Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

FinnGen

doi:10.1038/s41588-022-01058-3

Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

FinnGen

Research output: Contribution to journal › Article › peer-review

Abstract

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10-9), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.

Original language	English
Pages (from-to)	560-572
Number of pages	13
Journal	Nature Genetics
Volume	54
Issue number	5
DOIs	https://doi.org/10.1038/s41588-022-01058-3
Publication status	Published - 12 May 2022

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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translationFinal published version, 9.68 MBLicence: Creative Commons: Attribution (CC-BY)

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@article{9676888f1f6044ff8c6209196c2c8dee,

title = "Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation",

abstract = "We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10-9), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.",

author = "FinnGen and Anubha Mahajan and Spracklen, {Cassandra N} and Weihua Zhang and Ng, {Maggie C Y} and Petty, {Lauren E} and Hidetoshi Kitajima and Yu, {Grace Z} and Sina R{\"u}eger and Leo Speidel and Kim, {Young Jin} and Momoko Horikoshi and Mercader, {Josep M} and Daniel Taliun and Sanghoon Moon and Soo-Heon Kwak and Robertson, {Neil R} and Rayner, {Nigel W} and Marie Loh and Bong-Jo Kim and Joshua Chiou and Irene Miguel-Escalada and {Della Briotta Parolo}, Pietro and Kuang Lin and Fiona Bragg and Preuss, {Michael H} and Fumihiko Takeuchi and Jana Nano and Xiuqing Guo and Amel Lamri and Masahiro Nakatochi and Scott, {Robert A} and Jung-Jin Lee and Alicia Huerta-Chagoya and Mariaelisa Graff and Jin-Fang Chai and Parra, {Esteban J} and Jie Yao and Bielak, {Lawrence F} and Yasuharu Tabara and Yang Hai and Valgerdur Steinthorsdottir and Cook, {James P} and Mart Kals and Niels Grarup and Schmidt, {Ellen M} and Ian Pan and Tamar Sofer and Matthias Wuttke and Chloe Sarnowski and Christian Gieger and Darryl Nousome and Stella Trompet and Jirong Long and Meng Sun and Lin Tong and Wei-Min Chen and Meraj Ahmad and Raymond Noordam and Lim, {Victor J Y} and Tam, {Claudia H T} and Joo, {Yoonjung Yoonie} and Chien-Hsiun Chen and Raffield, {Laura M} and C{\'e}cile Lecoeur and Prins, {Bram Peter} and Aude Nicolas and Yanek, {Lisa R} and Guanjie Chen and Jensen, {Richard A} and Salman Tajuddin and Kabagambe, {Edmond K} and Ping An and Xiang, {Anny H} and Choi, {Hyeok Sun} and Cade, {Brian E} and Jingyi Tan and Jack Flanagan and Fernando Abaitua and Adair, {Linda S} and Adebowale Adeyemo and Aguilar-Salinas, {Carlos A} and Masato Akiyama and Anand, {Sonia S} and Alain Bertoni and Zheng