학술논문
Genetic drivers of heterogeneity in type 2 diabetes pathophysiology
Document Type
Original Paper
Author
Suzuki, Ken; Hatzikotoulas, Konstantinos; Southam, Lorraine; Taylor, Henry J.; Yin, Xianyong; Lorenz, Kim M.; Mandla, Ravi; Huerta-Chagoya, Alicia; Melloni, Giorgio E. M.; Kanoni, Stavroula; Rayner, Nigel W.; Bocher, Ozvan; Arruda, Ana Luiza; Sonehara, Kyuto; Namba, Shinichi; Lee, Simon S. K.; Preuss, Michael H.; Petty, Lauren E.; Schroeder, Philip; Vanderwerff, Brett; Kals, Mart; Bragg, Fiona; Lin, Kuang; Guo, Xiuqing; Zhang, Weihua; Yao, Jie; Kim, Young Jin; Graff, Mariaelisa; Takeuchi, Fumihiko; Nano, Jana; Lamri, Amel; Nakatochi, Masahiro; Moon, Sanghoon; Scott, Robert A.; Cook, James P.; Lee, Jung-Jin; Pan, Ian; Taliun, Daniel; Parra, Esteban J.; Chai, Jin-Fang; Bielak, Lawrence F.; Tabara, Yasuharu; Hai, Yang; Thorleifsson, Gudmar; Grarup, Niels; Sofer, Tamar; Wuttke, Matthias; Sarnowski, Chloé; Gieger, Christian; Nousome, Darryl; Trompet, Stella; Kwak, Soo-Heon; Long, Jirong; Sun, Meng; Tong, Lin; Chen, Wei-Min; Nongmaithem, Suraj S.; Noordam, Raymond; Lim, Victor J. Y.; Tam, Claudia H. T.; Joo, Yoonjung Yoonie; Chen, Chien-Hsiun; Raffield, Laura M.; Prins, Bram Peter; Nicolas, Aude; Yanek, Lisa R.; Chen, Guanjie; Brody, Jennifer A.; Kabagambe, Edmond; An, Ping; Xiang, Anny H.; Choi, Hyeok Sun; Cade, Brian E.; Tan, Jingyi; Broadaway, K. Alaine; Williamson, Alice; Kamali, Zoha; Cui, Jinrui; Thangam, Manonanthini; Adair, Linda S.; Adeyemo, Adebowale; Aguilar-Salinas, Carlos A.; Ahluwalia, Tarunveer S.; Anand, Sonia S.; Bertoni, Alain; Bork-Jensen, Jette; Brandslund, Ivan; Buchanan, Thomas A.; Burant, Charles F.; Butterworth, Adam S.; Canouil, Mickaël; Chan, Juliana C. N.; Chang, Li-Ching; Chee, Miao-Li; Chen, Ji; Chen, Shyh-Huei; Chen, Yuan-Tsong; Chen, Zhengming; Chuang, Lee-Ming; Cushman, Mary; Danesh, John; Das, Swapan K.; de Silva, H. Janaka; Dedoussis, George; Dimitrov, Latchezar; Doumatey, Ayo P.; Du, Shufa; Duan, Qing; Eckardt, Kai-Uwe; Emery, Leslie S.; Evans, Daniel S.; Evans, Michele K.; Fischer, Krista; Floyd, James S.; Ford, Ian; Franco, Oscar H.; Frayling, Timothy M.; Freedman, Barry I.; Genter, Pauline; Gerstein, Hertzel C.; Giedraitis, Vilmantas; González-Villalpando, Clicerio; González-Villalpando, Maria Elena; Gordon-Larsen, Penny; Gross, Myron; Guare, Lindsay A.; Hackinger, Sophie; Hakaste, Liisa; Han, Sohee; Hattersley, Andrew T.; Herder, Christian; Horikoshi, Momoko; Howard, Annie-Green; Hsueh, Willa; Huang, Mengna; Huang, Wei; Hung, Yi-Jen; Hwang, Mi Yeong; Hwu, Chii-Min; Ichihara, Sahoko; Ikram, Mohammad Arfan; Ingelsson, Martin; Islam, Md. Tariqul; Isono, Masato; Jang, Hye-Mi; Jasmine, Farzana; Jiang, Guozhi; Jonas, Jost B.; Jørgensen, Torben; Kamanu, Frederick K.; Kandeel, Fouad R.; Kasturiratne, Anuradhani; Katsuya, Tomohiro; Kaur, Varinderpal; Kawaguchi, Takahisa; Keaton, Jacob M.; Kho, Abel N.; Khor, Chiea-Chuen; Kibriya, Muhammad G.; Kim, Duk-Hwan; Kronenberg, Florian; Kuusisto, Johanna; Läll, Kristi; Lange, Leslie A.; Lee, Kyung Min; Lee, Myung-Shik; Lee, Nanette R.; Leong, Aaron; Li, Liming; Li, Yun; Li-Gao, Ruifang; Ligthart, Symen; Lindgren, Cecilia M.; Linneberg, Allan; Liu, Ching-Ti; Liu, Jianjun; Locke, Adam E.; Louie, Tin; Luan, Jian’an; Luk, Andrea O.; Luo, Xi; Lv, Jun; Lynch, Julie A.; Lyssenko, Valeriya; Maeda, Shiro; Mamakou, Vasiliki; Mansuri, Sohail Rafik; Matsuda, Koichi; Meitinger, Thomas; Melander, Olle; Metspalu, Andres; Mo, Huan; Morris, Andrew D.; Moura, Filipe