstetrics, Nordsjaellands Hospital, Hillerød, Denmark

Tine D. Clausen

Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

Tine D. Clausen, Peter Damm, Allan Linneberg & Elisabeth Mathiesen

Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen, Denmark

Peter Damm & Elisabeth Mathiesen

Department of Obstetrics, Rigshospitalet, Copenhagen, Denmark

Peter Damm

Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

Graciela E. Delgado & Winfried März

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland

Vanessa D. de Mello, Marcus E. Kleber, Angela P. Moissl & Vanessa D. de Mello

Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

Josée Dupuis, Ching-Ti Liu & Peitao Wu

Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Quebec, Canada

Josée Dupuis

Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland

Lilian Fernandes Silva & Markku Laakso

University of Exeter Medical School University of Exeter, Exeter, UK

Timothy M. Frayling

Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany

Christian Gieger, Annette Peters & Harald Grallert

Department of Medicine, Division of Endocrinology, Diabetes and Metabolism Cedars-Sinai Medical Center, Los Angeles, CA, USA

Mark O. Goodarzi

Department of Medical Sciences, Clinical Epidemiology, Uppsala University, Uppsala, Sweden

Stefan Gustafsson, Lars Lind & Johan Sundström

Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala, Sweden

Ulf Hammar & Tove Fall

Clinical Sciences Malmö, Genomics, Diabetes and Endocrinology, Lund University, Malmö, Sweden

Gad Hatem, Dina Mansour Aly, Rashmi B. Prasad & Emma Ahlqvist

Department of Internal Medicine III, Prevention and Care of Diabetes, Medical Faculty Carl Gustav Carus, Dresden, Germany

Sandra Herrmann & Peter E. H. Schwarz

Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark

Kurt Højlund

Medical Faculty Institute for Medical Informatics, Statistics and Epidemiology, Leipzig, Germany

Katrin Horn, Markus Scholz & Markus Loeffler

LIFE Leipzig Research Center for Civilization Diseases, Medical Faculty, Leipzig, Germany

Katrin Horn, Markus Scholz & Markus Loeffler

Internal Medicine, Endocrinology, Diabetes and Metabolism, The Ohio State University Wexner Medical Center, Columbus, OH, USA

Willa A. Hsueh

Institute of Preventive Medicine, National Defense Medical Center, New Taipei City, Taiwan

Yi-Jen Hung

Department of Medicine Section of Endocrinology and Metabolism, Taipei Veterans General Hospital, Taipei City, Taiwan

Chii-Min Hwu

Center for Clinical Research and Prevention, Copenhagen University Hospital – Bispebjerg and Frederiksberg, Copenhagen, Denmark

Line L. Kårhus & Allan Linneberg

SYNLAB MVZ Humangenetik Mannheim, Mannheim, Germany

Marcus E. Kleber

Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany

Peter Kovacs, Michael Stumvoll & Anke Tönjes

Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland

Timo A. Lakka

Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland

Timo A. Lakka

Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland

Timo A. Lakka, Kai Savonen, Pirjo Komulainen & Rainer Rauramaa

Department of Pediatrics, Genomic Outcomes, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA

Marie Lauzon & Yii-Der Ida Chen

Department of Internal Medicine Division of Endocrinology and Metabolism, Taichung Veterans General Hospital, Taichung City, Taiwan

I-Te Lee

School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan

I-Te Lee

School of Medicine, Chung Shan Medical University, Taichung City, Taiwan

I-Te Lee

Big Data Institute Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK

Cecilia M. Lindgren

Nuffield Department of Population Health, University of Oxford, Oxford, UK

Cecilia M. Lindgren

Wellcome Trust Centre Human Genetics, University of Oxford, Oxford, UK

Cecilia M. Lindgren

Broad Institute, Cambridge, MA, USA

Cecilia M. Lindgren

Finnish Institute for Health and Welfare, Helsinki, Finland

Jaana Lindström

Department of Endocrinology Rigshospitalet, Copenhagen, Denmark

Elisabeth Mathiesen

Institute of Nutritional Sciences, Friedrich-Schiller-University, Jena, Germany

Angela P. Moissl

Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena, Jena, Germany

Angela P. Moissl

Centre for Genetics and Genomics Versus Arthritis Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK

Andrew P. Morris

Department of Internal Medicine III, University Center for Vascular Medicine, Medical Faculty Carl Gustav Carus, Dresden, Germany

Roman N. Rodionov

College of Medicine and Public Health, Flinders University and Flinders Medical Centre, Adelaide, Australia

Roman N. Rodionov

Pediatrics, Genomic Outcomes, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA

Kathryn Roll

Department of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center, Houston, TX, USA

Chloé Sarnowski

Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany

Sapna Sharma & Harald Grallert

Food Chemistry and Molecular and Sensory Science, Technical University of Munich, Freising-Weihenstephan, München, Germany

Sapna Sharma

Department of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland

Matti Uusitupa

Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark

Dorte Vistisen

Department of Public Health, University of Copenhagen, Copenhagen, Denmark

Dorte Vistisen

Steno Diabetes Center Aarhus, Aarhus, Denmark

Daniel R. Witte

Department of Public Health, Aarhus University, Aarhus, Denmark

Daniel R. Witte

Department of Internal Medicine III, Pathobiochemistry, Medical Faculty Carl Gustav Carus, Dresden, Germany

Romy Walther

Research and Evaluation, Division of Biostatistics, Kaiser Permanente Southern California, Pasadena, CA, USA

Anny H. Xiang

Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden

Björn Zethelius

Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Richard N. Bergman

Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

Jose C. Florez

Programs in Metabolism and Medical and Population Genetics, The Broad Institute, Cambridge, MA, USA

Jose C. Florez

Department of Medicine, Harvard Medical School, Boston, MA, USA

Jose C. Florez

Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany

Andreas Fritsche, James B. Meigs & Robert Wagner

Clinical Sciences Malmö, Genomics, Diabetes and Endocrinology, Lund University, Lund, Sweden

Leif Groop & James B. Meigs

Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland

Heikki A. Koistinen

Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

Heikki A. Koistinen

Minerva Foundation Institute for Medical Research, Helsinki, Finland

Heikki A. Koistinen

Synlab Academy, SYNLAB Holding Deutschland GmbH, Mannheim, Germany

Winfried März

Department of Medicine Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA

James B. Meigs

Department of Pediatrics, Genetic and Genomic Medicine, University of California, Irvine, CA, USA

Leslie J. Raffel

The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA

Jerome I. Rotter

Folkhälsan Research Center, Helsinki, Finland

Tiinamaija Tuomi

Department of Public Health, University of Helsinki, Helsinki, Finland

Jaakko Tuomilehto

Population Health Unit, Finnish Institute for Health and Welfare, Helsinki, Finland

Jaakko Tuomilehto

Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia

Jaakko Tuomilehto

Exeter Centre of Excellence for Diabetes Research (EXCEED), Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK

Inês Barroso

Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

Mark Walker

Computational Medicine, Berlin Institute of Health at Charité–Universitätsmedizin, Berlin, Germany

Claudia Langenberg

Precision Healthcare University Research Institute, Queen Mary University of London, London, UK