Bian and Jette Bork-Jensen and Ivan Brandslund and Brody, {Jennifer A} and Brummett, {Chad M} and Buchanan, {Thomas A} and Micka{\"e}l Canouil and Chan, {Juliana C N} and Li-Ching Chang and Miao-Li Chee and Ji Chen and Shyh-Huei Chen and Yuan-Tsong Chen and Zhengming Chen and Lee-Ming Chuang and Mary Cushman and Das, {Swapan K} and {de Silva}, {H Janaka} and George Dedoussis and Latchezar Dimitrov and Doumatey, {Ayo P} and Shufa Du and Qing Duan and Kai-Uwe Eckardt and Emery, {Leslie S} and Evans, {Daniel S} and Evans, {Michele K} and Krista Fischer and Floyd, {James S} and Ian Ford and Myriam Fornage and Franco, {Oscar H} and Frayling, {Timothy M} and Freedman, {Barry I} and Christian Fuchsberger and Pauline Genter and Gerstein, {Hertzel C} and Vilmantas Giedraitis and Clicerio Gonz{\'a}lez-Villalpando and Gonz{\'a}lez-Villalpando, {Maria Elena} and Goodarzi, {Mark O} and Penny Gordon-Larsen and David Gorkin and Myron Gross and Yu Guo and Sophie Hackinger and Sohee Han and Hattersley, {Andrew T} and Christian Herder and Annie-Green Howard and Willa Hsueh and Mengna Huang and Wei Huang and Yi-Jen Hung and Hwang, {Mi Yeong} and Chii-Min Hwu and Sahoko Ichihara and Ikram, {Mohammad Arfan} and Martin Ingelsson and Islam, {Md Tariqul} and Masato Isono and Hye-Mi Jang and Farzana Jasmine and Guozhi Jiang and Jonas, {Jost B} and J{\o}rgensen, {Marit E} and Torben J{\o}rgensen and Yoichiro Kamatani and Kandeel, {Fouad R} and Anuradhani Kasturiratne and Tomohiro Katsuya and Varinderpal Kaur and Takahisa Kawaguchi and Keaton, {Jacob M} and Kho, {Abel N} and Chiea-Chuen Khor and Kibriya, {Muhammad G} and Duk-Hwan Kim and Katsuhiko Kohara and Jennifer Kriebel and Florian Kronenberg and Johanna Kuusisto and Kristi L{\"a}ll and Lange, {Leslie A} and Myung-Shik Lee and Lee, {Nanette R} and Aaron Leong and Liming Li and Yun Li and Ruifang Li-Gao and Symen Ligthart and Lindgren, {Cecilia M} and Allan Linneberg and Ching-Ti Liu and Jianjun Liu and Locke, {Adam E} and Tin Louie and Jian'an Luan and Luk, {Andrea O} and Xi Luo and Jun Lv and Valeriya Lyssenko and Vasiliki Mamakou and Mani, {K Radha} and Thomas Meitinger and Andres Metspalu and Morris, {Andrew P} and Nadkarni, {Girish N} and Nadler, {Jerry L} and Nalls, {Michael A} and Uma Nayak and Nongmaithem, {Suraj S} and Ioanna Ntalla and Yukinori Okada and Lorena Orozco and Patel, {Sanjay R} and Pereira, {Mark A} and Annette Peters and Pirie, {Fraser J} and Bianca Porneala and Gauri Prasad and Sebastian Preissl and Rasmussen-Torvik, {Laura J} and Reiner, {Alexander P} and Michael Roden and Rebecca Rohde and Kathryn Roll and Charumathi Sabanayagam and Maike Sander and Kevin Sandow and Naveed Sattar and Sebastian Sch{\"o}nherr and Claudia Schurmann and Mohammad Shahriar and Jinxiu