Browsing by Author "Chen, C.H."

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Genetic drivers of heterogeneity in type 2 diabetes pathophysiology
(Nature Publishing Group, 2024) Suzuki, K.; Hatzikotoulas, K.; Southam, L.; Taylor, H.J.; Yin, X.; Lorenz, K.M.; Mandla, R.; Huerta-Chagoya, A.; Melloni, G.E.M.; Kanoni, S.; Rayner, N.W.; Bocher, O.; Arruda, A.L.; Sonehara, K.; Namba, S.; Namba, S.S.K.; Preuss, M.H.; Petty, L.E.; Schroeder, P.; Vanderwerff, B.; Kals, M.; Bragg. F.; Lin, K.; Guo, X.; Zhang, W.; Yao, J.; Kim, Y.J.; Graff, M.; Takeuchi, F.; Nano, J.; Lamri, A.; Nakatochi, M.; Moon, S.; Scott, R.A.; Cook, J.P.; Lee, J.J.; Pan, I.; Taliun, D.; Parra, E.J.; Chai. J.F.; Bielak, L.F.; Tabara, Y.; Hai, Y.; Thorleifsson, G.; Grarup, N.; Sofer, T.; Wuttke, M.; Sarnowski, C.; Gieger, C.; Nousome, D.; Trompet, S.; Kwak, S.H.; Long, J.; Sun, M.; Tong, L.; Chen, W.M.; Nongmaithem, S.S.; Noordam, R.; Lim, V.J.Y.; Tam, C.H.T.; Joo, Y.Y.; Chen, C.H.; Raffield, L.M.; Prins, B.P.; Nicolas, A.; Yanek, L.R.; Chen, G.; Brody, J.A.; Kabagambe, E.; An, P.; Xiang, A.H.; Choi, H.S.; Cade, B.E.; Tan, J.; Broadaway, K.A.; Williamson, A.; Kamali, Z.; Cui, J.; Thangam, M.; Adair, L.S.; Adeyemo, A.; Aguilar-Salinas, C.A.; Ahluwalia, T.S.; Anand, S.S.; Bertoni, A.; Bork-Jensen, J.; Brandslund, I.; Buchanan, T.A.; Burant, C.F.; Butterworth, A.S.; Canouil, M.; Chan, J.C.N.; Chang, L.C.; Chee, M.L.; Chen, J.; Chen, S.H.; Chen, Y.T.; Chen, Z.; Chuang, L.M.; Cushman, M.; Danesh, J.; Das, S.K.; de Silva, H.J.; Dedoussis, G.; Dimitrov, L.; Doumatey, A.P.; Du, S.; Duan, Q.; Eckardt, K.U.; Emery, L.S.; Evans, D.S.; Evans, M.K.; Fischer, K.; Floyd, J.S.; Ford, I.; Franco, O.H.; Frayling, T.M.; Freedman, B.I.; Genter, P.; Gerstein, H.C.; Giedraitis, V.; González-Villalpando, C.; González-Villalpando, M.E.; Gordon-Larsen, P.; Gross, M.; Guare, L.A.; Hackinger, S.; Hakaste, L.; Han, S.; Hattersley, A.T.; Herder, C.; Horikoshi, M.; Howard, A.; Hsueh, W.; Huang, M.; Huang, W.; Hung, Y.; Hwang, M.Y.; Hwu, C.; Ichihara, S.; Ikram, M.A.; Ingelsson, M.; Islam, M.T.; Isono, M.; Jang, H.; Jasmine, F.; Jiang, G.; Jonas, J.B.; Jørgensen, T.; Kamanu, F.K.; Kandeel, F.R.; Kasturiratne, A.; Katsuya, T.; Kaur, V.; Kawaguchi,T.; Keaton, J.M.; Kho, A.N.; Khor, C.; Kibriya, M.G.; Kim, D.; Kronenberg, F.; Kuusisto , J.; Läll, K.; Lange, L.A.; Lee, K.M.; Lee, M.; Lee, N.R.; Leong, A.; Li, L.; Li, Y.; Li-Gao, R.; Ligthart, S.; Lindgren, C.M.; Linneberg, A.; Liu, C.; Liu, J.; Locke, A.E.; Louie, T.; Luan, J.; Luk, A.O.; Luo, X.; Lv, J.; Lynch, J.A.; Lyssenko, V.; Maeda, S.; Mamakou, V.; Mansuri, S.R.; Matsuda, K.; Meitinger, T.; Melander, O.; Metspalu, A.; Mo, H.; Morris, A.D.; Moura, F.A.; Nadler, J.L.; Nalls, M.A.; Nayak, U.; Ntalla, I.; Okada, Y.; Orozco, L.; Patel, S.R.; Patil, S.; Pei, P.; Pereira, M.A.; Peters, A.; Pirie, F.J.; Polikowsky, H.G.; Porneala, B.; Prasad, G.; Rasmussen-Torvik, L.J.; Reiner, A.P.; Roden, M.; Rohde, R.; Roll, K.; Sabanayagam, C.; Sandow, K.; Sankareswaran , A.; Sattar,N.; Schönherr, S.; Shahriar, M.; Shen , B.; Shi, J.; Shin, D.M.; Shojima, N.; Smith, J.A.; So, W.Y.; Stančáková, A.; Steinthorsdottir, V.; Stilp, A.M.; Strauch, K.; Taylor, K.D.; Thorand, B.; Thorsteinsdottir, U.; Tomlinson, B.; Tran, T.C.; Tsai, F.; Tuomilehto, J.; Tusie-Luna, T.; Udler , M.S.; Valladares-Salgado, A.; Dam, R.M.V.; Klinken, J.B.V.; Varma, R.; Wacher-Rodarte, N.; Wheeler,E.; Wickremasinghe, A.R.; Dijk, K.W.V.; Witte, D.R.; Yajnik, C.S.; Yamamoto, K.; Yamamoto, K.; Yoon, K.; Yu, C.; Yuan, J.; Yusuf, S.; Zawistowski, M.; Zhang, L.; Zheng, W.; Raffel, L.J.; Igase, M.; Ipp, E.; Redline, S.; Cho, Y.S.; Lind, L.; Province, M.A.; Fornage, .M.; Hanis, C.L.; Ingelsson, E.; Zonderman, A.B.; Psaty, B.M.; Wang, Y.; Rotimi, C.N.; Becker,D.M.; Matsuda,F.; Liu, Y.; Yokota,M.; Kardia, S.L.R.; Peyser, P.A.; Pankow, J.S.; Engert, J.C.; Bonnefond, A.; Froguel, P.; Wilson, J.G.; Sheu, W.H.H.; Wu, J.; Hayes, M.G.; Ma, R.C.W.; Wong, T.; Mook-Kanamori, D.O.; Tuomi, T.; Chandak, G.R.; Collins, F.S.; Bharadwaj, D.; Paré, G.; Sale, M.M.; Ahsan, H.; Motala, A.A.; Shu , X.; Park, K.; Jukema, J.W.; Cruz, M.; Chen, Y.I.; Rich, S.S.; McKean-Cowdin, R.; Grallert, H.; Cheng, C.; Ghanbari,M.; Tai , E.; Dupuis, J.; Kato, N.; Laakso, M.; Köttgen, A.; Koh, W.; Bowden, D.W.; Palmer, C.N.A.; Kooner, J.S.; Kooperberg, C.; Liu, S.; North, K.E.; Saleheen, D.; Hansen, T.; Pedersen, O.; Wareham, N.J.; Lee, J.; Kim, B.; Millwood , I.Y.; Walters, R.G.; Stefansson, K.; Ahlqvist, E.; Goodarzi, M.O.; Mohlke, K.L.; Langenberg, C.; Haiman, C.A.; Loos, R.J.F.; Florez, J.C.; Rader, D.J.; Ritchie, M.D.; Zöllner, S.; Mägi, R.; Marston, N.A.; Ruff, C.T.; Heel , D.A.V.; Finer, S.; Denny, J.C.; Yamauchi, T.; Kadowaki, T.; Chambers, J.C.; Ng, M.C.Y.; Sim, X.; Below, J.E.; Tsao, P.S.; Chang, K.; McCarthy, M.I.; Meigs, J.B.; Mahajan, A.; Spracklen, C.N.; Mercader, J.M.; Boehnke, M.; Rotter, J.I.; Vujkovic, M.; Voight, B.F.; Morris, A.P.; Zeggini, E.
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. 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, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized 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 cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.
Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture oftype 2 diabetes susceptibility
(Nature Publishing Company, 2014) Mahajan, A.; Go, M.J.; Zhang, W.; Below, J.E.; Gaulton, K.J.; Ferreira, T.; Horikoshi, M.; Johnson, A.D.; Ng, M.C.; 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.; Grrop, 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.; Hu, F.B.; 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, K.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.; Ma, R.C.; Maeda, S.; Mägi, R.; Männisto, 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.; Ng, P.K.; Nica, A.C.; Nilsson, P.M.; Njolstad, 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.; Rathman, 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.; Sigurdsson, G.; Sijbrands, E.; Silveira, A.; Sim, X.; Sivapalaratnam, S.; Small, K.S.; So, W.Y.; Stancáková, 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.; Wu, J.Y.; 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.
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.
Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
(Nature Publishing Company, New York, 2022) Mahajan, A.; Spracklen, C.N.; Zhang, W.; Ng, M.C.Y.; Petty, L.E.; Kitajima, H.; Yu, G.Z.; Rüeger, S.; Speidel, L.; Kim, Y.J.; Horikoshi, M.; Mercader, J.M .; Taliun, D.; Moon, S.; Kwak, S.H.; Robertson, N.R.; Rayner, N.W.; Loh, M.; Kim, B.; Chiou, J.; Miguel-Escalada, I.; Parolo, P.D.B.; Lin, K.; Bragg, F.; Preuss, M.H.; Takeuchi, F.; Nano, J.; Guo, X.; Lamri, A.; Nakatoch, M.; Scott, R.A.; Lee, J.J.; Huerta-Chagoya, A.; Graff, M.; Chai, J.F.; Parra, E. J.; Yao, J.; Bielak, L.F.; Tabara, Y.; Hai, Y.; Steinthorsdottir, V.; Cook, J.P.; Kals, M.; Grarup, N.; Schmidt, E.M.; Pan, I.; Sofer, T.; Wuttke, M.; Sarnowski, C.; Gieger, C.; Nousome, D.; Trompet, S.; Long, J.; Sun, M.; Tong, L.; Chen, W.M.; Ahmad, M.; Noordam, R.; Lim, V.J.Y.; Tam, C.H.T.; Joo, Y.Y.; Chen, C.H.; Raffield, L.M.; Lecoeur, C.; Prins, B.P.; Nicolas, A.; Yanek, L.R.; Chen, G.; Jensen, R.A.; Tajuddin, S.; Kabagambe, E.K.; An, P.; Xiang, A.H.; Choi, H.S.; Cade, B.E.; Tan, J.; Flanagan, J.; Abaitua, F.; Adair, L.S.; Adeyemo, A.; Aguilar-Salinas, C.A.; Akiyama, M.; Anand, S.S.; Bertoni, A.; Bian, Z.; Bork-Jensen, J.; Brandslund, I.; Brody, J.A.; Brummett, C.M.; Buchanan, T.A.; Canouil, M.; Chan, J.C.N.; Chang, L.C.; Chee, M.L.; Chen, J.; Chen, S.H.; Chen, Y.T.; Chen, Z.; Chuang, L.M.; Cushman, M.; Das, S.K.; de