Claudia Langenberg

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A.W., X.Y., K.A.B., E.P.W., N.G., M.B., N.J.W., K.L.M., E.W., S.O’R and C.L. contributed to central analysis group. A.W., X.Y., K.A.B., A.U.J, M.W., N.J.W., K.L.M., E.W., S.O’R and C.L. contributed to follow-up analysis and interpretation. A.H.M., S.V. and K.L.M. contributed to SLC2A4 in vitro follow-up. A.W., D.M.N. and D.J.F. contributed to siRNA knockdown screen. A.W., X.Y., K.A.B., A.U.J, V.A., M.K.A., Z.A., L.L.B., S.R.B., M.P.B., T.A.B., Y-C.C., L-M.C., R-H.C., T.D.C., P.D., G.E.D., V.D.dM., J.D., O.P.D., M.R.E, L.F., T.M.F., C.G., M.O.G., X.G., S.G., L.H., U.H., G.H., S.H., K.H., K.Horn, W.A.H., Y-J.H., C-M.H., A.J., L.L.K., M.E.K., P.K., T.A.L., M.L., I-T.L., C.L., J.L., A.L., C-T.L., J’an.L., D.M., E.M., A.P. Moissl, A.P. Morris, N.N., N.P., A. Peters, R.B.P., R.N.R., K.R., C.R., C.S., K.S., M. Scholz, S. Sharma, S.E.S., S. Suleman, J. Tan, K.T., M.U., D.V., P.W., D.R.W., R.W., A.H.X., B.Z., E.A., M. Laakso, L.L., J.B.M., R.R., J.S., M.W., N.G. and N.J.W. contributed to study-level GWAS—analysis, phenotyping and genotyping. E.A., R.N.B., Y.C., F.S.C., T.F., J.C.F., A.F., H.G., L.G., T.H., H.A.K., P.K., M. Laakso, L.L., M. Loeffler, W.M., J.B.M., L.J.R., R.R., J.I.R., P.E.H.S., M. Stumvoll, J.S., A.T., T.T., J. Tuomilehto, R.W., M.W., N.G., M.B., N.J.W., K.L.M. and C.L. contributed to study-level oversight/PI. A.W., D.M.N., A.H.M., I.B., K.L.M., E.W., S.O’R, D.J.F. and C.L. contributed to writing group. All authors read, edited and approved the final version of the manuscript.

Correspondence to Karen L. Mohlke, Eleanor Wheeler, Stephen O’Rahilly, Daniel J. Fazakerley or Claudia Langenberg.

I.B. and spouse declare stock ownership in GlaxoSmithKline, Incyte Ltd. and Inivata Ltd. J.C.F. has received consulting honoraria from Goldfinch Bio and AstraZeneca; speaker honoraria from Novo Nordisk, AstraZeneca and Merck for research lectures over which he had full control on content. M.E.K. is employed by SYNLAB Holding Deutschland GmbH. C.L. receives grants from Bayer Ag & Novo Nordisk and her husband works for Vertex. W.M. reports grants and personal fees from Siemens Diagnostics, Aegerion Pharmaceuticals, AMGEN, AstraZeneca, Danone Research, Sanofi, Pfizer, BASF and Numares; personal fees from Hoffmann LaRoche, MSD, Synageva; grants from Abbott Diagnostics, outside the submitted work. W.M. is employed by Synlab Holding Deutschland GmbH. J.B.M. serves as an Academic Associate for Quest Diagnostics. S.O’R. has undertaken remunerated consultancy work for Pfizer, AstraZeneca, GSK and ERX Pharmaceuticals. N.P. reports consulting honoraria from Bayer Vital GmbH and speaker honoraria from Novo Nordisk. J.S. is shareholder in Anagram kommunikation AB and Symptoms Europe AB, outside of the present study. D.V. has received research grants from Bayer A/S, Sanofi, Novo Nordisk A/S and Boehringer Ingelheim and holds shares in Novo Nordisk A/S. E.W. is now an employee of AstraZeneca. B.Z. is employed at the Swedish Medical Products Agency, SE-751 03 Uppsala, Sweden. The views expressed in this paper are the personal views of the authors and not necessarily the views of the Swedish government agency. All other authors declare no competing interests.

Nature Genetics thanks Constantin Polychronakos, Miriam Udler and John Todd for their contribution to the peer review of this work. Peer reviewer reports are available.

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Created with BioRender.com.

Pairwise Spearman's rank correlation. Red shades denote positive correlation, blue shared denote negative correlation between trait pairs. X denotes no significant correlation (P > 0.05).

