Genetic drivers of heterogeneity in type 2 diabetes pathophysiology
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 associat...
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| Format: | Journal Article |
| Language: | English |
| Published: |
2024
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/178721 |
| _version_ | 1826122236258418688 |
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| 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 Campbell 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 |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) 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 Campbell 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 |
| author_sort | Suzuki, Ken |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T05:45:11Z |
| format | Journal Article |
| id | ntu-10356/178721 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:45:11Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1787212024-07-07T15:37:48Z Genetic drivers of heterogeneity in type 2 diabetes pathophysiology 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 Campbell 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 Lee Kong Chian School of Medicine (LKCMedicine) Medicine, Health and Life Sciences Type 2 diabetes Genetic predisposition 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. Published version Open access funding provided by Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH). Central analyses were supported by the Japan Agency for Medical Research and Development (JP21km0405213, JP20km0405202 and JP21tm0424218), NHGRI (HG011723), the American Diabetes Association Innovative and a Clinical Translational Award (1-19-ICTS-068), the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 101017802 (OPTOMICS), American Heart Association Postdoctoral Fellowships (15POST24470131 and 17POST33650016), the American Diabetes Association (11-22-JDFPM-06), Corporal Michael J Crescenz VA Medical Center Research, NIDDK (DK126194 and DK105535), Versus Arthritis (21754), NIHR Manchester Biomedical Research Centre (NIHR203308) and the MRC (MR/W029626/1). A complete list of acknowledgments and funding appears in the Supplementary Note. 2024-07-03T05:43:40Z 2024-07-03T05:43:40Z 2024 Journal Article 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., ...Zeggini, E. (2024). Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. Nature, 627(8003), 347-. https://dx.doi.org/10.1038/s41586-024-07019-6 0028-0836 https://hdl.handle.net/10356/178721 10.1038/s41586-024-07019-6 38374256 2-s2.0-85186615049 8003 627 347 en Nature © 2024 The Author(s). Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. application/pdf |
| spellingShingle | Medicine, Health and Life Sciences Type 2 diabetes Genetic predisposition 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 Campbell 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 Genetic drivers of heterogeneity in type 2 diabetes pathophysiology |
| title | Genetic drivers of heterogeneity in type 2 diabetes pathophysiology |
| title_full | Genetic drivers of heterogeneity in type 2 diabetes pathophysiology |
| title_fullStr | Genetic drivers of heterogeneity in type 2 diabetes pathophysiology |
| title_full_unstemmed | Genetic drivers of heterogeneity in type 2 diabetes pathophysiology |
| title_short | Genetic drivers of heterogeneity in type 2 diabetes pathophysiology |
| title_sort | genetic drivers of heterogeneity in type 2 diabetes pathophysiology |
| topic | Medicine, Health and Life Sciences Type 2 diabetes Genetic predisposition |
| url | https://hdl.handle.net/10356/178721 |
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