Silva, H.J.; Dedoussis, G.; Dimitrov, L.; Doumatey, A.P.; Du, S.; Duan, Q.; Eckardt, K.U.; Emery, L.S.; Evans, D.S.; Evans, M.K.; Fischer, K.; Floyd, J.S.; Ford, I.; Fornage, M.; Franco, O.H.; Frayling, T.M.; Freedman, B.I.; Fuchsberger, C.; Genter, P.; Gerstein, H.C.; Giedraitis, V.; Villalpando, C.G.; Villalpando, M.E.G.; Goodarzi, M.O.; Larsen, P.G.; Gorkin, D.; Gross, M.; Guo, Y.; Hackinger, S.; Han, S.; Hattersley, A.T.; Herder, C.; Howard, A.G.; Hsueh, W.; Huang, M.; Huang, W.; Hung, Y.; Hwang, M.Y.; Hwu, C.; Ichihara, S.; Ikram, M.A.; Ingelsson, M.; Islam, M.T.; Isono, M.; Jang, H.M.; Jasmine, F.; Jiang, G.; Jonas, J.B.; Jørgensen, M.E.; Jørgensen, T.; Kamatani, Y.; Kandeel, F.R.; Kasturiratne, A.; Katsuya, T.; Kaur, V.; Kawaguchi, T.; Keaton, J.M.; Kho, A.N.; Khor, C.C.; Kibriya, M.G.; Kim, D.H.; Kohara, K.; Kriebel, J.; Kronenberg, F.; Kuusisto, J.; Läll, K.; Lange, L.A.; Lee, M.; Lee, N.R.; Leong, A.; Li, L.; Li, Y.; Li-Gao, R.; Ligthart, S.; Lindgren, C.M.; Linneberg, A.; Liu, C.; Liu, J.; Locke, A.E.; Louie, T.; Luan, J.; Luk, A.O.; Luo, X.; Lv, J.; Lyssenko, V.; Mamakou, V.; Mani, K.R.; Meitinger, T.; Metspalu, A.; Morris, A.D.; Nadkarni, G.N.; Nadler, J.L.; Nalls, M.A.; Nayak, U.; Nongmaithem, S.S.; Ntalla, I.; Okada, Y.; Orozco, L.; Patel, S.R.; Pereira, M.A.; Peters, A.; Pirie, F.J.; Porneala, B.; Prasad, G.; Preissl, S.; Rasmussen-Torvik, L.J.; Reiner, A.P.; Roden, M.; Rohde, R.; Roll, K.; Sabanayagam, C.; Sander, M.; Sandow, K.; Sattar, N.; Schönherr, S.; Schurmann, C.; Shahriar, M.; Shi, J.; Shin, D.M.; Shriner, D.; Smith, J.A.; So, W.Y.; Stančáková, A.; Stilp, A.M.; Strauch, K.; Suzuki, K.; Takahashi, A.; Taylor, K.D.; Thorand, B.; Thorleifsson, G.; Thorsteinsdottir, U.; Tomlinson, B.; Torres, J.M.; Tsai, F.; Tuomilehto, J.; Tusie-Luna, T.; Udler, M.S.; Salgado, A.V.; Dam, R.M.; Klinken, J.B.; Varma, R.; Vujkovic, M.; Wacher-Rodarte, N.; Wheeler, E.; Whitsel, E.A.; Wickremasinghe, A.R.; Dijk, K.W.; Witte, D.R.; Yajnik, C.S; Yamamoto, K.; Yamauchi, T.; Yengo, L.; Yoon, K.; Yu, C.; Yuan, J.M.; Yusuf, S.; Zhang, L.; Zheng, W.; FinnGen; eMERGE Consortium; Leslie J Raffel; Igase, M.; Ipp, E.; Redline, S.; Cho, Y.S.; Lind, L.; Province, M.A.; Hanis, C.L.; Peyser, P.A.; Ingelsson, E.; Zonderman, A.B.; Psaty, B.M.; Wang, Y.; Rotimi, C.N.; Becker, D.M.; Matsuda, F.; Liu, Y.; Zeggini, E.; Yokota, M.; Rich, S.S.; Kooperberg, C.; Pankow, J.S.; Engert, J.C.; Chen, Y.I.; Froguel, P.; Wilson, J.G.; Sheu, W.H.H.; Kardia, S.L.R.; Wu, J.Y.; Hayes, M.G.; Ma, R.C.W.; Wong, T.Y.; Groop, L.; Mook-Kanamori, D.O.; Chandak, G.R.; Collins, F.S.; Bharadwaj, D.; Paré, G.; Sale, M.M.; Ahsan, H.; Motala, A.A.; Shu, X.O.; Park, K.S.; Jukema, J.W.; Cruz, M.; Cowdin, R.M.; Grallert, H.; Cheng, C.Y.; Bottinger, E.P.; Dehghan, A.; Tai, E.S.; Dupuis, J.; Kato, N.; Laakso, M.; Köttgen, A.; Koh, W.P.; Palmer, C.N.A.; Liu, S.; Abecasis, G.; Kooner, J.S.; Loos, R.J.F.; North, K.E.; Haiman, C.A.; Florez, J.C.; Saleheen, D.; Hansen, T.; Pedersen, O.; Mägi, R.; Langenberg, C.; Wareham, N.J.; Maeda, S.; Kadowaki, T.; Lee, J.; Millwood, I.Y.; Walters, R.G.; Stefansson, K.; Myers, S.R.; Ferrer, J.; Gaulton, K.J.; Meigs, J.B.; Mohlke, K.L.; Gloyn, A.L.; Bowden, D.W.; Below, J.E.; Chambers, J.C.; Sim, X.; Boehnke, M.; Rotter, J.I.; McCarthy, M.I.; Morris, A.P.
