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Cited by 606Genetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and AnimalsDiabetes and associated disorders

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

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Suzuki, Ken, Hatzikotoulas, Konstantinos, Southam, Lorraine, Taylor, Henry J., Yin, Xianyong, Lorenz, Kim M., Mandla, Ravi, Huerta-Chagoya, Alicia +366 more·2024·Nature
DOI 10.1038/s41586-024-07019-6PMC PMC10937372
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Abstract

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes 1,2 and molecular mechanisms that are often specific to cell type 3,4 . Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance ( P < 5 × 10 −8 ) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores 5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

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  • Risk factors for type 2 diabetes include overweight and obesity, physical inactivity, age, family history, race and ethnicity, history of gestational diabetes, and presence of other conditions (eg, hypertension, dyslipidemia, cardiovascular disease).

    “Risk factors for type 2 diabetes include overweight and obesity, physical inactivity, age, family history, race and ethnicity, history of gestational diabetes, and presence of other conditions (eg, hypertension, dyslipidemia, cardiovascular disease).9–14”

    From Diagnosis and Treatment of Type 2 Diabetes in Adults (2025) · cites this paper as [12]

    The Main section identifies environment, lifestyle and heritability as T2D risk factors, and the Mechanistic clusters section links obesity-related processes and metabolic syndrome to T2D risk. The paper does not establish the full attributed list: it does not identify physical inactivity, age, family history or gestational diabetes as risk factors, and its analyses of ancestry groups and cardiovascular outcomes do not establish race or ethnicity or cardiovascular disease as risk factors for developing T2D. Page numbers are not available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The A allele at rs62492368 was associated positively with CSF and negatively with plasma abundance of AOC1, with the CSF pQTL also representing a deleterious GWAS association for T2D.

    “Another example is for the A allele at rs62492368, associated positively with CSF and negatively with plasma abundance of amine oxidase copper–containing 1 (AOC1), with the CSF pQTL also representing a deleterious GWAS association for type 2 diabetes (T2D; fig. S4B) (27).”

    From Low overlap of plasma and CSF protein quantitative trait loci affects protein discovery for neurological disease (2026) · cites this paper as [27]

    The Discovery of T2D loci section reports T2D association signals in general, but does not identify rs62492368 or the direction of its association with T2D. Searches for rs62492368, AOC1, CSF pQTLs, and plasma protein abundance found no passage addressing the claimed allele-specific findings. (LLM, conf=0.74)

