Genetic drivers of heterogeneity in type 2 diabetes pathophysiology Journal Articles uri icon

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abstract

  • AbstractType 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.

authors

  • Suzuki, Ken
  • Hatzikotoulas, Konstantinos
  • Southam, Lorraine
  • Taylor, Henry J
  • Yin, Xianyong
  • Lorenz, Kim M
  • Mandla, Ravi
  • Huerta-Chagoya, Alicia
  • Melloni, Giorgio EM
  • Kanoni, Stavroula
  • Rayner, Nigel W
  • Bocher, Ozvan
  • Arruda, Ana Luiza
  • Sonehara, Kyuto
  • Namba, Shinichi
  • Lee, Simon SK
  • 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 JY
  • Tam, Claudia HT
  • 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
  • Bertoni, Alain
  • Bork-Jensen, Jette
  • Brandslund, Ivan
  • Buchanan, Thomas A
  • Burant, Charles F
  • Butterworth, Adam S
  • Canouil, Mickaël
  • Chan, Juliana CN
  • 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 Chaim
  • 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
  • Kanona, Stavroula
  • van Heel, David A
  • 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 LR
  • Peyser, Patricia A
  • Pankow, James S
  • Engert, James C
  • Bonnefond, Amélie
  • Froguel, Philippe
  • Wilson, James G
  • Sheu, Wayne HH
  • Wu, Jer-Yuarn
  • Hayes, M Geoffrey
  • Ma, Ronald CW
  • 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 NA
  • 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 JF
  • 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 CY
  • 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

publication date

  • March 14, 2024

has subject area

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