Citation
Suzuki, Ken; Hatzikotoulas, Konstantinos; Southam, Lorraine; Taylor, Henry J.; Yin, Xianyong; Lorenz, Kim M.; Mandla, Ravi; Huerta-Chagoya, Alicia; Rayner, Nigel W.; & Bocher, Ozvan, et al. (Preprint). Multi-Ancestry Genome-Wide Study in >2.5 Million Individuals Reveals Heterogeneity in Mechanistic Pathways of Type 2 Diabetes and Complications. medRxiv. PMCID: PMC10081410Abstract
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. 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 previously unreported. We define eight non-overlapping clusters of T2D signals characterised 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, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.URL
http://dx.doi.org/10.1101/2023.03.31.23287839Reference Type
Journal ArticleYear Published
PreprintJournal Title
medRxivAuthor(s)
Suzuki, KenHatzikotoulas, Konstantinos
Southam, Lorraine
Taylor, Henry J.
Yin, Xianyong
Lorenz, Kim M.
Mandla, Ravi
Huerta-Chagoya, Alicia
Rayner, Nigel W.
Bocher, Ozvan
Ana Luiza de, S. V. Arruda
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 K.
An, Ping
Xiang, Anny H.
Choi, Hyeok Sun
Cade, Brian E.
Tan, Jingyi
Alaine Broadaway, K.
Williamson, Alice
Kamali, Zoha
Cui, Jinrui
Adair, Linda S.
Adeyemo, Adebowale A.
Aguilar-Salinas, Carlos A.
Ahluwalia, Tarunveer S.
Anand, Sonia S.
Bertoni, Alain G.
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.
Janaka de Silva, H.
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 M.
Gerstein, Hertzel C.
Giedraitis, Vilmantas
González-Villalpando, Clicerio
González-Villalpando, Maria Elena
Gordon-Larsen, Penny
Gross, Myron D.
Guare, Lindsay A.
Hackinger, Sophie
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
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
Lithgart, 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
Metspalu, Andres
Mo, Huan
Morris, Andrew D.
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
Stan
č
áková, 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
VA Million Veteran Program,
AMED GRIFIN Diabetes Initiative Japan,
Biobank Japan Project,
Penn Medicine BioBank,
eMERGE Consortium,
International Consortium for Blood Pressure (ICBP),
Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC),
Raffel, Leslie J.
Igase, Michiya
Ipp, Eli
Redline, Susan S.
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
Geoffrey Hayes, M.
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
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
Denny, Josh 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
Article Type
RegularPMCID
PMC10081410Continent/Country
NonspecificRace/Ethnicity
European AncestryHispanic Ancestry
African Ancestry
Asian Ancestry