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Suzuki, K., Hatzikotoulas, K., Southam, L., Taylor, H. J., Yin, X., Lorenz, K. M., Mandla, R., Huerta-Chagoya, A., Melloni, G. E. M., Kanoni, S., Rayner, N. W., Bocher, O., Arruda, A. L., Sonehara, K., Namba, S., Lee, S. S. K., Preuss, M. H., Petty, L. E., Schroeder, P., Vanderwerff, B., Kals, M., Bragg, F., Lin, K., Guo, X., Zhang, W., Yao, J., Kim, Y. J., Graff, M., Takeuchi, F., Nano, J., Lamri, A., Nakatochi, M., Moon, S., Scott, R. A., Cook, J. P., Lee, J.-J., Pan, I., Taliun, D., Parra, E. J., Chai, J.-F., Bielak, L. F., Tabara, Y., Hai, Y., Thorleifsson, G., Grarup, N., Sofer, T., Wuttke, M., Sarnowski, C., Gieger, C., Nousome, D., Trompet, S., Kwak, S.-H., Long, J., Sun, M., Tong, L., Chen, W.-M., Nongmaithem, S. S., Noordam, R., Lim, V. J. Y., Tam, C. H. T., Joo, Y. Y., Chen, C.-H., Raffield, L. M., Prins, B. P., Nicolas, A., Yanek, L. R., Chen, G., Brody, J. A., Kabagambe, E., An, P., Xiang, A. H., Choi, H. S., Cade, B. E., Tan, J., Broadaway, K. A., Williamson, A., Kamali, Z., Cui, J., Thangam, M., Adair, L. S., Adeyemo, A., Aguilar-Salinas, C. A., Ahluwalia, T. S., Anand, S. S., Bertoni, A., Bork-Jensen, J., Brandslund, I., Buchanan, T. A., Burant, C. F., Butterworth, A. S., Canouil, M., Chan, J. C. N., Chang, L.-C., Chee, M.-L., Chen, J., Chen, S.-H., Chen, Y.-T., Chen, Z., Chuang, L.-M., Cushman, M., Danesh, J., Das, S. K., de Silva, H. J., Dedoussis, G., Dimitrov, L., Doumatey, A. P., Du, S., Duan, Q., Eckardt, K.-U., Emery, L. S., Evans, D. S., Evans, M. K., Fischer, K., Floyd, J. S., Ford, I., Franco, O. H., Frayling, T. M., Freedman, B. I., Genter, P., Gerstein, H. C., Giedraitis, V., González-Villalpando, C., González-Villalpando, M. E., Gordon-Larsen, P., Gross, M., Guare, L. A., Hackinger, S., Hakaste, L., Han, S., Hattersley, A. T., Herder, C., Horikoshi, M., Howard, A.-G., Hsueh, W., Huang, M., Huang, W., Hung, Y.-J., Hwang, M. Y., Hwu, C.-M., Ichihara, S., Ikram, M. A., Ingelsson, M., Islam, M. T., Isono, M., Jang, H.-M., Jasmine, F., Jiang, G., Jonas, J. B., Jørgensen, T., Kamanu, F. K., Kandeel, F. R., Kasturiratne, A., Katsuya, T., Kaur, V., Kawaguchi, T., Keaton, J. M., Kho, A. N., Khor, C.-C., Kibriya, M. G., Kim, D.-H., Kronenberg, F., Kuusisto, J., Läll, K., Lange, L. A., Lee, K. M., Lee, M.-S., Lee, N. R., Leong, A., Li, L., Li, Y., Li-Gao, R., Ligthart, S., Lindgren, C. M., Linneberg, A., Liu, C.-T., Liu, J., Locke, A. E., Louie, T., Luan, J., Luk, A. O., Luo, X., Lv, J., Lynch, J. A., Lyssenko, V., Maeda, S., Mamakou, V., Mansuri, S. R., Matsuda, K., Meitinger, T., Melander, O., Metspalu, A., Mo, H., Morris, A. D., Moura, F. A., Nadler, J. L., Nalls, M. A., Nayak, U., Ntalla, I., Okada, Y., Orozco, L., Patel, S. R., Patil, S., Pei, P., Pereira, M. A., Peters, A., Pirie, F. J., Polikowsky, H. G., Porneala, B., Prasad, G., Rasmussen-Torvik, L. J., Reiner, A. P., Roden, M., Rohde, R., Roll, K., Sabanayagam, C., Sandow, K., Sankareswaran, A., Sattar, N., Schönherr, S., Shahriar, M., Shen, B., Shi, J., Shin, D. M., Shojima, N., Smith, J. A., So, W. Y., Stančáková, A., Steinthorsdottir, V., Stilp, A. M., Strauch, K., Taylor, K. D., Thorand, B., Thorsteinsdottir, U., Tomlinson, B., Tran, T. C., Tsai, F.-J., Tuomilehto, J., Tusie-Luna, T., Udler, M. S., Valladares-Salgado, A., van Dam, R. M., van Klinken, J. B., Varma, R., Wacher-Rodarte, N., Wheeler, E., Wickremasinghe, A. R., van Dijk, K. W., Witte, D. R., Yajnik, C. S., Yamamoto, K., Yamamoto, K., Yoon, K., Yu, C., Yuan, J.