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.
A saturated map of common genetic variants associated with human height
(Nature Publishing Group, 2022) Vedantam, S.; Marouli, E.; Sidorenko, J.; Bartell, E.; Sakaue, S.; Graff, M.; Eliasen, A.U.; Jiang, Y.; Raghavan, S.; Miao, J.; Arias, J.D.; Graham, S.E.; Mukamel, R.E.; Spracklen, C.N.; Yin, X.; Chen, S.H.; Ferreira, T.; Highland, H.H.; Ji, Y.; Karaderi. T,; Lin, K.; Lüll, K.; Malden, D.E.; Medina-Gomez, C.; Machado, M.; Moore, A.; Rüeger, S.; Sim. X,; Vrieze, S.; Ahluwalia, T.S.; Akiyama, M.; Allison, M.A.; Alvarez, M.; Andersen, M.K.; Ani, A.; Appadurai, V.; Arbeeva, L.; Bhaskar, S.; Bielak, L.F.; Bollepalli, S.; Bonnycastle, L.L.; Bork-Jensen, J.; Bradfield, J.P.; Bradford, Y.; Braund, P.S.; Brody, J.A.; Burgdorf, K.S.; Cade, B.E.; Cai, H.; Cai, Q.; Campbell, A.; Cañadas-Garre, M.; Catamo, E.; Chai, J.F.; Chai, X.; Chang, L.C.; Chen, C.H.; Chesi, A.; Choi, S.H.; Chung, R.H.; Cocca, M.; Concas, M.P.; Couture, C.; Cuellar-Partida, G.; Danning, R.; Daw, E.W.; Degenhard, F.; Delgado, G.E.; Delitala, A.; Demirkan, A.; Deng, X.; Devineni, P.; Dietl, A.; Dimitriou, M.; Dimitrov, L.; Dorajoo, R.; Ekici, A.B.; Engmann, J.E.; Fairhurst-Hunter, Z.; Farmaki, A.E.; Faul, J.D.; Fernandez-Lopez, J.C.; Forer, L.; Francescatto, M.; Freitag-Wolf, S.; Fuchsberger, C.; Galesloot, T.E.; Gao, Y.; Gao, Z.; Geller, F.; Giannakopoulou, O.; Giulianini,F.; Gjesing, A.P.; Goel, A.; Gordon, S.D.; Gorski, M.; Grove, J.; Guo, X.; Gustafsson, S.; Haessler, J.; Hansen, T.F.; Havulinna, A.S.; Haworth, S.J.; He, J.; Heard-Costa, N.; Hebbar, P.; Hindy, G.; Ho, Y.A.; Hofer, E.; Holliday, E.; Horn, K.; Hornsby, W.E.; Hottenga, J.J.; Huang, H.; Huang, J.; Huerta-Chagoya, A.; Huffman, J.E.; Hung, Y.J.; Huo, S.; Hwang, M.Y.; Ha, H.; Ikeda, D.D.; Isono, M.; Jackson, A.U.; Jäger, S.; Jansen, I.E.; Johansson, I.; Jonas, J.B.; Jonsson, A.; Jørgensen, T.; Kalafati, I.P.; Kanai, M.; Kanoni, S.; Kårhus, L.L.; Kasturiratne, A.; Katsuya, T.; Kawaguchi, T.; Kember, R.L.; Kentistou, K.A.; Kim, H.N.; Kim, Y.J.; Kleber, M.E.; Knol, M.J.; Kurbasic, A.; Lauzon, M.; Le, P.; Lea, R.; Lee, J.Y.; Leonard, H.L.; Li, S.A.; Li, X.; Li, X.; Liang, J.; Lin, H.; Lin, S.Y.; Liu, J.; Liu, X.; Lo, K.S.; Long, J.; Lores-Motta, L.; Luan, J.; Lyssenko, V.; Lyytikäinen, L.P.; Mahajan, A.; Mamakou, V.; Mangino, M.; Manichaikul, A.; Marten, J.,; Mattheisen, M.; Mavarani, L.; McDaid, A.F.; Meidtner, K.; Melendez, T.L.; Mercader, J.M.; Milaneschi, Y.; Miller, J.E.; Millwood, I.Y.; Mishra, P.P.; Mitchell, R.E.; Møllehave, L.T.; Morgan, A.; Mucha, S.; Munz, M.; Nakatochi, M.; Nelson, C.P.; Nethander, M.; Nho, C.W.; Nielsen, A.A.; Nolte, I.M.; Nongmaithem, S.S.; Noordam, R.; Ntalla, I.; Nutile, T.; Pandit, A.; Christofidou, P.; Pärna, K.; Pauper, M.; Petersen, E.R.B.; Petersen, L.V.; Pitkänen, N.; Polašek, O.; Poveda, A.; Preuss, M.H.; Pyarajan, S.; Raffield, L.M.; Rakugi, H.; Ramirez, J.; Rasheed, A.; Raven, D.; Rayner, N.W.; Riveros, C.; Rohde, R.; Ruggiero, D.; Ruotsalainen, S.E.; Ryan, K.A.; Sabater-Lleal, M.; Saxena, R.; Scholz, M.; Sendamarai, A.; Shen, B.; Shi, J.; Shin, J.H.; Sidore, C.; Sitlani, C.M.; Slieker, R.C.; Smit, R.A.J.; Smith, A.V.; Smith, J.A.; Smyth, L.J.; Southam, L.; Steinthorsdottir, V.; Sun, L.; Takeuchi, F.; Tallapragada, D.S.P.; Taylor, K.D.; Tayo, B.O.; Tcheandjieu, C.; Terzikhan, N.; Tesolin, P.; Teumer, A.; Theusch, E.; Thompson, D.J.; Thorleifsson, G.; Timmers, P.R.H.J.; Trompet, S.; Turman, C.; Vaccargiu, S.; van