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

Mahajan, A.; M. J., G.; Zhang, W.; Below, J.E.; Gaulton, K.J.; Ferreira, T.; Horikoshi, M.; Johnson, A.D.; M. C., N.; Prokopenko, I.; Saleheen, D.; Wang, X.; Zeggini, E.; Abecasis, G.R.; Adair, L.S.; Almgren, P.; Atalay, M.; Aung, T.; Baldassarre, D.; Balkau, B.; Bao, Y.; Barnett, A.H.; Barroso, I.; Basit, A.; Been, L.F.; Beilby, J.; Bell, G.I.; Benediktsson, R.; Bergman, R.N.; Boehm, B.O.; Boerwinkle, E.; Bonnycastle, L.L.; Burtt, N.; Cai, Q.; Campbell, H.; Carey, J.; Cauchi, S.; Caulfield, M.; Chan, J.C.; Chang, L.C.; Chang, T.J.; Chang, Y.C.; Charpentier, G.; Chen, C.H.; Chen, H.; Chen, Y.T.; Chia, K.S.; Chidambaram, M.; Chines, P.S.; Cho, N.H.; Cho, Y.M.; Chuang, L.M.; Collins, F.S.; Cornelis, M.C.; Couper, D.J.; Crenshaw, A.T.; van Dam, R.M.; Danesh, J.; Das, D.; de Faire, U.; Dedoussis, G.; Deloukas, P.; Dimas, A.S.; Dina, C.; Doney, A.S.; Donnelly, P.J.; Dorkhan, M.; van Duijn, C.; Dupuis, J.; Edkins, S.; Elliott, P.; Emilsson, V.; Erbel, R.; Eriksson, J.G.; Escobedo, J.; Esko, T.; Eury, E.; Florez, J.C.; Fontanillas, P.; Forouhi, N.G.; Forsen, T.; Fox, C.; Fraser, R.M.; Frayling, T.M.; Froguel, P.; Frossard, P.; Gao, Y.; Gertow, K.; Gieger, C.; Gigante, B.; Grallert, H.; Grant, G.B.; Groop, L.C.; Groves, C.J.; Grundberg, E.; Guiducci, C.; Hamsten, A.; Han, B.G.; Hara, K.; Hassanali, N.; Hattersley, A.T.; Hayward, C.; Hedman, A.K.; Herder, C.; Hofman, A.; Holmen, O.L.; Hovingh, K.; Hreidarsson, A.B.; Hu, C.; F. B., H.; Hui, J.; Humphries, S.E.; Hunt, S.E.; Hunter, D.J.; Hveem, K.; Hydrie, Z.I.; Ikegami, H.; Illig, T.; Ingelsson, E.; Islam, M.; Isomaa, B.; Jackson, A.U.; Jafar, T.; James, A.; Jia, W.; Jöckel, K.H.; Jonsson, A.; Jowett, J.B.; Kadowaki, T.; Kang, H.M.; Kanoni, S.; Kao, W.H.; Kathiresan, S.; Kato, N.; Katulanda, P.; Keinanen Kiukaanniemi, S.M.; Kelly, A.M.; Khan, H.; Khaw, K.T.; Khor, C.C.; Kim, H.L.; Kim, S.; Kim, Y.J.; Kinnunen, L.; Klopp, N.; Kong, A.; Korpi