Shi and Shin, {Dong Mun} and Daniel Shriner and Smith, {Jennifer A} and So, {Wing Yee} and Alena Stan{\v c}{\'a}kov{\'a} and Stilp, {Adrienne M} and Konstantin Strauch and Ken Suzuki and Atsushi Takahashi and Taylor, {Kent D} and Barbara Thorand and Gudmar Thorleifsson and Unnur Thorsteinsdottir and Brian Tomlinson and Torres, {Jason M} and Fuu-Jen Tsai and Jaakko Tuomilehto and Teresa Tusie-Luna and Udler, {Miriam S} and Adan Valladares-Salgado and {van Dam}, {Rob M} and {van Klinken}, {Jan B} and Rohit Varma and Marijana Vujkovic and Niels Wacher-Rodarte and Eleanor Wheeler and Whitsel, {Eric A} and Wickremasinghe, {Ananda R} and {van Dijk}, {Ko Willems} and Witte, {Daniel R} and Yajnik, {Chittaranjan S} and Ken Yamamoto and Toshimasa Yamauchi and Lo{\"i}c Yengo and Kyungheon Yoon and Canqing Yu and Jian-Min Yuan and Salim Yusuf and Liang Zhang and Wei Zheng and Raffel, {Leslie J} and Michiya Igase and Eli Ipp and Susan Redline and Cho, {Yoon Shin} and Lars Lind and Province, {Michael A} and Hanis, {Craig L} and Peyser, {Patricia A} and Erik Ingelsson and Zonderman, {Alan B} and Psaty, {Bruce M} and Ya-Xing Wang and Rotimi, {Charles N} and Becker, {Diane M} and Fumihiko Matsuda and Yongmei Liu and Eleftheria Zeggini and Mitsuhiro Yokota and Rich, {Stephen S} and Charles Kooperberg and Pankow, {James S} and Engert, {James C} and Chen, {Yii-Der Ida} and Philippe Froguel and Wilson, {James G} and Sheu, {Wayne H H} and Kardia, {Sharon L R} and Jer-Yuarn Wu and Hayes, {M Geoffrey} and Ma, {Ronald C W} and Tien-Yin Wong and Leif Groop and Mook-Kanamori, {Dennis O} and Chandak, {Giriraj R} and Collins, {Francis S} and Dwaipayan Bharadwaj and Guillaume Par{\'e} and Sale, {Mich{\`e}le M} and Habibul Ahsan and Motala, {Ayesha A} and Xiao-Ou Shu and Kyong-Soo Park and Jukema, {J Wouter} and Miguel Cruz and Roberta McKean-Cowdin and Harald Grallert and Ching-Yu Cheng and Bottinger, {Erwin P} and Abbas Dehghan and E-Shyong Tai and Jos{\'e}e Dupuis and Norihiro Kato and Markku Laakso and Anna K{\"o}ttgen and Woon-Puay Koh and Palmer, {Colin N A} and Simin Liu and Goncalo Abecasis and Kooner, {Jaspal S} and Loos, {Ruth J F} and North, {Kari E} and Haiman, {Christopher A} and Florez, {Jose C} and Danish Saleheen and Torben Hansen and Oluf Pedersen and Reedik M{\"a}gi and Claudia Langenberg and Wareham, {Nicholas J} and Shiro Maeda and Takashi Kadowaki and Juyoung Lee and Millwood, {Iona Y} and Walters, {Robin G} and Kari Stefansson and Myers, {Simon R} and Jorge Ferrer and Gaulton, {Kyle J} and Meigs, {James B} and Mohlke, {Karen L} and Gloyn, {Anna L} and Bowden, {Donald W} and Below, {Jennifer E} and Chambers, {John C} and Xueling Sim and Michael Boehnke and Rotter, {Jerome I} and McCarthy, {Mark I} and Morris, {Andrew P}",