-M., Yusuf, S., Zawistowski, M., Zhang, L., Zheng, W., Program, V. M. V., Japan, A. G. D. I., Biobank Japan Project, BioBank, P. M., Regeneron Genetics Center, Genes & Health Research Team, Kanona, S., van Heel, D. A., eMERGE Consortium, International Consortium of Blood Pressure (ICBP), Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC), Raffel, L. J., Igase, M., Ipp, E., Redline, S., Cho, Y. S., Lind, L., Province, M. A., Fornage, M., Hanis, C. L., Ingelsson, E., Zonderman, A. B., Psaty, B. M., Wang, Y.-X., Rotimi, C. N., Becker, D. M., Matsuda, F., Liu, Y., Yokota, M., Kardia, S. L. R., Peyser, P. A., Pankow, J. S., Engert, J. C., Bonnefond, A., Froguel, P., Wilson, J. G., Sheu, W. H. H., Wu, J.-Y., Hayes, M. G., Ma, R. C. W., Wong, T.-Y., Mook-Kanamori, D. O., Tuomi, T., Chandak, G. R., Collins, F. S., Bharadwaj, D., Paré, G., Sale, M. M., Ahsan, H., Motala, A. A., Shu, X.-O., Park, K.-S., Jukema, J. W., Cruz, M., Chen, Y.-D. I., Rich, S. S., McKean-Cowdin, R., Grallert, H., Cheng, C.-Y., Ghanbari, M., Tai, E.-S., Dupuis, J., Kato, N., Laakso, M., Köttgen, A., Koh, W.-P., Bowden, D. W., Palmer, C. N. A., Kooner, J. S., Kooperberg, C., Liu, S., North, K. E., Saleheen, D., Hansen, T., Pedersen, O., Wareham, N. J., Lee, J., Kim, B.-J., Millwood, I. Y., Walters, R. G., Stefansson, K., Ahlqvist, E., Goodarzi, M. O., Mohlke, K. L., Langenberg, C., Haiman, C. A., Loos, R. J. F., Florez, J. C., Rader, D. J., Ritchie, M. D., Zöllner, S., Mägi, R., Marston, N. A., Ruff, C. T., van Heel, D. A., Finer, S., Denny, J. C., Yamauchi, T., Kadowaki, T., Chambers, J. C., Ng, M. C. Y., Sim, X., Below, J. E., Tsao, P. S., Chang, K.-M., McCarthy, M. I., Meigs, J. B., Mahajan, A., Spracklen, C. N., Mercader, J. M., Boehnke, M., Rotter, J. I., Vujkovic, M., Voight, B. F., Morris, A. P., & Zeggini, E.
Affiliations
  • Helmholtz Munich (DE)
  • National Institutes of Health (US)
  • University of Michigan (US)
  • Broad Institute (US)
  • Brigham and Women's Hospital (US)
  • Queen Mary University of London (GB)
  • RIKEN Center for Integrative Medical Sciences (JP)
  • The University of Osaka (JP)
  • Icahn School of Medicine at Mount Sinai (US)
  • Vanderbilt University Medical Center (US)
  • University of Tartu (EE)
  • University of Oxford (GB)
  • The Lundquist Institute (US)
  • Ealing Hospital (GB)
  • Korea National Institute of Health (KR)
  • University of North Carolina at Chapel Hill (US)
  • National Center for Global Health and Medicine (JP)
  • Population Health Research Institute (CA)
  • Nagoya University (JP)
  • University of Cambridge (GB)
  • University of Liverpool (GB)
  • Brown University (US)
  • University of Toronto (CA)
  • National University of Singapore (SG)
  • Kyoto University (JP)
  • University of Copenhagen (DK)
  • University of Freiburg (DE)
  • The University of Texas Health Science Center at Houston (US)
  • University of Southern California (US)
  • Leiden University Medical Center (NL)
  • Seoul National University (KR)
  • Vanderbilt University (US)
  • University of Virginia (US)
  • Centre for Cellular and Molecular Biology (IN)
  • Chinese University of Hong Kong (HK)
  • Northwestern University (US)
  • Institute of Biomedical Sciences, Academia Sinica (TW)
  • Wellcome Sanger Institute (GB)
  • Johns Hopkins University (US)
  • University of Washington (US)
  • Ochsner Health System (US)
  • Washington University in St. Louis (US)
  • Kaiser Permanente (US)
  • Hallym University (KR)
  • Isfahan University of Medical Sciences (IR)
  • Cedars-Sinai Medical Center (US)
  • Lund University (SE)
  • Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (MX)
  • Wake Forest University Health Sciences (US)
  • University of Southern Denmark (DK)
  • Centre National de la Recherche Scientifique (FR)
  • Singapore National Eye Center (SG)
