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Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.

ABSTRACT: 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.

SUBMITTER: Suzuki K

PROVIDER: S-EPMC10081410 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.

Suzuki Ken K Hatzikotoulas Konstantinos K Southam Lorraine L Taylor Henry J HJ Yin Xianyong X Lorenz Kim M KM Mandla Ravi R Huerta-Chagoya Alicia A Rayner Nigel W NW Bocher Ozvan O Arruda Ana Luiza de S V ALSV Sonehara Kyuto K Namba Shinichi S Lee Simon S K SSK Preuss Michael H MH Petty Lauren E LE Schroeder Philip P Vanderwerff Brett B Kals Mart M Bragg Fiona F Lin Kuang K Guo Xiuqing X Zhang Weihua W Yao Jie J Kim Young Jin YJ Graff Mariaelisa M Takeuchi Fumihiko F Nano Jana J Lamri Amel A Nakatochi Masahiro M Moon Sanghoon S Scott Robert A RA Cook James P JP Lee Jung-Jin JJ Pan Ian I Taliun Daniel D Parra Esteban J EJ Chai Jin-Fang JF Bielak Lawrence F LF Tabara Yasuharu Y Hai Yang Y Thorleifsson Gudmar G Grarup Niels N Sofer Tamar T Wuttke Matthias M Sarnowski Chloé C Gieger Christian C Nousome Darryl D Trompet Stella S Kwak Soo-Heon SH Long Jirong J Sun Meng M Tong Lin L Chen Wei-Min WM Nongmaithem Suraj S SS Noordam Raymond R Lim Victor J Y VJY Tam Claudia H T CHT Joo Yoonjung Yoonie YY Chen Chien-Hsiun CH Raffield Laura M LM Prins Bram Peter BP Nicolas Aude A Yanek Lisa R LR Chen Guanjie G Brody Jennifer A JA Kabagambe Edmond E An Ping P Xiang Anny H AH Choi Hyeok Sun HS Cade Brian E BE Tan Jingyi J Broadaway K Alaine KA Williamson Alice A Kamali Zoha Z Cui Jinrui J Adair Linda S LS Adeyemo Adebowale A Aguilar-Salinas Carlos A CA Ahluwalia Tarunveer S TS Anand Sonia S SS Bertoni Alain A Bork-Jensen Jette J Brandslund Ivan I Buchanan Thomas A TA Burant Charles F CF Butterworth Adam S AS Canouil Mickaël M Chan Juliana C N JCN Chang Li-Ching LC Chee Miao-Li ML Chen Ji J Chen Shyh-Huei SH Chen Yuan-Tsong YT Chen Zhengming Z Chuang Lee-Ming LM Cushman Mary M Danesh John J Das Swapan K SK de Silva H Janaka HJ Dedoussis George G Dimitrov Latchezar L Doumatey Ayo P AP Du Shufa S Duan Qing Q Eckardt Kai-Uwe KU Emery Leslie S LS Evans Daniel S DS Evans Michele K MK Fischer Krista K Floyd James S JS Ford Ian I Franco Oscar H OH Frayling Timothy M TM Freedman Barry I BI Genter Pauline P Gerstein Hertzel C HC Giedraitis Vilmantas V González-Villalpando Clicerio C González-Villalpando Maria Elena ME Gordon-Larsen Penny P Gross Myron M Guare Lindsay A LA Hackinger Sophie S Han Sohee S Hattersley Andrew T AT Herder Christian C Horikoshi Momoko M Howard Annie-Green AG Hsueh Willa W Huang Mengna M Huang Wei W Hung Yi-Jen YJ Hwang Mi Yeong MY Hwu Chii-Min CM Ichihara Sahoko S Ikram Mohammad Arfan MA Ingelsson Martin M Islam Md Tariqul MT Isono Masato M Jang Hye-Mi HM Jasmine Farzana F Jiang Guozhi G Jonas Jost B JB Jørgensen Torben T Kandeel Fouad R FR Kasturiratne Anuradhani A Katsuya Tomohiro T Kaur Varinderpal V Kawaguchi Takahisa T Keaton Jacob M JM Kho Abel N AN Khor Chiea-Chuen CC Kibriya Muhammad G MG Kim Duk-Hwan DH Kronenberg Florian F Kuusisto Johanna J Läll Kristi K Lange Leslie A LA Lee Kyung Min KM Lee Myung-Shik MS Lee Nanette R NR Leong Aaron A Li Liming L Li Yun Y Li-Gao Ruifang R Lithgart Symen S Lindgren Cecilia M CM Linneberg Allan A Liu Ching-Ti CT Liu Jianjun J Locke Adam E AE Louie Tin T Luan Jian'an J Luk Andrea O AO Luo Xi X Lv Jun J Lynch Julie A JA Lyssenko Valeriya V Maeda Shiro S Mamakou Vasiliki V Mansuri Sohail Rafik SR Matsuda Koichi K Meitinger Thomas T Metspalu Andres A Mo Huan H Morris Andrew D AD Nadler Jerry L JL Nalls Michael A MA Nayak Uma U Ntalla Ioanna I Okada Yukinori Y Orozco Lorena L Patel Sanjay R SR Patil Snehal S Pei