Abstract / Description of output
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.
Original language | English |
---|---|
Pages (from-to) | 347-357 |
Number of pages | 11 |
Journal | Nature |
Volume | 627 |
DOIs | |
Publication status | Published - 19 Feb 2024 |
Keywords / Materials (for Non-textual outputs)
- Humans
- Diabetes Mellitus, Type 2/genetics
- Genome-Wide Association Study
- Endothelial Cells
- Genetic Predisposition to Disease/genetics
- Islets of Langerhans
- Polymorphism, Single Nucleotide
Access to Document
- Genetic drivers_SUZUKI_01032024_VOR_CC-BYFinal published version, 4.76 MBLicence: Creative Commons: Attribution (CC-BY)
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In: Nature, Vol. 627, 19.02.2024, p. 347-357.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Genetic drivers of heterogeneity in type 2 diabetes pathophysiology
AU - Suzuki, Ken
AU - Hatzikotoulas, Konstantinos
AU - Southam, Lorraine
AU - Taylor, Henry J
AU - Yin, Xianyong
AU - Lorenz, Kim M
AU - Mandla, Ravi
AU - Huerta-Chagoya, Alicia
AU - Melloni, Giorgio E M
AU - Kanoni, Stavroula
AU - Rayner, Nigel W
AU - Bocher, Ozvan
AU - Arruda, Ana Luiza
AU - Sonehara, Kyuto
AU - Namba, Shinichi
AU - Lee, Simon S K
AU - Preuss, Michael H
AU - Petty, Lauren E
AU - Schroeder, Philip
AU - Vanderwerff, Brett
AU - Kals, Mart
AU - Bragg, Fiona
AU - Lin, Kuang
AU - Guo, Xiuqing
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AU - Yao, Jie
AU - Kim, Young Jin
AU - Graff, Mariaelisa
AU - Takeuchi, Fumihiko
AU - Nano, Jana
AU - Lamri, Amel
AU - Nakatochi, Masahiro
AU - Moon, Sanghoon
AU - Scott, Robert A
AU - Cook, James P
AU - Lee, Jung-Jin
AU - Pan, Ian
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AU - Parra, Esteban J
AU - Chai, Jin-Fang
AU - Bielak, Lawrence F
AU - Tabara, Yasuharu
AU - Hai, Yang
AU - Thorleifsson, Gudmar
AU - Grarup, Niels
AU - Sofer, Tamar
AU - Wuttke, Matthias
AU - Sarnowski, Chloé
AU - Gieger, Christian
AU - Nousome, Darryl
AU - Trompet, Stella
AU - Kwak, Soo-Heon
AU - Long, Jirong
AU - Sun, Meng
AU - Tong, Lin
AU - Chen, Wei-Min
AU - Nongmaithem, Suraj S
AU - Noordam, Raymond
AU - Lim, Victor J Y
AU - Tam, Claudia H T
AU - Joo, Yoonjung Yoonie
AU - Chen, Chien-Hsiun
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AU - Prins, Bram Peter
AU - Nicolas, Aude
AU - Yanek, Lisa R
AU - Chen, Guanjie
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AU - Kabagambe, Edmond
AU - An, Ping
AU - Xiang, Anny H
AU - Choi, Hyeok Sun
AU - Cade, Brian E
AU - Tan, Jingyi
AU - Broadaway, K Alaine
AU - Williamson, Alice
AU - Kamali, Zoha
AU - Cui, Jinrui
AU - Thangam, Manonanthini
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AU - Adeyemo, Adebowale
AU - Aguilar-Salinas, Carlos A
AU - Ahluwalia, Tarunveer S
AU - Anand, Sonia S
AU - Bertoni, Alain
AU - Bork-Jensen, Jette
AU - Brandslund, Ivan
AU - Buchanan, Thomas A
AU - Burant, Charles F
AU - Butterworth, Adam S
AU - Canouil, Mickaël
AU - Chan, Juliana C N
AU - Chang, Li-Ching
AU - Chee, Miao-Li
AU - Chen, Ji
AU - Chen, Shyh-Huei
AU - Chen, Yuan-Tsong
AU - Chen, Zhengming
AU - Chuang, Lee-Ming
AU - Cushman, Mary
AU - Danesh, John