der Laan, S.W.; van der Most, P.J.; van Klinken, J.B.; van Setten, J.; Verma, S.S.; Verweij, N.; Veturi, Y.; Wang, C.A.; Wang, C.; Wang, L.; Wang, Z.; Warren, H.R.; Bin Wei, W.; Wickremasinghe, A.R.; Wielscher, M.; Wiggins, K.L.; Winsvold, B.S.; Wong, A.; Wu, Y.; Wuttke, M.; Xia, R.; Xie, T.; Yamamoto, K.; Yang, J.; Yao, J.; Young, H.; Yousri, N.A.; Yu, L.; Zeng, L.; Zhang, W.; Zhang, X.; Zhao, J.H.; Zhao. W.; Zhou, W.; Zimmermann, M.E.; Zoledziewska, M.; Adair, L.S.; Adams, H.H.H.; Aguilar-Salinas, C.A.; Al-Mulla, F.; Arnett, D.K.; Arnett, D.K.; Asselbergs, F.W.; Åsvold, B.O.; Attia, J.; Banas, B.; Bandinelli, S.; Bennett D.A.; Bergler, T.; Bharadwaj, D.; Biino, G.; Bisgaard, H.; Boerwinkle, E.; Böger, C.A.; Bønnelykke, K.; Boomsma, D.I.; Børglum, A.D.; Borja, J.B.; Bouchard, C.; Bowden, D.W.; Brandslund, I.; Brumpton, B.; Buring, J.E.; Caulfield, M.J.; Chambers, J.C.; Chandak, G.R.; Chanock, S.J.; Chaturvedi, N.; Chen, Y.I.; Chen, Z.; Cheng, C.Y.; Christophersen, I.E.; Ciullo, M.; Cole, J.W.; Collins, F.S.; Cooper, R.S.; Cruz, M.; Cucca, F.; Cupples, L.A.; Cutler, M.J.; Damrauer, S.M.; Dantoft, T.M.; de Borst, G.J.; de Groot, L.C.P.G.M.; de Jager, P.L.; de Kleijn, D.P.V.; de Silva, H.J.; Dedoussis, G.V.; den Hollander, A.I.; Du, S.; Easton, D.F.; Elders, P.J.M.; Eliassen, A.H.; Ellinor, P.T.; Elmståhl, S.; Erdmann, J.; Evans, M.K.; Fatkin, D.; Feenstra, B.; Feitosa, M.F.; Ferrucci, L.; Ford, I.; Fornage, M.; Franke, A.; Franks, P.W.; Freedman, B.I.; Gasparini, P.; Gieger, C.; Girotto, G.; Goddard, M.E.; Golightly, Y.M.; Gonzalez-Villalpando. C.; Gordon-Larsen, P.; Grallert, H.; Grant, S.F.A.; Grarup, N.; Griffiths, L.; Gudnason, V.; Haiman, C.; Hakonarson, H.; Hansen, T.; Hartman, C.A.; Hattersley, A.T.; Hayward, C.; Heckbert, S.R.; Heng, C.K.; Hengstenberg, C.; Hewitt, A.W.; Hishigaki, H.; Hoyng, C.B.; Huang, P.L.; Huang, W.; Hunt, S.C.; Hveem, K.; Hyppönen, E.; Iacono, W.G.; Ichihara, S.; Ikram, M.A.; Isasi, C.R.; Jackson, R.D.; Jarvelin, M.R.; Jin, Z.B.; Jöckel, K.H.; Joshi, P.K.; Jousilahti, P.; Jukema, J.W.; Kähönen, M.; Kamatani, Y.; Kang, K.D.; Kaprio, J.; Kardia, S.L.R.; Karpe, F.; Kato, N.; Kee, F.; Kessler, T.; Khera, A.V.; Khor, C.C.; Kiemeney, L.A.L.M.; Kim, B.J.; Kim, E.K.; Kim, H.L.; Kirchhof, P.; Kivimaki, M.; Koh, W.P.; Koistinen, H.A.; Kolovou, G.D.; Kooner, J.S.; Kooperberg, C.; Köttgen, A.; Kovacs, P.; Kraaijeveld, A.; Kraft, P.; Krauss, R.M.; Kumari, M.; Kutalik, Z.; Laakso, M.; Lange, L.A.; Langenberg, C.; Launer, L.J.; Le