Hyövälti, E.; Kowlessur, S.; Kraft, P.; Kravic, J.; Kristensen, M.M.; Krithika, S.; Kumar, A.; Kumate, J.; Kuusisto, J.; Kwak, S.H.; Laakso, M.; Lagou, V.; Lakka, T.A.; Langenberg, C.; Langford, C.; Lawrence, R.; Leander, K.; Lee, J.M.; Lee, N.R.; Li, M.; Li, X.; Li, Y.; Liang, J.; Liju, S.; Lim, W.Y.; Lind, L.; Lindgren, C.M.; Lindholm, E.; Liu, C.T.; Liu, J.J.; Lobbens, S.; Long, J.; Loos, R.J.; Lu, W.; Luan, J.; Lyssenko, V.; R. C., M.; Maeda, S.; Mägi, R.; Männistö, S.; Matthews, D.R.; Meigs, J.B.; Melander, O.; Metspalu, A.; Meyer, J.; Mirza, G.; Mihailov, E.; Moebus, S.; Mohan, V.; Mohlke, K.L.; Morris, A.D.; Mühleisen, T.W.; Müller Nurasyid, M.; Musk, B.; Nakamura, J.; Nakashima, E.; Navarro, P.; P. K., N.; Nica, A.C.; Nilsson, P.M.; Njølstad, I.; Nöthen, M.M.; Ohnaka, K.; Ong, T.H.; Owen, K.R.; Palmer, C.N.; Pankow, J.S.; Park, K.S.; Parkin, M.; Pechlivanis, S.; Pedersen, N.L.; Peltonen, L.; Perry, J.R.; Peters, A.; Pinidiyapathirage, J.M.; Platou, C.G.; Potter, S.; Price, J.F.; Qi, L.; Radha, V.; Rallidis, L.; Rasheed, A.; Rathmann, W.; Rauramaa, R.; Raychaudhuri, S.; Rayner, N.W.; Rees, S.D.; Rehnberg, E.; Ripatti, S.; Robertson, N.; Roden, M.; Rossin, E.J.; Rudan, I.; Rybin, D.; Saaristo, T.E.; Salomaa, V.; Saltevo, J.; Samuel, M.; Sanghera, D.K.; Saramies, J.; Scott, J.; Scott, L.J.; Scott, R.A.; Segrè, A.V.; Sehmi, J.; Sennblad, B.; Shah, N.; Shah, S.; Shera, A.S.; Shu, X.O.; Shuldiner, A.R.; Sigurðsson, G.; Sijbrands, E.; Silveira, A.; Sim, X.; Sivapalaratnam, S.; Small, K.S.; W. Y., S.; Stančáková, A.; Stefansson, K.; Steinbach, G.; Steinthorsdottir, V.; Stirrups, K.; Strawbridge, R.J.; Stringham, H.M.; Sun, Q.; Suo, C.; Syvänen, A.C.; Takayanagi, R.; Takeuchi, F.; Tay, W.T.; Teslovich, T.M.; Thorand, B.; Thorleifsson, G.; Thorsteinsdottir, U.; Tikkanen, E.; Trakalo, J.; Tremoli, E.; Trip, M.D.; Tsai, F.J.; Tuomi, T.; Tuomilehto, J.; Uitterlinden, A.G.; Valladares Salgado, A.; Vedantam, S.; Veglia, F.; Voight, B.F.; Wang, C.; Wareham, N.J.; Wennauer, R.; Wickremasinghe, A.R.; Wilsgaard, T.; Wilson, J.F.; Wiltshire, S.; Winckler, W.; Wong, T.Y.; Wood, A.R.; J. Y., W.; Wu, Y.; Yamamoto, K.; Yamauchi, T.; Yang, M.; Yengo, L.; Yokota, M.; Young, R.; Zabaneh, D.; Zhang, F.; Zhang, R.; Zheng, W.; Zimmet, P.Z.; Altshuler, D.; Bowden, D.W.; Cho, Y.S.; Cox, N.J.; Cruz, M.; Hanis, C.L.; Kooner, J.; Lee, J.Y.; Seielstad, M.; Teo, Y.Y.; Boehnke, M.; Parra, E.J.; Chambers, J.C.; Tai, E.S.; Mccarthy, M.I.; Morris, A.P.