  • National Taiwan University (TW)
  • University of Vermont (US)
  • Harokopio University of Athens (GR)
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • California Pacific Medical Center (US)
  • National Institute on Aging (US)
  • University of Glasgow (GB)
  • Erasmus MC (NL)
  • University of Exeter (GB)
  • Uppsala University (SE)
  • University of Minnesota (US)
  • University of Pennsylvania (US)
  • University of Helsinki (FI)
  • Düsseldorf University Hospital (DE)
  • The Ohio State University Wexner Medical Center (US)
  • Tri-Service General Hospital Songshan Branch (TW)
  • National Yang Ming Chiao Tung University (TW)
  • Jichi Medical University (JP)
  • University of Chicago Research Bangladesh (BD)
  • University of Chicago (US)
  • Institute of Molecular and Clinical Ophthalmology Basel (CH)
  • City Of Hope National Medical Center (US)
  • University of Kelaniya (LK)
  • Massachusetts General Hospital (US)
  • Agency for Science, Technology and Research (SG)
  • Sungkyunkwan University (KR)
  • Innsbruck Medical University (AT)
  • University of Eastern Finland (FI)
  • University of Colorado Anschutz (US)
  • University of Utah (US)
  • Soonchunhyang University (KR)
  • University of San Carlos (PH)
  • Harvard University (US)
  • Peking University (CN)
  • Boston University (US)
  • Regeneron (United States) (US)
  • University of the Ryukyus (JP)
  • National and Kapodistrian University of Athens (GR)
  • The University of Tokyo (JP)
  • University of Manchester (GB)
  • New York Medical College (US)
  • National Institute of Genomic Medicine (MX)
  • University of Pittsburgh (US)
  • University of KwaZulu-Natal (ZA)
  • Institute of Genomics and Integrative Biology (IN)
  • Johannes Gutenberg University Mainz (DE)
  • Macau University of Science and Technology (MO)
  • China Medical University Hospital (TW)
  • Southern California Eye Institute (US)
  • Mexican Social Security Institute (MX)
  • Aarhus University (DK)
  • King Edward Memorial Hospital Research Centre (IN)
  • Kurume University (JP)
  • University of California, Irvine (US)
  • Ehime University (JP)
  • Beijing Tongren Hospital (CN)
  • Beth Israel Deaconess Medical Center (US)
  • Jawaharlal Nehru University (IN)
  • Imperial College Healthcare NHS Trust (GB)
  • Columbia University Irving Medical Center (US)
  • deCODE Genetics (Iceland) (IS)
  • Toranomon Hospital (JP)
  • Centre for Human Genetics (GB)
  • University of Massachusetts Amherst (US)
  • Philadelphia VA Medical Center (US)
  • TUM Klinikum (DE)
Corresponding author
  • Hatzikotoulas, Konstantinos
  • Morris, Andrew D.
  • Voight, Benjamin F.
  • Morris, Andrew P.
  • Zeggini, Eleftheria
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2024-02-19
Volume
627
Issue
8003
Pages
347-357
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-024-07019-6
PMC
PMC10937372
OpenAlex
W4391925503
Cited by
606
References
13
Citations by year
2026: 261 · 2025: 252 · 2024: 92 · 2023: 1
FWCI
160.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, other-oa)
  • Leiden Repository (Leiden University) (submittedVersion, cc-by)
  • Discovery Research Portal (University of Dundee) (submittedVersion, cc-by)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • VBN Forskningsportal (Aalborg Universitet) (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • Touro Scholar (Touro College) (submittedVersion)
  • KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
  • HAL (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DR-NTU (Nanyang Technological University) (submittedVersion, cc-by)