Marchand, L.; Lee, H.; Lee, N.R.; Lehtimäki, T.; Li, H.; Li, L.; Lieb, W.; Lin, X.; Lind, L.; Linneberg, A.; Liu, C.T.; Liu, J.; Loeffler, M.; London, B.; Lubitz, S.A.; Lye, S.J.; Mackey, D.A.; Mägi, R.; Magnusson, P.K.E.; Marcus, G.M.; Vidal, P.M.; Martin, N.G.; Martin, N.G.; Lieb, W.; Lin, X.; Lind, L.; Linneberg, A.; Liu, C.T.; Liu, J.; Loeffler, M.; London, B.; Lubitz, S.A.; Lye, S.J.; Mackey, D.A.; Mägi, R.; Mägi, R.; Magnusson, P.K.E.; Marcus, G.M.; Vidal, P.M.; Martin, N.G.; März, W.; Matsuda, F.; McGarrah, R.W.; McGue, M.; McKnight, A.J.; Medland, S.E.; Mellström, D.; Metspalu, A.; Mitchell, B.D.; Mitchell, P.; Mook-Kanamori, D.O.; Morris, A.D.; Mucci, L.A.; Munroe, P.B.; Nalls, M.A.; Nazarian, S.; Nelson, A.E.; Neville, M.J.; Newton-Cheh, C.; Nielsen, C.S.; Nöthen, M.M.; Ohlsson, C.; Oldehinkel, A.J.; Oldehinkel, A.J.; Orozco, L.; Pahkala, K.; Pajukanta, P.; Palmer, C.N.A.; Parra, E.J.; Pattaro, C.; Pedersen, O.; Pennell, C.E.; Penninx, B.W.J.H.; Perusse, L.; Peters, A.; Peyser, P.A.; Porteous, D.J.; Posthuma, D.; Power, C.; Pramstaller, P.P.; Province, M.A.; Qi, Q.; Qu, J.; Rader, D.J.; Raitakari, O.T.; Ralhan, S.; Rallidis, L.S.; Rao, D.C.; Redline, S.; Reilly, D.F.; Reiner, A.P.; Rhee, S.Y.; Ridker, P.M.; Rienstra, M.; Ripatti, S.; Ritchie, M.D.; Roden, D.M.; Rosendaal, F.R.; Rotter, J.I.; Rudan, I.; Rutters, F.; Sabanayagam, C.; Saleheen, D.; Salomaa, V.; Samani, N.J.; Sanghera, D.K.; Sattar, N.; Schmidt, B.; Schmidt, H.; Schmidt, R.; Schulze, M.B.; Schunkert, H.; Scott, L.J.; Scott, R.J.; Sever, P.; Shiroma, E.J.; Shoemaker, M.B.; Shu, X.O.; Simonsick, E.M.; Sims, M.; Singh, J.R.; Singleton, A.B.; Sinner, M.F.; Smith, J.G.; Snieder, H.; Spector, T.D.; Stampfer, M.J.; Stark, K.J.; Strachan, D.P.; 't Hart, L.M.; Tabara, Y.; Tang, H.; Tardif, J.C.; Thanaraj, T.A.; Timpson, N.J.; Tönjes, A.; Tremblay, A.; Tuomi, T.; Tuomilehto, J.; Tusié-Luna, M.T.; Uitterlinden, A.G.; van Dam, R.M.; van der Harst, P.; Van der Velde, N.; van Duijn, C.M.; van Schoor, N.M.; Vitart, V.; Völker, U.; Vollenweider, P.; Völzke, H.; Wacher-Rodarte, N.H.; Walker, M.; Wang, Y.X.; Wareham, N.J.; Watanabe, R.M.; Watkins, H.; Weir, D.R.; Werge, T.M.; Widen, E.; Wilkens, L.R.; Willemsen, G.; Willett, W.C.; Wilson, J.F.; Wong, T.Y.; Woo, J.T.; Wright, A.F.; Wu, J.Y.; Xu, H.; Yajnik, C.S.; Yokota, M.; Yuan, J.M.; Zeggini, E.; Zemel, B.S.; Zheng, W.; Zhu, X.; Zmuda, J.M.; Zonderman, A.B.; Zwart, J.A.; 23andMe Research Team; VA Million Veteran Program.; DiscovEHR (DiscovEHR and MyCode Community Health Initiative).; eMERGE (Electronic Medical Records and Genomics Network).; Lifelines Cohort Study.; PRACTICAL Consortium.; Understanding Society Scientific Group.; Chasman, D.I.; Cho, Y.S.; Heid, I.M.; McCarthy, M.I.; Ng, M.C.Y.; O'Donnell, C.J.; Rivadeneira, F.; Thorsteinsdottir, U.; Sun, Y.V.; Tai, E.S.; Boehnke, M.; Deloukas, P.; Justice, A.E.; Lindgren, C.M.; Loos, R.J.F.; Mohlke, K.L.; North, K.E.; Stefansson, K.; Walters R.G.v.; Winkler, T.W.; Young, K.L.; Loh, P.R.; Yang, J.; Esko, T.; Assimes, T.L.; Auton, A.; Abecasis, G.R.; Willer, C.J.; Locke, A.E.; Berndt, S.I.; Lettre, G.; Frayling, T.M.; Frayling, T.M.; Okada, Y.; Wood, A.R.; Visscher, P.M.; Hirschhorn, J.N.
Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.