doi:10.1038/ng.2897

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.

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility / A. Mahajan, M.J. Go, W. Zhang, J.E. Below, K.J. Gaulton, T. Ferreira, M. Horikoshi, A.D. Johnson, M.C. Ng, I. Prokopenko, D. Saleheen, X. Wang, E. Zeggini, G.R. Abecasis, L.S. Adair, P. Almgren, M. Atalay, T. Aung, D. Baldassarre, B. Balkau, Y. Bao, A.H. Barnett, I. Barroso, A. Basit, L.F. Been, J. Beilby, G.I. Bell, R. Benediktsson, R.N. Bergman, B.O. Boehm, E. Boerwinkle, L.L. Bonnycastle, N. Burtt, Q. Cai, H. Campbell, J. Carey, S. Cauchi, M. Caulfield, J.C. Chan, L.C. Chang, T.J. Chang, Y.C. Chang, G. Charpentier, C.H. Chen, H. Chen, Y.T. Chen, K.S. Chia, M. Chidambaram, P.S. Chines, N.H. Cho, Y.M. Cho, L.M. Chuang, F.S. Collins, M.C. Cornelis, D.J. Couper, A.T. Crenshaw, R.M. van Dam, J. Danesh, D. Das, U. de Faire, G. Dedoussis, P. Deloukas, A.S. Dimas, C. Dina, A.S. Doney, P.J. Donnelly, M. Dorkhan, C. van Duijn, J. Dupuis, S. Edkins, P. Elliott, V. Emilsson, R. Erbel, J.G. Eriksson, J. Escobedo, T. Esko, E. Eury, J.C. Florez, P. Fontanillas, N.G. Forouhi, T. Forsen, C. Fox, R.M. Fraser, T.M. Frayling, P. Froguel, P. Frossard, Y. Gao, K. Gertow, C. Gieger, B. Gigante, H. Grallert, G.B. Grant, L.C. Groop, C.J. Groves, E. Grundberg, C. Guiducci, A. Hamsten, B.G. Han, K. Hara, N. Hassanali, A.T. Hattersley, C. Hayward, A.K. Hedman, C. Herder, A. Hofman, O.L. Holmen, K. Hovingh, A.B. Hreidarsson, C. Hu, F.B. Hu, J. Hui, S.E. Humphries, S.E. Hunt, D.J. Hunter, K. Hveem, Z.I. Hydrie, H. Ikegami, T. Illig, E. Ingelsson, M. Islam, B. Isomaa, A.U. Jackson, T. Jafar, A. James, W. Jia, K.H. Jöckel, A. Jonsson, J.B. Jowett, T. Kadowaki, H.M. Kang, S. Kanoni, W.H. Kao, S. Kathiresan, N. Kato, P. Katulanda, S.M. Keinanen-Kiukaanniemi, A.M. Kelly, H. Khan, K.T. Khaw, C.C. Khor, H.L. Kim, S. Kim, Y.J. Kim, L. Kinnunen, N. Klopp, A. Kong, E. Korpi-Hyövälti, S. Kowlessur, P. Kraft, J. Kravic, M.M. Kristensen, S. Krithika, A. Kumar, J. Kumate, J. Kuusisto, S.H. Kwak, M. Laakso, V. Lagou, T.A. Lakka, C. Langenberg, C. Langford, R. Lawrence, K. Leander, J.M. Lee, N.R. Lee, M. Li, X. Li, Y. Li, J. Liang, S. Liju, W.Y. Lim, L. Lind, C.M. Lindgren, E. Lindholm, C.T. Liu, J.J. Liu, S. Lobbens, J. Long, R.J. Loos, W. Lu, J. Luan, V. Lyssenko, R.C. Ma, S. Maeda, R. Mägi, S. Männistö, D.R. Matthews, J.B. Meigs, O. Melander, A. Metspalu, J. Meyer, G. Mirza, E. Mihailov, S. Moebus, V. Mohan, K.L. Mohlke, A.D. Morris, T.W. Mühleisen, M. Müller-Nurasyid, B. Musk, J. Nakamura, E. Nakashima, P. Navarro, P.K. Ng, A.C. Nica, P.M. Nilsson, I. Njølstad, M.M. Nöthen, K. Ohnaka, T.H. Ong, K.R. Owen, C.N. Palmer, J.S. Pankow, K.S. Park, M. Parkin, S. Pechlivanis, N.L. Pedersen, L. Peltonen, J.R. Perry, A. Peters, J.M. Pinidiyapathirage, C.G. Platou, S. Potter, J.F. Price, L. Qi, V. Radha, L. Rallidis, A. Rasheed, W. Rathmann, R. Rauramaa, S. Raychaudhuri, N.W. Rayner, S.D. Rees, E. Rehnberg, S. Ripatti, N. Robertson, M. Roden, E.J. Rossin, I. Rudan, D. Rybin, T.E. Saaristo, V. Salomaa, J. Saltevo, M. Samuel, D.K. Sanghera, J. Saramies, J. Scott, L.J. Scott, R.A. Scott, A.V. Segrè, J. Sehmi, B. Sennblad, N. Shah, S. Shah, A.S. Shera, X.O. Shu, A.R. Shuldiner, G. Sigurðsson, E. Sijbrands, A. Silveira, X. Sim, S. Sivapalaratnam, K.S. Small, W.Y. So, A. Stančáková, K. Stefansson, G. Steinbach, V. Steinthorsdottir, K. Stirrups, R.J. Strawbridge, H.M. Stringham, Q. Sun, C. Suo, A.C. Syvänen, R. Takayanagi, F. Takeuchi, W.T. Tay, T.M. Teslovich, B. Thorand, G. Thorleifsson, U. Thorsteinsdottir, E. Tikkanen, J. Trakalo, E. Tremoli, M.D. Trip, F.J. Tsai, T. Tuomi, J. Tuomilehto, A.G. Uitterlinden, A. Valladares-Salgado, S. Vedantam, F. Veglia, B.F. Voight, C. Wang, N.J. Wareham, R. Wennauer, A.R. Wickremasinghe, T. Wilsgaard, J.F. Wilson, S. Wiltshire, W. Winckler, T.Y. Wong, A.R. Wood, J.Y. Wu, Y. Wu, K. Yamamoto, T. Yamauchi, M. Yang, L. Yengo, M. Yokota, R. Young, D. Zabaneh, F. Zhang, R. Zhang, W. Zheng, P.Z. Zimmet, D. Altshuler, D.W. Bowden, Y.S. Cho, N.J. Cox, M. Cruz, C.L. Hanis, J. Kooner, J.Y. Lee, M. Seielstad, Y.Y. Teo, M. Boehnke, E.J. Parra, J.C. Chambers, E.S. Tai, M.I. McCarthy, A.P. Morris.. - In: NATURE GENETICS. - ISSN 1061-4036. - 46:3(2014 Feb 09), pp. 234-244. [10.1038/ng.2897]