Pei P Pereira Mark A MA Peters Annette A Pirie Fraser J FJ Polikowsky Hannah G HG Porneala Bianca B Prasad Gauri G Rasmussen-Torvik Laura J LJ Reiner Alexander P AP Roden Michael M Rohde Rebecca R Roll Katheryn K Sabanayagam Charumathi C Sandow Kevin K Sankareswaran Alagu A Sattar Naveed N Schönherr Sebastian S Shahriar Mohammad M Shen Botong B Shi Jinxiu J Shin Dong Mun DM Shojima Nobuhiro N Smith Jennifer A JA So Wing Yee WY Stančáková Alena A Steinthorsdottir Valgerdur V Stilp Adrienne M AM Strauch Konstantin K Taylor Kent D KD Thorand Barbara B Thorsteinsdottir Unnur U Tomlinson Brian B Tran Tam C TC Tsai Fuu-Jen FJ Tuomilehto Jaakko J Tusie-Luna Teresa T Udler Miriam S MS Valladares-Salgado Adan A van Dam Rob M RM van Klinken Jan B JB Varma Rohit R Wacher-Rodarte Niels N Wheeler Eleanor E Wickremasinghe Ananda R AR van Dijk Ko Willems KW Witte Daniel R DR Yajnik Chittaranjan S CS Yamamoto Ken K Yamamoto Kenichi K Yoon Kyungheon K Yu Canqing C Yuan Jian-Min JM Yusuf Salim S Zawistowski Matthew M Zhang Liang L Zheng Wei W Raffel Leslie J LJ Igase Michiya M Ipp Eli E Redline Susan S Cho Yoon Shin YS Lind Lars L Province Michael A MA Fornage Myriam M Hanis Craig L CL Ingelsson Erik E Zonderman Alan B AB Psaty Bruce M BM Wang Ya-Xing YX Rotimi Charles N CN Becker Diane M DM Matsuda Fumihiko F Liu Yongmei Y Yokota Mitsuhiro M Kardia Sharon L R SLR Peyser Patricia A PA Pankow James S JS Engert James C JC Bonnefond Amélie A Froguel Philippe P Wilson James G JG Sheu Wayne H H WHH Wu Jer-Yuarn JY Hayes M Geoffrey MG Ma Ronald C W RCW Wong Tien-Yin TY Mook-Kanamori Dennis O DO Tuomi Tiinamaija T Chandak Giriraj R GR Collins Francis S FS Bharadwaj Dwaipayan D Paré Guillaume G Sale Michèle M MM Ahsan Habibul H Motala Ayesha A AA Shu Xiao-Ou XO Park Kyong-Soo KS Jukema J Wouter JW Cruz Miguel M Chen Yii-Der Ida YI Rich Stephen S SS McKean-Cowdin Roberta R Grallert Harald H Cheng Ching-Yu CY Ghanbari Mohsen M Tai E-Shyong ES Dupuis Josee J Kato Norihiro N Laakso Markku M Köttgen Anna A Koh Woon-Puay WP Bowden Donald W DW Palmer Colin N A CNA Kooner Jaspal S JS Kooperberg Charles C Liu Simin S North Kari E KE Saleheen Danish D Hansen Torben T Pedersen Oluf O Pedersen Oluf O Wareham Nicholas J NJ Lee Juyoung J Kim Bong-Jo BJ Millwood Iona Y IY Walters Robin G RG Stefansson Kari K Goodarzi Mark O MO Mohlke Karen L KL Langenberg Claudia C Haiman Christopher A CA Loos Ruth J F RJF Florez Jose C JC Rader Daniel J DJ Ritchie Marylyn D MD Zöllner Sebastian S Mägi Reedik R Denny Joshua C JC Yamauchi Toshimasa T Kadowaki Takashi T Chambers John C JC Ng Maggie C Y MCY Sim Xueling X Below Jennifer E JE Tsao Philip S PS Chang Kyong-Mi KM McCarthy Mark I MI Meigs James B JB Mahajan Anubha A Spracklen Cassandra N CN Mercader Josep M JM Boehnke Michael M Rotter Jerome I JI Vujkovic Marijana M Voight Benjamin F BF Morris Andrew P AP Zeggini Eleftheria E

medRxiv : the preprint server for health sciences 20230331

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 (<i>P</i><5×10<sup>-8</sup>) that map to 611 loci, of which 145 loci are previously unr ...[more]

PMID: 37034649

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Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.

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Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.

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Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.

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Multi-ancestry genome-wide study in &gt;2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.

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Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.