The Trans-ancestral genomic architecture of glycemic traits
(Nature Pub. Co., 2021) Chen, J.; Spracklen, C.N.; Marenne, G.; Varshney, A.; Corbin, L.J.; Luan, J.; Willems, S.M.; Wu, Y.; Zhang, X.; Horikoshi, M.; Boutin, T.S.; Mägi, R.; Waage, J.; Li-Gao, R.; Chan, K.H.K; Yao, J.; Anasanti, M.D.; Chu, A.Y.; Claringbould, A.; Heikkinen, J.; Hong, J.; Hottenga, J.J.; Huo, S.; Kaakinen, M.A.; Louie, T.; März, W.; Moreno-Macias, H.; Ndungu, A.; Nelson, S.C.; Nolte, I.M.; North, K.E.; Raulerson, C.K.; Ray, D.; Rohde, R.; Rybin, D.; Schurmann, C.; Sim, X.; Southam, L.; Stewart, I.D.; Wang, C.A.; Wang, Y.; Wu, P.; Zhang, W.; Ahluwalia, T.S.; Appel, E.V.R.; Bielak, L.F.; Brody, J.A.; Burtt, N.P.; Cabrera, C.P.; Cade, B.E.; Chai, J.F.; Chai, X.; Chang, L.C.; Chen, C.H.; Chen, B.H.; Chitrala, K.N.; Chiu, Y.F.; De Haan, H.G.; Delgado, G.E.; Demirkan, A.; Duan, Q.; Engmann, J.; Fatumo, S.A.; Gayán, J.; Giulianini, F.; Gong, J.H.; Gustafsson, S.; Hai, Y.; Hartwig, F.P.; He, J.; Heianza, Y.; Huang, T.; Huerta-Chagoya, A.; Hwang, M.Y.; Jensen, R.A.; Kawaguchi, T.; Kentistou, K.A.; Kim, Y.J.; Kleber, M.E.; Kooner, I.K.; Lai, S.; Lange, L.A.; Langefeld, C.D.; Lauzon, M.; Li, M.; Ligthart, S.; Liu, J.; Loh, M.; Long, J.; Lyssenko, V.; Mangino, M.; Marzi, C.; Montasser, M.E.; Nag, A.; Nakatochi, M.; Noce, D.; Noordam, R.; Pistis, G.; Preuss, M.; Raffield, L.; Rasmussen-Torvik, L.J.; Rich, S.S.; Robertson, N.R.; Rueedi, R.; Ryan, K.; Sanna, S.; Saxena, R.; Schraut, K.E.; Sennblad, B.; Setoh, K.; Smith, A.V.; Sparsø, T.; Strawbridge, R.J.; Takeuchi, F.; Tan, J.; Trompet, S.; Van den Akker, E.; Van der Most, P.J.; Verweij, N.; Vogel, M.; Wang, H.; Wang, C.; Wang, N.; Warren, H.R.; Wen, W.; Wilsgaard, T.; Wong, A.; Wood, A.R.; Xie, T.; Zafarmand, M.H.; Zhao, J.H.; Zhao, W.; Amin, N.; Arzumanyan, Z.; Astrup, A.; Bakker, S.J.L.; Baldassarre, D.; Beekman, M.; Bergman, R.N.; Bertoni, A.; Blüher, M.; Bonnycastle, L.L.; Bornstein, S.R.; Bowden, D.W.; Cai, Q.; Campbell, A.; Campbell, H.; Chang, Y.C.; de Geus, E.J.C.; Dehghan, A.; Du, S.; Eiriksdottir, G.; Farmaki, A.E.; Frånberg, M.; Fuchsberger, C.; Gao, Y.; Gjesing, A.P.; Goel, A.; Han, S.; Hartman, C.A.; Herder, C.; Hicks, A.A.; Hsieh, C.H.; Hsueh, W.A.; Ichihara, S.; Igase, M.; Ikram, M.A.; Johnson, W.C.; Jørgensen, M.E.; Joshi, P.K.; Kalyani, R.R.; Kandeel, F.R.; Katsuya, T.; Khor, C.C.; Kiess, W.; Kolcic, I.; Kuulasmaa, T.; Kuusisto, J.; Läll, K.; Lam, K.; Lawlor, D.A.; Lee, N.R.; Lemaitre, R.N.; Li, H.; Lifelines Cohort Study; Lin, S.Y.; Lindström, J.; Linneberg, A.; Liu, J.; Lorenzo, C.; Matsubara, T.; Matsuda, F.; Mingrone, G.; Mooijaart, S.; Moon, S.; Nabika, T.; Nadkarni, G.N.; Nadler, J.L.; Nelis, M.; Neville, M.J.; Norris, J.M.; Ohyagi, Y.; Peters, A.; Peyser, P.A.; Polasek, O.; Qi, Q.; Raven, D.; Reilly, D.F.; Reiner, A.; Rivideneira, F.; Roll, K.; Rudan, I.; Sabanayagam, C.; Sandow, K.; Sattar, N.; Schürmann, A.; Shi, J.; Stringham, H.M.; Taylor, K.D.; Teslovich, T.M.; Thuesen, B.; Timmers, P.R.H.J.; Tremoli, E.; Tsai, M.Y.; Uitterlinden, A.; van Dam, R.M.; van Heemst, D.; van Hylckama Vlieg, A.; van Vliet-Ostaptchouk, J.V.; Vangipurapu, J.; Vestergaard, H.; Wang, T.; Willems van Dijk, K.; Zemunik, T.; Abecasis, G.R.; Adair, L.S.; Aguilar-Salinas, C.A.; Alarcón-Riquelme, M.E.; An, P.; Aviles-Santa, L.; Becker, D.M.; Beilin, L.J.; Bergmann, S.; Bisgaard, H.; Black, C.; Boehnke, M.; Boerwinkle, E.; Böhm, B.O.; Bønnelykke, K.; Boomsma, D.I.; Bottinger, E.P.; Buchanan, T.A.; Canouil, M.; Caulfield, M.J.; Chambers, J.C.; Chasman, D.I.; Chen, Y.I.; Cheng, C.Y.; Collins, F.S.; Correa, A.; Cucca, F.; de