A.; Nadler, Jerry L.; Nalls, Michael A.; Nayak, Uma; Ntalla, Ioanna; Okada, Yukinori; Orozco, Lorena; Patel, Sanjay R.; Patil, Snehal; Pei, Pei; Pereira, Mark A.; Peters, Annette; Pirie, Fraser J.; Polikowsky, Hannah G.; Porneala, Bianca; Prasad, Gauri; Rasmussen-Torvik, Laura J.; Reiner, Alexander P.; Roden, Michael; Rohde, Rebecca; Roll, Katheryn; Sabanayagam, Charumathi; Sandow, Kevin; Sankareswaran, Alagu; Sattar, Naveed; Schönherr, Sebastian; Shahriar, Mohammad; Shen, Botong; Shi, Jinxiu; Shin, Dong Mun; Shojima, Nobuhiro; Smith, Jennifer A.; So, Wing Yee; Stančáková, Alena; Steinthorsdottir, Valgerdur; Stilp, Adrienne M.; Strauch, Konstantin; Taylor, Kent D.; Thorand, Barbara; Thorsteinsdottir, Unnur; Tomlinson, Brian; Tran, Tam C.; Tsai, Fuu-Jen; Tuomilehto, Jaakko; Tusie-Luna, Teresa; Udler, Miriam S.; Valladares-Salgado, Adan; van Dam, Rob M.; van Klinken, Jan B.; Varma, Rohit; Wacher-Rodarte, Niels; Wheeler, Eleanor; Wickremasinghe, Ananda R.; van Dijk, Ko Willems; Witte, Daniel R.; Yajnik, Chittaranjan S.; Yamamoto, Ken; Yamamoto, Kenichi; Yoon, Kyungheon; Yu, Canqing; Yuan, Jian-Min; Yusuf, Salim; Zawistowski, Matthew; Zhang, Liang; Zheng, Wei; Raffel, Leslie J.; Igase, Michiya; Ipp, Eli; Redline, Susan; Cho, Yoon Shin; Lind, Lars; Province, Michael A.; Fornage, Myriam; Hanis, Craig L.; Ingelsson, Erik; Zonderman, Alan B.; Psaty, Bruce M.; Wang, Ya-Xing; Rotimi, Charles N.; Becker, Diane M.; Matsuda, Fumihiko; Liu, Yongmei; Yokota, Mitsuhiro; Kardia, Sharon L. R.; Peyser, Patricia A.; Pankow, James S.; Engert, James C.; Bonnefond, Amélie; Froguel, Philippe; Wilson, James G.; Sheu, Wayne H. H.; Wu, Jer-Yuarn; Hayes, M. Geoffrey; Ma, Ronald C. W.; Wong, Tien-Yin; Mook-Kanamori, Dennis O.; Tuomi, Tiinamaija; Chandak, Giriraj R.; Collins, Francis S.; Bharadwaj, Dwaipayan; Paré, Guillaume; Sale, Michèle M.; Ahsan, Habibul; Motala, Ayesha A.; Shu, Xiao-Ou; Park, Kyong-Soo; Jukema, J. Wouter; Cruz, Miguel; Chen, Yii-Der Ida; Rich, Stephen S.; McKean-Cowdin, Roberta; Grallert, Harald; Cheng, Ching-Yu; Ghanbari, Mohsen; Tai, E-Shyong; Dupuis, Josee; Kato, Norihiro; Laakso, Markku; Köttgen, Anna; Koh, Woon-Puay; Bowden, Donald W.; Palmer, Colin N. A.; Kooner, Jaspal S.; Kooperberg, Charles; Liu, Simin; North, Kari E.; Saleheen, Danish; Hansen, Torben; Pedersen, Oluf; Wareham, Nicholas J.; Lee, Juyoung; Kim, Bong-Jo; Millwood, Iona Y.; Walters, Robin G.; Stefansson, Kari; Ahlqvist, Emma; Goodarzi, Mark O.; Mohlke, Karen L.; Langenberg, Claudia; Haiman, Christopher A.; Loos, Ruth J. F.; Florez, Jose C.; Rader, Daniel J.; Ritchie, Marylyn D.; Zöllner, Sebastian; Mägi, Reedik; Marston, Nicholas A.; Ruff, Christian T.; van Heel, David A.; Finer, Sarah; Denny, Joshua C.; Yamauchi, Toshimasa; Kadowaki, Takashi; Chambers, John C.; Ng, Maggie C. Y.; Sim, Xueling; Below, Jennifer E.; Tsao, Philip S.; Chang, Kyong-Mi; McCarthy, Mark I.; Meigs, James B.; Mahajan, Anubha; Spracklen, Cassandra N.; Mercader, Josep M.; Boehnke, Michael; Rotter, Jerome I.; Vujkovic, Marijana; Voight, Benjamin F.; Morris, Andrew P.; Zeggini, Eleftheria
Source
Nature: International weekly journal of science. 627(8003):347-357
Subject
Language
English
ISSN
0028-0836
1476-4687
1476-4687
Abstract
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 < 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 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.
A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.
A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.