Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

Anubha Mahajan; Min Jin Go; Weihua Zhang; Jennifer E. Below; Kyle J. Gaulton; Teresa Ferreira; Momoko Horikoshi; Andrew D. Johnson; Maggie C. Y. Ng; Inga Prokopenko; Danish Saleheen; Xu Wang; Eleftheria Zeggini; Goncalo R. Abecasis; Linda S. Adair; Peter Almgren; Mustafa Atalay; Tin Aung; Damiano Baldassarre; Beverley Balkau; Yuqian Bao; Anthony H. Barnett; Ines Barroso; Abdul Basit; Latonya F. Been; John Beilby; Graeme I. Bell; Rafn Benediktsson; Richard N. Bergman; Bernhard O. Boehm; Eric Boerwinkle; Lori L. Bonnycastle; Noel Burtt; Qiuyin Cai; Harry Campbell; Jason Carey; Stephane Cauchi; Mark Caulfield; Juliana C. N. Chan; Li-Ching Chang; Tien-Jyun Chang; Yi-Cheng Chang; Guillaume Charpentier; Chien-Hsiun Chen; Han Chen; Yuan-Tsong Chen; Kee-Seng Chia; Manickam Chidambaram; Elin Grundberg; Kerrin S. Small; DIAbet Genetics Replication & Meta; Asian Genetic Epidemiology Network; South Asian Type Diabet SAT2D Cons; Mexican Amer Type 2 Diabet MAT2D C; Type 2 Diabet Genetic Exploration

doi:10.1038/ng.2897

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

Anubha Mahajan, Min Jin Go, Weihua Zhang, Jennifer E. Below, Kyle J. Gaulton, Teresa Ferreira, Momoko Horikoshi, Andrew D. Johnson, Maggie C. Y. Ng, Inga Prokopenko, Danish Saleheen, Xu Wang, Eleftheria Zeggini, Goncalo R. Abecasis, Linda S. Adair, Peter Almgren, Mustafa Atalay, Tin Aung, Damiano Baldassarre, Beverley BalkauYuqian Bao, Anthony H. Barnett, Ines Barroso, Abdul Basit, Latonya F. Been, John Beilby, Graeme I. Bell, Rafn Benediktsson, Richard N. Bergman, Bernhard O. Boehm, Eric Boerwinkle, Lori L. Bonnycastle, Noel Burtt, Qiuyin Cai, Harry Campbell, Jason Carey, Stephane Cauchi, Mark Caulfield, Juliana C. N. Chan, Li-Ching Chang, Tien-Jyun Chang, Yi-Cheng Chang, Guillaume Charpentier, Chien-Hsiun Chen, Han Chen, Yuan-Tsong Chen, Kee-Seng Chia, Manickam Chidambaram, Elin Grundberg, Kerrin S. Small, DIAbet Genetics Replication & Meta, Asian Genetic Epidemiology Network, South Asian Type Diabet SAT2D Cons, Mexican Amer Type 2 Diabet MAT2D C, Type 2 Diabet Genetic Exploration

Twin Research & Genetic Epidemiology

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

834 Citations (Scopus)

Abstract

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

Original language	English
Pages (from-to)	234-+
Number of pages	13
Journal	Nature Genetics
Volume	46
Issue number	3
DOIs	https://doi.org/10.1038/ng.2897
Publication status	Published - Mar 2014

Keywords

SCALE ASSOCIATION ANALYSIS
TRANSETHNIC METAANALYSIS
GLUCOSE-HOMEOSTASIS
LOCI
VARIANTS
POPULATIONS
MAP
INDIVIDUALS
IMPUTATION
CHROMATIN

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.2897

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Mahajan, A., Go, M. J., Zhang, W., Below, J. E., Gaulton, K. J., Ferreira, T., Horikoshi, M., Johnson, A. D., Ng, M. C. Y., Prokopenko, I., Saleheen, D., Wang, X., Zeggini, E., Abecasis, G. R., Adair, L. S., Almgren, P., Atalay, M., Aung, T., Baldassarre, D., ... Type 2 Diabet Genetic Exploration (2014). Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nature Genetics, 46(3), 234-+. https://doi.org/10.1038/ng.2897

@article{8d12f3ea09c14006ad9e885f46c71f86,

title = "Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility",

abstract = "To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.",

keywords = "SCALE ASSOCIATION ANALYSIS, TRANSETHNIC METAANALYSIS, GLUCOSE-HOMEOSTASIS, LOCI, VARIANTS, POPULATIONS, MAP, INDIVIDUALS, IMPUTATION, CHROMATIN",