  • Työväentutkimus Vuosikirja (submittedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • Research Explorer (The University of Manchester) (submittedVersion, cc-by)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, cc-by)
  • STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
  • Apollo (cc-by)
Funders
  • U.S. Department of Health and Human Services (DK126194)
  • American Diabetes Association (11-22-JDFPM-06, 1-19-ICTS-068)
  • U.S. Department of Veterans Affairs (I01-BX003362)
  • American Heart Association (17POST33650016, 15POST24470131)
  • Amgen
  • Eli Lilly and Company
  • Pfizer
  • AstraZeneca
  • GlaxoSmithKline
  • Sanofi
  • Brigham and Women's Hospital
  • Massachusetts General Hospital
  • Yale University
  • Vanderbilt University
  • University of Pennsylvania
  • Harvard University
  • Hamilton Health Sciences
  • Queen Mary University of London
  • McMaster University
  • Regeneron Pharmaceuticals
  • Wellcome Trust (212946/Z/18/Z)
  • National Center for Global Health and Medicine
  • Vanderbilt University Medical Center
  • Broad Institute
  • Ionis Pharmaceuticals
  • Medicines Company
  • Quest Diagnostics
  • Kowa Company
  • Zora Biosciences
  • Abiomed
  • ARCA Biopharma
  • Cancer Research UK (29186)
  • National Institute for Health and Care Research (NIHR 203308, 21754)
  • British Heart Foundation (RG/18/13/33946, CH/12/2/29428)
  • Department of Health and Social Care
  • Imperial College London
  • University of Oxford
  • European Commission (HORIZON2020, 101017802)
  • Daiichi-Sankyo
  • Novo Nordisk
  • Technische Universität München
  • Nanjing Medical University
  • Tartu Ülikool
  • Novo Nordisk Fonden (NNF20OC0059313, NNF17SA0031230-2)
  • Servier
  • Versus Arthritis (NIHR203308, 21754)
  • Guangdong Provincial People's Hospital
  • National Institutes of Health (11-22-JDFPM-06)
  • Genentech
  • University of North Carolina at Chapel Hill
  • Perelman School of Medicine, University of Pennsylvania
  • Manchester Biomedical Research Centre (NIHR 203308, 21754)
  • Respicardia
  • Medical Research Council (MR/W029626/1, MC_PC_14135, MC_UU_00017/1, HDR-23007)
  • Japan Society for the Promotion of Science (21H03206, 23K14451, 21H04850)
  • Barts and The London School of Medicine and Dentistry
  • RIKEN
  • Helmholtz Zentrum München
  • National Institute on Aging (R00AG066849)
  • National Heart, Lung, and Blood Institute (R01HL105756, R01HL142302, R01HL153805)
  • National Human Genome Research Institute (U01HG011723)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK078150, R01DK072193, UM1DK126185, R03DK131249, L30 DK126146, U01DK105535, DK126194, K23DK114551, UM1DK126194, P30DK020572, R01DK118011, R01DK139598, R01DK093757, P30DK089503, R01DK062370, R01DK134575)
  • National Institute of Environmental Health Sciences (P30ES010126)
  • Janssen Research and Development
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD030880)
  • Steno Diabetes Center Aarhus
Topics
  • 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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
type 2 diabetes, genetic heterogeneity, disease pathophysiology, non-European ancestry, vascular outcomes, coronary artery disease, peripheral arterial disease, diabetic nephropathy, obesity, single-cell epigenomics, cardiometabolic traits
MeSH terms
Chromatin, Coronary Artery Disease, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Humans, Islets of Langerhans, Adipocytes, Disease Progression, Enteroendocrine Cells, Genetic Predisposition to Disease, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Endothelial Cells, Genome-Wide Association Study, Epigenomics, Peripheral Arterial Disease, Single-Cell Analysis

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