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

A. Mahajan;M. J. Go;W. Zhang;J. E. Below;K. J. Gaulton;T. Ferreira;M. Horikoshi;A. D. Johnson;M. C. Ng;I. Prokopenko;D. Saleheen;X. Wang;E. Zeggini;G. R. Abecasis;L. S. Adair;P. Almgren;M. Atalay;T. Aung;D. Baldassarre;B. Balkau;Y. Bao;A. H. Barnett;I. Barroso;A. Basit;L. F. Been;J. Beilby;G. I. Bell;R. Benediktsson;R. N. Bergman;B. O. Boehm;E. Boerwinkle;L. L. Bonnycastle;N. Burtt;Q. Cai;H. Campbell;J. Carey;S. Cauchi;M. Caulfield;J. C. Chan;L. C. Chang;T. J. Chang;Y. C. Chang;G. Charpentier;C. H. Chen;H. Chen;Y. T. Chen;K. S. Chia;M. Chidambaram;P. S. Chines;N. H. Cho;Y. M. Cho;L. M. Chuang;F. S. Collins;M. C. Cornelis;D. J. Couper;A. T. Crenshaw;R. M. van Dam;J. Danesh;D. Das;U. de Faire;G. Dedoussis;P. Deloukas;A. S. Dimas;C. Dina;A. S. Doney;P. J. Donnelly;M. Dorkhan;C. van Duijn;J. Dupuis;S. Edkins;P. Elliott;V. Emilsson;R. Erbel;J. G. Eriksson;J. Escobedo;T. Esko;E. Eury;J. C. Florez;P. Fontanillas;N. G. Forouhi;T. Forsen;C. Fox;R. M. Fraser;T. M. Frayling;P. Froguel;P. Frossard;Y. Gao;K. Gertow;C. Gieger;B. Gigante;H. Grallert;G. B. Grant;L. C. Groop;C. J. Groves;E. Grundberg;C. Guiducci;A. Hamsten;B. G. Han;K. Hara;N. Hassanali;A. T. Hattersley;C. Hayward;A. K. Hedman;C. Herder;A. Hofman;O. L. Holmen;K. Hovingh;A. B. Hreidarsson;C. Hu;F. B. Hu;J. Hui;S. E. Humphries;S. E. Hunt;D. J. Hunter;K. Hveem;Z. I. Hydrie;H. Ikegami;T. Illig;E. Ingelsson;M. Islam;B. Isomaa;A. U. Jackson;T. Jafar;A. James;W. Jia;K. H. Jöckel;A. Jonsson;J. B. Jowett;T. Kadowaki;H. M. Kang;S. Kanoni;W. H. Kao;S. Kathiresan;N. Kato;P. Katulanda;S. M. Keinanen Kiukaanniemi;A. M. Kelly;H. Khan;K. T. Khaw;C. C. Khor;H. L. Kim;S. Kim;Y. J. Kim;L. Kinnunen;N. Klopp;A. Kong;E. Korpi Hyövälti;S. Kowlessur;P. Kraft;J. Kravic;M. M. Kristensen;S. Krithika;A. Kumar;J. Kumate;J. Kuusisto;S. H. Kwak;M. Laakso;V. Lagou;T. A. Lakka;C. Langenberg;C. Langford;R. Lawrence;K. Leander;J. M. Lee;N. R. Lee;M. Li;X. Li;Y. Li;J. Liang;S. Liju;W. Y. Lim;L. Lind;C. M. Lindgren;E. Lindholm;C. T. Liu;J. J. Liu;S. Lobbens;J. Long;R. J. Loos;W. Lu;J. Luan;V. Lyssenko;R. C. Ma;S. Maeda;R. Mägi;S. Männistö;D. R. Matthews;J. B. Meigs;O. Melander;A. Metspalu;J. Meyer;G. Mirza;E. Mihailov;S. Moebus;V. Mohan;K. L. Mohlke;A. D. Morris;T. W. Mühleisen;M. Müller