Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Suzuki, K. et al. (2024) Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. Nature, 627(8003), pp. 347-357. (doi: 10.1038/s41586-024-07019-6) (PMID:38374256)

Abstract

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. 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) 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 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.

• Item Type: Articles
• Additional Information: Funding: Open access funding provided by Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sattar, Professor Naveed and Ford, Professor Ian
• Authors: 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.'a., 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., 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., and Zeggini, E.
• Subjects: R Medicine > R Medicine (General)
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre; College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Nature
• Publisher: Nature Research
• ISSN: 0028-0836
• ISSN (Online): 1476-4687
• Published Online: 19 February 2024
• Copyright Holders: Copyright: © The Author(s) 2024
• First Published: First published in Nature 627(8003): 347-357
• Publisher Policy: Reproduced under a Creative Commons licence