Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.
Suzuki K., Hatzikotoulas K., Southam L., Taylor HJ., Yin X., Lorenz KM., Mandla R., Huerta-Chagoya A., Melloni GEM., Kanoni S., Rayner NW., Bocher O., Arruda AL., Sonehara K., Namba S., Lee SSK., Preuss MH., Petty LE., Schroeder P., Vanderwerff B., Kals M., Bragg F., Lin K., Guo X., Zhang W., Yao J., Kim YJ., Graff M., Takeuchi F., Nano J., Lamri A., Nakatochi M., Moon S., Scott RA., Cook JP., Lee J-J., Pan I., Taliun D., Parra EJ., Chai J-F., Bielak LF., 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 SS., Noordam R., Lim VJY., Tam CHT., Joo YY., Chen C-H., Raffield LM., Prins BP., Nicolas A., Yanek LR., Chen G., Brody JA., Kabagambe E., An P., Xiang AH., Choi HS., Cade BE., Tan J., Broadaway KA., Williamson A., Kamali Z., Cui J., Thangam M., Adair LS., Adeyemo A., Aguilar-Salinas CA., Ahluwalia TS., Anand SS., Bertoni A., Bork-Jensen J., Brandslund I., Buchanan TA., Burant CF., Butterworth AS., Canouil M., Chan JCN., Chang L-C., Chee M-L., Chen J., Chen S-H., Chen Y-T., Chen Z., Chuang L-M., Cushman M., Danesh J., Das SK., de Silva HJ., Dedoussis G., Dimitrov L., Doumatey AP., Du S., Duan Q., Eckardt K-U., Emery LS., Evans DS., Evans MK., Fischer K., Floyd JS., Ford I., Franco OH., Frayling TM., Freedman BI., Genter P., Gerstein HC., Giedraitis V., González-Villalpando C., González-Villalpando ME., Gordon-Larsen P., Gross M., Guare LA., Hackinger S., Hakaste L., Han S., Hattersley AT., Herder C., Horikoshi M., Howard A-G., Hsueh W., Huang M., Huang W., Hung Y-J., Hwang MY., Hwu C-M., Ichihara S., Ikram MA., Ingelsson M., Islam MT., Isono M., Jang H-M., Jasmine F., Jiang G., Jonas JB., Jørgensen T., Kamanu FK., Kandeel FR., Kasturiratne A., Katsuya T., Kaur V., Kawaguchi T., Keaton JM., Kho AN., Khor C-C., Kibriya MG., Kim D-H., Kronenberg F., Kuusisto J., Läll K., Lange LA., Lee KM., Lee M-S., Lee NR., Leong A., Li L., Li Y., Li-Gao R., Ligthart S., Lindgren CM., Linneberg A., Liu C-T., Liu J., Locke AE., Louie T., Luan J., Luk AO., Luo X., Lv J., Lynch JA., Lyssenko V., Maeda S., Mamakou V., Mansuri SR., Matsuda K., Meitinger T., Melander O., Metspalu A., Mo H., Morris AD., Moura FA., Nadler JL., Nalls MA., Nayak U., Ntalla I., Okada Y., Orozco L., Patel SR., Patil S., Pei P., Pereira MA., Peters A., Pirie FJ., Polikowsky HG., Porneala B., Prasad G., Rasmussen-Torvik LJ., Reiner AP., Roden M., Rohde R., Roll K., Sabanayagam C., Sandow K., Sankareswaran A., Sattar N., Schönherr S., Shahriar M., Shen B., Shi J., Shin DM., Shojima N., Smith JA., So WY., Stančáková A., Steinthorsdottir V., Stilp AM., Strauch K., Taylor KD., Thorand B., Thorsteinsdottir U., Tomlinson B., Tran TC., Tsai F-J., Tuomilehto J., Tusie-Luna T., Udler MS., Valladares-Salgado A., van Dam RM., van Klinken JB., Varma R., Wacher-Rodarte N., Wheeler E., Wickremasinghe AR., van Dijk KW., Witte DR., Yajnik CS., Yamamoto K., Yamamoto K., Yoon K., Yu C., Yuan J-M., Yusuf S., Zawistowski M., Zhang L., Zheng W., VA Million Veteran Program None., Raffel LJ., Igase M., Ipp E., Redline S., Cho YS., Lind L., Province MA., Fornage M., Hanis CL., Ingelsson E., Zonderman AB., Psaty BM., Wang Y-X., Rotimi CN., Becker DM., Matsuda F., Liu Y., Yokota M., Kardia SLR., Peyser PA., Pankow JS., Engert JC., Bonnefond A., Froguel P., Wilson JG., Sheu WHH., Wu J-Y., Hayes MG., Ma RCW., Wong T-Y., Mook-Kanamori DO., Tuomi T., Chandak GR., Collins FS., Bharadwaj D., Paré G., Sale MM., Ahsan H., Motala AA., Shu X-O., Park K-S., Jukema JW., Cruz M., Chen Y-DI., Rich SS., 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 DW., Palmer CNA., Kooner JS., Kooperberg C., Liu S., North KE., Saleheen D., Hansen T., Pedersen O., Wareham NJ., Lee J., Kim B-J., Millwood IY., Walters RG., Stefansson K., Ahlqvist E., Goodarzi MO., Mohlke KL., Langenberg C., Haiman CA., Loos RJF., Florez JC., Rader DJ., Ritchie MD., Zöllner S., Mägi R., Marston NA., Ruff CT., van Heel DA., Finer S., Denny JC., Yamauchi T., Kadowaki T., Chambers JC., Ng MCY., Sim X., Below JE., Tsao PS., Chang K-M., McCarthy MI., Meigs JB., Mahajan A., Spracklen CN., Mercader JM., Boehnke M., Rotter JI., Vujkovic M., Voight BF., Morris AP., Zeggini E.
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. 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 -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 scores5 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.