author = "Anubha Mahajan and Go, {Min Jin} and Weihua Zhang and Below, {Jennifer E.} and Gaulton, {Kyle J.} and Teresa Ferreira and Momoko Horikoshi and Johnson, {Andrew D.} and Ng, {Maggie C. Y.} and Inga Prokopenko and Danish Saleheen and Xu Wang and Eleftheria Zeggini and Abecasis, {Goncalo R.} and Adair, {Linda S.} and Peter Almgren and Mustafa Atalay and Tin Aung and Damiano Baldassarre and Beverley Balkau and Yuqian Bao and Barnett, {Anthony H.} and Ines Barroso and Abdul Basit and Been, {Latonya F.} and John Beilby and Bell, {Graeme I.} and Rafn Benediktsson and Bergman, {Richard N.} and Boehm, {Bernhard O.} and Eric Boerwinkle and Bonnycastle, {Lori L.} and Noel Burtt and Qiuyin Cai and Harry Campbell and Jason Carey and Stephane Cauchi and Mark Caulfield and Chan, {Juliana C. N.} and Li-Ching Chang and Tien-Jyun Chang and Yi-Cheng Chang and Guillaume Charpentier and Chien-Hsiun Chen and Han Chen and Yuan-Tsong Chen and Kee-Seng Chia and Manickam Chidambaram and Elin Grundberg and Small, {Kerrin S.} and {DIAbet Genetics Replication & Meta} and {Asian Genetic Epidemiology Network} and {South Asian Type Diabet SAT2D Cons} and {Mexican Amer Type 2 Diabet MAT2D C} and {Type 2 Diabet Genetic Exploration}",

year = "2014",

month = mar,

doi = "10.1038/ng.2897",

language = "English",

volume = "46",

pages = "234--+",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "3",

}

Mahajan, A, Go, MJ, Zhang, W, Below, JE, Gaulton, KJ, Ferreira, T, Horikoshi, M, Johnson, AD, Ng, MCY, Prokopenko, I, Saleheen, D, Wang, X, Zeggini, E, Abecasis, GR, Adair, LS, Almgren, P, Atalay, M, Aung, T, Baldassarre, D, Balkau, B, Bao, Y, Barnett, AH, Barroso, I, Basit, A, Been, LF, Beilby, J, Bell, GI, Benediktsson, R, Bergman, RN, Boehm, BO, Boerwinkle, E, Bonnycastle, LL, Burtt, N, Cai, Q, Campbell, H, Carey, J, Cauchi, S, Caulfield, M, Chan, JCN, Chang, L-C, Chang, T-J, Chang, Y-C, Charpentier, G, Chen, C-H, Chen, H, Chen, Y-T, Chia, K-S, Chidambaram, M, Grundberg, E , Small, KS, DIAbet Genetics Replication & Meta, Asian Genetic Epidemiology Network, South Asian Type Diabet SAT2D Cons, Mexican Amer Type 2 Diabet MAT2D C & Type 2 Diabet Genetic Exploration 2014, 'Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility', Nature Genetics, vol. 46, no. 3, pp. 234-+. https://doi.org/10.1038/ng.2897

TY - JOUR

T1 - Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

AU - Mahajan, Anubha

AU - Go, Min Jin

AU - Zhang, Weihua

AU - Below, Jennifer E.

AU - Gaulton, Kyle J.

AU - Ferreira, Teresa

AU - Horikoshi, Momoko

AU - Johnson, Andrew D.

AU - Ng, Maggie C. Y.

AU - Prokopenko, Inga

AU - Saleheen, Danish

AU - Wang, Xu

AU - Zeggini, Eleftheria

AU - Abecasis, Goncalo R.

AU - Adair, Linda S.

AU - Almgren, Peter

AU - Atalay, Mustafa

AU - Aung, Tin

AU - Baldassarre, Damiano

AU - Balkau, Beverley

AU - Bao, Yuqian

AU - Barnett, Anthony H.

AU - Barroso, Ines

AU - Basit, Abdul

AU - Been, Latonya F.

AU - Beilby, John

AU - Bell, Graeme I.

AU - Benediktsson, Rafn

AU - Bergman, Richard N.

AU - Boehm, Bernhard O.

AU - Boerwinkle, Eric

AU - Bonnycastle, Lori L.

AU - Burtt, Noel

AU - Cai, Qiuyin

AU - Campbell, Harry

AU - Carey, Jason

AU - Cauchi, Stephane

AU - Caulfield, Mark

AU - Chan, Juliana C. N.

AU - Chang, Li-Ching

AU - Chang, Tien-Jyun

AU - Chang, Yi-Cheng

AU - Charpentier, Guillaume

AU - Chen, Chien-Hsiun

AU - Chen, Han

AU - Chen, Yuan-Tsong

AU - Chia, Kee-Seng

AU - Chidambaram, Manickam

AU - Grundberg, Elin

AU - Small, Kerrin S.

AU - DIAbet Genetics Replication & Meta

AU - Asian Genetic Epidemiology Network

AU - South Asian Type Diabet SAT2D Cons

AU - Mexican Amer Type 2 Diabet MAT2D C

AU - Type 2 Diabet Genetic Exploration

PY - 2014/3

Y1 - 2014/3

N2 - To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

AB - To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

KW - SCALE ASSOCIATION ANALYSIS

KW - TRANSETHNIC METAANALYSIS

KW - GLUCOSE-HOMEOSTASIS

KW - LOCI

KW - VARIANTS

KW - POPULATIONS

KW - MAP

KW - INDIVIDUALS

KW - IMPUTATION

KW - CHROMATIN

U2 - 10.1038/ng.2897

DO - 10.1038/ng.2897

M3 - Article

SN - 1061-4036

VL - 46

SP - 234-+

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

Abstract

Keywords

UN SDGs

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