Nurasyid;B. Musk;J. Nakamura;E. Nakashima;P. Navarro;P. K. Ng;A. C. Nica;P. M. Nilsson;I. Njølstad;M. M. Nöthen;K. Ohnaka;T. H. Ong;K. R. Owen;C. N. Palmer;J. S. Pankow;K. S. Park;M. Parkin;S. Pechlivanis;N. L. Pedersen;L. Peltonen;J. R. Perry;A. Peters;J. M. Pinidiyapathirage;C. G. Platou;S. Potter;J. F. Price;L. Qi;V. Radha;L. Rallidis;A. Rasheed;W. Rathmann;R. Rauramaa;S. Raychaudhuri;N. W. Rayner;S. D. Rees;E. Rehnberg;S. Ripatti;N. Robertson;M. Roden;E. J. Rossin;I. Rudan;D. Rybin;T. E. Saaristo;V. Salomaa;J. Saltevo;M. Samuel;D. K. Sanghera;J. Saramies;J. Scott;L. J. Scott;R. A. Scott;A. V. Segrè;J. Sehmi;B. Sennblad;N. Shah;S. Shah;A. S. Shera;X. O. Shu;A. R. Shuldiner;G. Sigurðsson;E. Sijbrands;A. Silveira;X. Sim;S. Sivapalaratnam;K. S. Small;W. Y. So;A. Stančáková;K. Stefansson;G. Steinbach;V. Steinthorsdottir;K. Stirrups;R. J. Strawbridge;H. M. Stringham;Q. Sun;C. Suo;A. C. Syvänen;R. Takayanagi;F. Takeuchi;W. T. Tay;T. M. Teslovich;B. Thorand;G. Thorleifsson;U. Thorsteinsdottir;E. Tikkanen;J. Trakalo;E. Tremoli;M. D. Trip;F. J. Tsai;T. Tuomi;J. Tuomilehto;A. G. Uitterlinden;A. Valladares Salgado;S. Vedantam;F. Veglia;B. F. Voight;C. Wang;N. J. Wareham;R. Wennauer;A. R. Wickremasinghe;T. Wilsgaard;J. F. Wilson;S. Wiltshire;W. Winckler;T. Y. Wong;A. R. Wood;J. Y. Wu;Y. Wu;K. Yamamoto;T. Yamauchi;M. Yang;L. Yengo;M. Yokota;R. Young;D. Zabaneh;F. Zhang;R. Zhang;W. Zheng;P. Z. Zimmet;D. Altshuler;D. W. Bowden;Y. S. Cho;N. J. Cox;M. Cruz;C. L. Hanis;J. Kooner;J. Y. Lee;M. Seielstad;Y. Y. Teo;M. Boehnke;E. J. Parra;J. C. Chambers;E. S. Tai;M. I. McCarthy;A. P. Morris

2014

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.

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			Settore BIO/14 - Farmacologia
		
	Data di pubblicazione
	
			9-feb-2014
		
	Rivista in ANCE
	
			NATURE GENETICS
		
	DOI
	
			https://dx.doi.org/10.1038/ng.2897
		
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			01 - Articolo su periodico

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