AU - Das, Swapan K
AU - de Silva, H Janaka
AU - Dedoussis, George
AU - Dimitrov, Latchezar
AU - Doumatey, Ayo P
AU - Du, Shufa
AU - Duan, Qing
AU - Eckardt, Kai-Uwe
AU - Emery, Leslie S
AU - Evans, Daniel S
AU - Evans, Michele K
AU - Fischer, Krista
AU - Floyd, James S
AU - Ford, Ian
AU - Franco, Oscar H
AU - Frayling, Timothy M
AU - Freedman, Barry I
AU - Genter, Pauline
AU - Gerstein, Hertzel C
AU - Giedraitis, Vilmantas
AU - González-Villalpando, Clicerio
AU - González-Villalpando, Maria Elena
AU - Gordon-Larsen, Penny
AU - Gross, Myron
AU - Guare, Lindsay A
AU - Hackinger, Sophie
AU - Hakaste, Liisa
AU - Han, Sohee
AU - Hattersley, Andrew T
AU - Herder, Christian
AU - Horikoshi, Momoko
AU - Howard, Annie-Green
AU - Hsueh, Willa
AU - Huang, Mengna
AU - Huang, Wei
AU - Hung, Yi-Jen
AU - Hwang, Mi Yeong
AU - Hwu, Chii-Min
AU - Ichihara, Sahoko
AU - Ikram, Mohammad Arfan
AU - Ingelsson, Martin
AU - Islam, Md Tariqul
AU - Isono, Masato
AU - Jang, Hye-Mi
AU - Jasmine, Farzana
AU - Jiang, Guozhi
AU - Jonas, Jost B
AU - Jørgensen, Torben
AU - Kamanu, Frederick K
AU - Kandeel, Fouad R
AU - Kasturiratne, Anuradhani
AU - Katsuya, Tomohiro
AU - Kaur, Varinderpal
AU - Kawaguchi, Takahisa
AU - Keaton, Jacob M
AU - Kho, Abel N
AU - Khor, Chiea-Chuen
AU - Kibriya, Muhammad G
AU - Kim, Duk-Hwan
AU - Kronenberg, Florian
AU - Kuusisto, Johanna
AU - Läll, Kristi
AU - Lange, Leslie A
AU - Lee, Kyung Min
AU - Lee, Myung-Shik
AU - Lee, Nanette R
AU - Leong, Aaron
AU - Li, Liming
AU - Li, Yun
AU - Li-Gao, Ruifang
AU - Ligthart, Symen
AU - Lindgren, Cecilia M
AU - Linneberg, Allan
AU - Liu, Ching-Ti
AU - Liu, Jianjun
AU - Locke, Adam E
AU - Louie, Tin
AU - Luan, Jian'an
AU - Luk, Andrea O
AU - Luo, Xi
AU - Lv, Jun
AU - Lynch, Julie A
AU - Lyssenko, Valeriya
AU - Maeda, Shiro
AU - Mamakou, Vasiliki
AU - Mansuri, Sohail Rafik
AU - Matsuda, Koichi
AU - Meitinger, Thomas
AU - Melander, Olle
AU - Metspalu, Andres
AU - Mo, Huan
AU - Morris, Andrew D
AU - Moura, Filipe A
AU - Nadler, Jerry L
AU - Nalls, Michael A
AU - Nayak, Uma
AU - Ntalla, Ioanna
AU - Okada, Yukinori
AU - Orozco, Lorena
AU - Patel, Sanjay R
AU - Patil, Snehal
AU - Pei, Pei
AU - Pereira, Mark A
AU - Peters, Annette
AU - Pirie, Fraser J
AU - Polikowsky, Hannah G
AU - Porneala, Bianca
AU - Prasad, Gauri
AU - Rasmussen-Torvik, Laura J
AU - Reiner, Alexander P
AU - Roden, Michael
AU - Rohde, Rebecca
AU - Roll, Katheryn
AU - Sabanayagam, Charumathi
AU - Sandow, Kevin
AU - Sankareswaran, Alagu
AU - Sattar, Naveed
AU - Schönherr, Sebastian
AU - Shahriar, Mohammad
AU - Shen, Botong
AU - Shi, Jinxiu
AU - Shin, Dong Mun
AU - Shojima, Nobuhiro
AU - Smith, Jennifer A
AU - So, Wing Yee
AU - Stančáková, Alena
AU - Steinthorsdottir, Valgerdur
AU - Stilp, Adrienne M
AU - Strauch, Konstantin
AU - Taylor, Kent D
AU - Thorand, Barbara
AU - Thorsteinsdottir, Unnur
AU - Tomlinson, Brian
AU - Tran, Tam C
AU - Tsai, Fuu-Jen
AU - Tuomilehto, Jaakko
AU - Tusie-Luna, Teresa
AU - Udler, Miriam S
AU - Valladares-Salgado, Adan
AU - van Dam, Rob M
AU - van Klinken, Jan B
AU - Varma, Rohit
AU - Wacher-Rodarte, Niels
AU - Wheeler, Eleanor
AU - Wickremasinghe, Ananda R
AU - van Dijk, Ko Willems