note = "{\textcopyright} 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = may,

day = "12",

doi = "10.1038/s41588-022-01058-3",

language = "English",

volume = "54",

pages = "560--572",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "5",

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TY - JOUR

T1 - Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

AU - FinnGen

AU - Mahajan, Anubha

AU - Spracklen, Cassandra N

AU - Zhang, Weihua

AU - Ng, Maggie C Y

AU - Petty, Lauren E

AU - Kitajima, Hidetoshi

AU - Yu, Grace Z

AU - Rüeger, Sina

AU - Speidel, Leo

AU - Kim, Young Jin

AU - Horikoshi, Momoko

AU - Mercader, Josep M

AU - Taliun, Daniel

AU - Moon, Sanghoon

AU - Kwak, Soo-Heon

AU - Robertson, Neil R

AU - Rayner, Nigel W

AU - Loh, Marie

AU - Kim, Bong-Jo

AU - Chiou, Joshua

AU - Miguel-Escalada, Irene

AU - Della Briotta Parolo, Pietro

AU - Lin, Kuang

AU - Bragg, Fiona

AU - Preuss, Michael H

AU - Takeuchi, Fumihiko

AU - Nano, Jana

AU - Guo, Xiuqing

AU - Lamri, Amel

AU - Nakatochi, Masahiro

AU - Scott, Robert A

AU - Lee, Jung-Jin

AU - Huerta-Chagoya, Alicia

AU - Graff, Mariaelisa

AU - Chai, Jin-Fang

AU - Parra, Esteban J

AU - Yao, Jie

AU - Bielak, Lawrence F

AU - Tabara, Yasuharu

AU - Hai, Yang

AU - Steinthorsdottir, Valgerdur

AU - Cook, James P

AU - Kals, Mart

AU - Grarup, Niels

AU - Schmidt, Ellen M

AU - Pan, Ian

AU - Sofer, Tamar

AU - Wuttke, Matthias

AU - Sarnowski, Chloe

AU - Gieger, Christian

AU - Nousome, Darryl

AU - Trompet, Stella

AU - Long, Jirong

AU - Sun, Meng

AU - Tong, Lin

AU - Chen, Wei-Min

AU - Ahmad, Meraj

AU - Noordam, Raymond

AU - Lim, Victor J Y

AU - Tam, Claudia H T

AU - Joo, Yoonjung Yoonie

AU - Chen, Chien-Hsiun

AU - Raffield, Laura M

AU - Lecoeur, Cécile

AU - Prins, Bram Peter

AU - Nicolas, Aude

AU - Yanek, Lisa R

AU - Chen, Guanjie

AU - Jensen, Richard A

AU - Tajuddin, Salman

AU - Kabagambe, Edmond K

AU - An, Ping

AU - Xiang, Anny H

AU - Choi, Hyeok Sun

AU - Cade, Brian E

AU - Tan, Jingyi

AU - Flanagan, Jack

AU - Abaitua, Fernando

AU - Adair, Linda S

AU - Adeyemo, Adebowale

AU - Aguilar-Salinas, Carlos A

AU - Akiyama, Masato

AU - Anand, Sonia S

AU - Bertoni, Alain

AU - Bian, Zheng

AU - Bork-Jensen, Jette

AU - Brandslund, Ivan

AU - Brody, Jennifer A

AU - Brummett, Chad M

AU - Buchanan, Thomas A

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 - 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 - Fornage, Myriam