Pairwise Spearman's rank correlation. Red shades denote positive correlation, blue shared denote negative correlation between trait pairs, legend along bottom of heatmap shows color scale relative to rho value. X denotes no significant correlation (P > 0.05). Abbreviations denote: IFC_OGTT – IFC calculated using OGTT measures, ISI_OGTT – Modified Stumvoll ISI calculated using OGTT measures. M_I – M/I index of insulin sensitivity measured by clamp. InsC0c – insulin measured at 0 min during clamp. InsO0c—insulin measured at 0 min during OGTT. InsC120c—insulin measured at 120 min during clamp. InsO120c—insulin measured at 120 min during OGTT. InsC_20c—insulin measured at 20 min before clamp. EGP_B—basal glucose production, EGP_SS—glucose production during clamp, GCR_B—basal glucose clearance, ml/min/kg lean body mass, GCR_SS—steady state glucose clearance, ml min−1 kg−1 lean body mass, icl_clamp—peripheral insulin clearance (1 min−1 m−2), icl_OGTT—endogenous ‘pre-hepatic’ clearance during the OGTT, hie_0—hepatic insulin extraction during clamp, OGIS—oral glucose insulin sensitivity index (ml min−1 m−2). ISR5dr—insulin secretion 5 mM glucose, beta cell dose response (pmol min−1 m−2). ISR0 basal insulin secretion (pmol min-1m-2). ISRtot—total insulin secretion (nmol m−2).

Analysis workflow for the meta-analysis of study-level GWAS results for Insulin fold change and modified Stumvoll ISI. Created with BioRender.com.

Conditional analyses identify a second independent signal at PPP1R3B for insulin fold change adjusted for BMI. The regional association plot shows the primary signal in red and the secondary signal in blue for marginal summary statistics for insulin fold change adjusted for BMI. Shade of point indicates pairwise linkage disequilibrium (R2) with indicated lead variant.

Labels on the right-hand side indicate the ancestry of the study and study name. EUR- European ancestry, HIS-AMR—Hispanic American ancestry, EAS—East Asian ancestry. Left-hand side values are beta estimate and 95% confidence interval. Error bars denote a 95% confidence interval. X-axis denotes the beta estimate of associations with insulin fold change in BMI adjusted analyses.

Unadjusted -log10 p-values are indicated on the y axis. Lead variant indicated by purple diamond.

An EMSA using 6 µg per lane of nuclear extract from undifferentiated LHCN-M2 cells shows protein–DNA interactions for probes centered around each both alleles of rs117643180. The probe containing rs117643180-A shows allele-specific protein binding (arrow A, lane 6), relative to the probe containing rs117643180-C (lane 2). A 25-fold excess unlabeled probe containing the A allele competed away A-specific bands more effectively (lane 7) than 25-fold excess unlabeled probe containing the C allele (lane 8). Arrow B shows a biotinylated free probe (200 fmol per lane). Uncropped image is available in Source Data.

Source data

Representative blot from N = 2. Marker indicates protein size in kDa is outlined on the right-hand side of the blot. siGenome and OT+ represent siRNA pools with their corresponding targets indicated below (see Methods) and NT denotes non-targeting control. Antibodies are outlined on the left-hand side of the blot with Tubulin and B-actin used as loading controls. Uncropped blots are provided in Source Data.

Source data

Supplementary Note—Study and Individual Acknowledgments, Supplementary Methods, Supplementary Results and Discussion and Supplementary Figs. 1–25.

Supplementary Tables 1–33.

Unprocessed ESMA blot corresponding to extended data figure 8. Unprocessed western blots corresponding to extended data figure 9

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Williamson, A., Norris, D.M., Yin, X. et al. Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake. Nat Genet 55, 973–983 (2023). https://doi.org/10.1038/s41588-023-01408-9

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Received: 04 August 2022

Accepted: 26 April 2023

Published: 08 June 2023

Issue Date: June 2023

DOI: https://doi.org/10.1038/s41588-023-01408-9

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