AU - Witte, Daniel R
AU - Yajnik, Chittaranjan S
AU - Yamamoto, Ken
AU - Yamamoto, Kenichi
AU - Yoon, Kyungheon
AU - Yu, Canqing
AU - Yuan, Jian-Min
AU - Yusuf, Salim
AU - Zawistowski, Matthew
AU - Zhang, Liang
AU - Zheng, Wei
AU - Raffel, Leslie J
AU - Igase, Michiya
AU - Ipp, Eli
AU - Redline, Susan
AU - Cho, Yoon Shin
AU - Lind, Lars
AU - Province, Michael A
AU - Fornage, Myriam
AU - Hanis, Craig L
AU - Ingelsson, Erik
AU - Zonderman, Alan B
AU - Psaty, Bruce M
AU - Wang, Ya-Xing
AU - Rotimi, Charles N
AU - Becker, Diane M
AU - Matsuda, Fumihiko
AU - Liu, Yongmei
AU - Yokota, Mitsuhiro
AU - Kardia, Sharon L R
AU - Peyser, Patricia A
AU - Pankow, James S
AU - Engert, James C
AU - Bonnefond, Amélie
AU - Froguel, Philippe
AU - Wilson, James G
AU - Sheu, Wayne H H
AU - Wu, Jer-Yuarn
AU - Hayes, M Geoffrey
AU - Ma, Ronald C W
AU - Wong, Tien-Yin
AU - Mook-Kanamori, Dennis O
AU - Tuomi, Tiinamaija
AU - Chandak, Giriraj R
AU - Collins, Francis S
AU - Bharadwaj, Dwaipayan
AU - Paré, Guillaume
AU - Sale, Michèle M
AU - Ahsan, Habibul
AU - Motala, Ayesha A
AU - Shu, Xiao-Ou
AU - Park, Kyong-Soo
AU - Jukema, J Wouter
AU - Cruz, Miguel
AU - Chen, Yii-Der Ida
AU - Rich, Stephen S
AU - McKean-Cowdin, Roberta
AU - Grallert, Harald
AU - Cheng, Ching-Yu
AU - Ghanbari, Mohsen
AU - Tai, E-Shyong
AU - Dupuis, Josee
AU - Kato, Norihiro
AU - Laakso, Markku
AU - Köttgen, Anna
AU - Koh, Woon-Puay
AU - Bowden, Donald W
AU - Palmer, Colin N A
AU - Kooner, Jaspal S
AU - Kooperberg, Charles
AU - Liu, Simin
AU - North, Kari E
AU - Saleheen, Danish
AU - Hansen, Torben
AU - Pedersen, Oluf
AU - Wareham, Nicholas J
AU - Lee, Juyoung
AU - Kim, Bong-Jo
AU - Millwood, Iona Y
AU - Walters, Robin G
AU - Stefansson, Kari
AU - Ahlqvist, Emma
AU - Goodarzi, Mark O
AU - Mohlke, Karen L
AU - Langenberg, Claudia
AU - Haiman, Christopher A
AU - Loos, Ruth J F
AU - Florez, Jose C
AU - Rader, Daniel J
AU - Ritchie, Marylyn D
AU - Zöllner, Sebastian
AU - Mägi, Reedik
AU - Marston, Nicholas A
AU - Ruff, Christian T
AU - van Heel, David A
AU - Finer, Sarah
AU - Denny, Joshua C
AU - Yamauchi, Toshimasa
AU - Kadowaki, Takashi
AU - Chambers, John C
AU - Ng, Maggie C Y
AU - Sim, Xueling
AU - Below, Jennifer E
AU - Tsao, Philip S
AU - Chang, Kyong-Mi
AU - McCarthy, Mark I
AU - Meigs, James B
AU - Mahajan, Anubha
AU - Spracklen, Cassandra N
AU - Mercader, Josep M
AU - Boehnke, Michael
AU - Rotter, Jerome I
AU - Vujkovic, Marijana
AU - Voight, Benjamin F
AU - Morris, Andrew P
AU - Zeggini, Eleftheria
N1 - © 2024. The Author(s). Open access funding provided by Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH).
PY - 2024/2/19
Y1 - 2024/2/19
N2 - 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.
AB - 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.
KW - Humans
KW - Diabetes Mellitus, Type 2/genetics
KW - Genome-Wide Association Study
KW - Endothelial Cells
KW - Genetic Predisposition to Disease/genetics
KW - Islets of Langerhans
KW - Polymorphism, Single Nucleotide
U2 - 10.1038/s41586-024-07019-6
DO - 10.1038/s41586-024-07019-6
M3 - Article
C2 - 38374256
SN - 0028-0836
VL - 627
SP - 347
EP - 357
JO - Nature
JF - Nature
ER -