AU - Franco, Oscar H

AU - Frayling, Timothy M

AU - Freedman, Barry I

AU - Fuchsberger, Christian

AU - Genter, Pauline

AU - Gerstein, Hertzel C

AU - Giedraitis, Vilmantas

AU - González-Villalpando, Clicerio

AU - González-Villalpando, Maria Elena

AU - Goodarzi, Mark O

AU - Gordon-Larsen, Penny

AU - Gorkin, David

AU - Gross, Myron

AU - Guo, Yu

AU - Hackinger, Sophie

AU - Han, Sohee

AU - Hattersley, Andrew T

AU - Herder, Christian

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, Marit E

AU - Jørgensen, Torben

AU - Kamatani, Yoichiro

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 - Kohara, Katsuhiko

AU - Kriebel, Jennifer

AU - Kronenberg, Florian

AU - Kuusisto, Johanna

AU - Läll, Kristi

AU - Lange, Leslie A

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 - Lyssenko, Valeriya

AU - Mamakou, Vasiliki

AU - Mani, K Radha

AU - Meitinger, Thomas

AU - Metspalu, Andres

AU - Morris, Andrew P

AU - Nadkarni, Girish N

AU - Nadler, Jerry L

AU - Nalls, Michael A

AU - Nayak, Uma

AU - Nongmaithem, Suraj S

AU - Ntalla, Ioanna

AU - Okada, Yukinori

AU - Orozco, Lorena

AU - Patel, Sanjay R

AU - Pereira, Mark A

AU - Peters, Annette

AU - Pirie, Fraser J

AU - Porneala, Bianca

AU - Prasad, Gauri

AU - Preissl, Sebastian

AU - Rasmussen-Torvik, Laura J

AU - Reiner, Alexander P

AU - Roden, Michael

AU - Rohde, Rebecca

AU - Roll, Kathryn

AU - Sabanayagam, Charumathi

AU - Sander, Maike

AU - Sandow, Kevin

AU - Sattar, Naveed

AU - Schönherr, Sebastian

AU - Schurmann, Claudia

AU - Shahriar, Mohammad

AU - Shi, Jinxiu

AU - Shin, Dong Mun

AU - Shriner, Daniel

AU - Smith, Jennifer A

AU - So, Wing Yee

AU - Stančáková, Alena

AU - Stilp, Adrienne M

AU - Strauch, Konstantin

AU - Suzuki, Ken

AU - Takahashi, Atsushi

AU - Taylor, Kent D

AU - Thorand, Barbara

AU - Thorleifsson, Gudmar

AU - Thorsteinsdottir, Unnur

AU - Tomlinson, Brian

AU - Torres, Jason M

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 - Vujkovic, Marijana

AU - Wacher-Rodarte, Niels

AU - Wheeler, Eleanor

AU - Whitsel, Eric A

AU - Wickremasinghe, Ananda R

AU - van Dijk, Ko Willems

AU - Witte, Daniel R

AU - Yajnik, Chittaranjan S

AU - Yamamoto, Ken

AU - Yamauchi, Toshimasa

AU - Yengo, Loïc

AU - Yoon, Kyungheon

AU - Yu, Canqing

AU - Yuan, Jian-Min

AU - Yusuf, Salim

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 - Hanis, Craig L

AU - Peyser, Patricia A

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 - Zeggini, Eleftheria

AU - Yokota, Mitsuhiro

AU - Rich, Stephen S

AU - Kooperberg, Charles

AU - Pankow, James S

AU - Engert, James C

AU - Chen, Yii-Der Ida

AU - Froguel, Philippe

AU - Wilson, James G

AU - Sheu, Wayne H H

AU - Kardia, Sharon L R

AU - Wu, Jer-Yuarn

AU - Hayes, M Geoffrey

AU - Ma, Ronald C W

AU - Wong, Tien-Yin

AU - Groop, Leif

AU - Mook-Kanamori, Dennis O

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 - McKean-Cowdin, Roberta

AU - Grallert, Harald

AU - Cheng, Ching-Yu

AU - Bottinger, Erwin P

AU - Dehghan, Abbas

AU - Tai, E-Shyong

AU - Dupuis, Josée

AU - Kato, Norihiro

AU - Laakso, Markku

AU - Köttgen, Anna

AU - Koh, Woon-Puay

AU - Palmer, Colin N A

AU - Liu, Simin

AU - Abecasis, Goncalo

AU - Kooner, Jaspal S

AU - Loos, Ruth J F

AU - North, Kari E

AU - Haiman, Christopher A

AU - Florez, Jose C

AU - Saleheen, Danish

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Mägi, Reedik

AU - Langenberg, Claudia

AU - Wareham, Nicholas J

AU - Maeda, Shiro

AU - Kadowaki, Takashi

AU - Lee, Juyoung

AU - Millwood, Iona Y

AU - Walters, Robin G

AU - Stefansson, Kari

AU - Myers, Simon R

AU - Ferrer, Jorge

AU - Gaulton, Kyle J

AU - Meigs, James B

AU - Mohlke, Karen L

AU - Gloyn, Anna L

AU - Bowden, Donald W

AU - Below, Jennifer E

AU - Chambers, John C

AU - Sim, Xueling

AU - Boehnke, Michael

AU - Rotter, Jerome I

AU - McCarthy, Mark I

AU - Morris, Andrew P

PY - 2022/5/12

Y1 - 2022/5/12

N2 - We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10-9), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.

AB - We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10-9), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.

U2 - 10.1038/s41588-022-01058-3

DO - 10.1038/s41588-022-01058-3

M3 - Article

C2 - 35551307

VL - 54

SP - 560

EP - 572

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 5

ER -

Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

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