Silva, H.J.; Dedoussis, G.; Elmståhl, S.; Evans, M.K.; Ferrannini, E.; Ferrucci, L.; Florez, J.C.; Franks, P.W.; Frayling, T.M.; Froguel, P.; Gigante, B.; Goodarzi, M.O.; Gordon-Larsen, P.; Grallert, H.; Grarup, N.; Grimsgaard, S.; Groop, L.; Gudnason, V.; Guo, X.; Hamsten, A.; Hansen, T.; Hayward, C.; Heckbert, S.R.; Horta, B.L.; Huang, W.; Ingelsson, E.; James, P.S.; Jarvelin, M.R.; Jonas, J.B.; Jukema, J.W.; Kaleebu, P.; Kaplan, R.; Kardia, S.L.R.; Kato, N.; Keinanen-Kiukaanniemi, S.M.; Kim, B.J.; Kivimaki, M.; Koistinen, H.A.; Kooner, J.S.; Körner, A.; Kovacs, P.; Kuh, D.; Kumari, M.; Kutalik, Z.; Laakso, M.; Lakka, T.A.; Launer, L.J.; Leander, K.; Li, H.; Lin, X.; Lind, L.; Lindgren, C.; Liu, S.; Loos, R.J.F.; Magnusson, P.K.E.; Mahajan, A.; Metspalu, A.; Mook-Kanamori, D.O.; Mori, T.A.; Munroe, P.B.; Njølstad, I.; O'Connell, J.R.; Oldehinkel, A.J.; Ong, K.K.; Padmanabhan, S.; Palmer, C.N.A.; Palmer, N.D.; Pedersen, O.; Pennell, C.E.; Porteous, D.J.; Pramstaller, P.P.; Province, M.A.; Psaty, B.M.; Qi, L.; Raffel, L.J.; Rauramaa, R.; Redline, S.; Ridker, P.M.; Rosendaal, F.R.; Saaristo, T.E.; Sandhu, M.; Saramies, J.; Schneiderman, N.; Schwarz, P.; Scott, L.J.; Selvin, E.; Sever, P.; Shu, X.O.; Slagboom, P.E.; Small, K.S.; Smith, B.H.; Snieder, H.; Sofer, T.; Sørensen, T.I.A.; Spector, T.D.; Stanton, A.; Steves, C.J.; Stumvoll, M.; Sun, L.; Tabara, Y.; Tai, E.S.; Timpson, N.J.; Tönjes, A.; Tuomilehto, J.; Tusie, T.; Uusitupa, M.; van der Harst, P.; van Duijn, C.; Vitart, V.; Vollenweider, P.; Vrijkotte, T.G.M.; Wagenknecht, L.E.; Walker, M.; Wang, Y.X.; Wareham, N.J.; Watanabe, R.M.; Watkins, H.; Wei, W.B.; Wickremasinghe, A.R.; Willemsen, G.; Wilson, J.F.; Wong, T.Y.; Wu, J.Y.; Xiang, A.H.; Yanek, L.R.; Yengo, L.; Yokota, M.; Zeggini, E.; Zheng, W.; Zonderman, A.B.; Rotter, J.I.; Gloyn, A.L.; McCarthy, M.I.; Dupuis, J.; Meigs, J.B.; Scott, R.A.; Prokopenko, I.; Leong, A.; Liu, C.T.; Parker, S.C.J.; Mohlke, K.L.; Langenberg, C.; Wheeler, E.; Morris, A.P.; Barroso, I.; Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC) Collaborators.
ABSTRACT: Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation
(Nature Publishing Company, 2015) Kato, N.; Loh, M.; Takeuchi, F.; Verweij, N.; Wang, X.; Zhang, W.; Kelly, T.N.; Saleheen, D.; Lehne, B.; Leach, I.M.; Drong, A.W.; Abbott, J.; Wahl, S.; Tan, S.T.; Scott, W.R.; Campanella, G.; Chadeau-Hyam, M.; Afzal, U.; Ahluwalia, T.S.; Bonder, M.J.; Chen, P.; Dehghan, A.; Edwards, T.L.; Esko, T.; Go, M.J.; Harris, S.E.; Hartiala, J.; Kasela, S.; Kasturiratne, A.; Khor, C.C.; Kleber, M.E.; Li, H.; Mok, Z.Y.; Nakatochi, M.; Sapari, N.S.; Saxena, R.; Stewart, A.F.; Stolk, L.; Tabara, Y.; Teh, A.L.; Wu, Y.; Wu, J.Y.; Zhang, Y.; Aits, I.; Da Silva Couto Alves, A.; Das, S.; Dorajoo, R.; Hopewell, J.C.; Kim, Y.K.; Koivula, R.W.; Luan, J.; Lyytikäinen, L.P.; Nguyen, Q.N.; Pereira, M.A.; Postmus, I.; Raitakari, O.T.; Bryan, M.S.; Scott, R.A.; Sorice, R.; Tragante, V.; Traglia, M.; White, J.; Yamamoto, K.; Zhang, Y.; Adair, L.S.; Ahmed, A.; Akiyama, K.; Asif, R.; Aung, T.; Barroso, I.; Bjonnes, A.; Braun, T.R.; Cai, H.; Chang, L.C.; Chen, C.H.; Cheng, C.Y.; Chong, Y.S.; Collins, R.; Courtney, R.; Davies, G.; Delgado, G.; Do, L.D.; Doevendans, P.A.; Gansevoort, R.T.; Gao, Y.T.; Grammer, T.B.; Grarup, N.; Grewal, J.; Gu, D.; Wander, G.S.; Hartikainen, A.L.; Hazen, S.L.; He, J.; Heng, C.K.; Hixson, J.E.; Hofman, A.; Hsu, C.; Huang, W.; Husemoen, L.L.; Hwang, J.Y.; Ichihara, S.; Igase, M.; Isono, M.; Justesen, J.M.; Katsuya, T.; Kibriya, M.G.; Kim, Y.J.; Kishimoto, M.; Koh, W.P.; Kohara, K.; Kumari, M.; Kwek, K.; Lee, N.R.; Lee, J.; Liao, J.; Lieb, W.; Liewald, D.C.; Matsubara, T.; Matsushita, Y.; Meitinger, T.; Mihailov, E.; Milani, L.; Mills, R.; Mononen, N.; Müller-Nurasyid, M.; Nabika, T.; Nakashima, E.; Ng, H.K.; Nikus, K.; Nutile, T.; Ohkubo, T.; Ohnaka, K.; Parish, S.; Paternoster, L.; Peng, H.; Peters, A.; Pham, S.T.; Pinidiyapathirage, M.J.; Rahman, M.; Rakugi, H.; Rolandsson, O.; Rozario, M.A.; Ruggiero, D.; Sala, C.F.; Sarju, R.; Shimokawa, K.; Snieder, H.; Sparso, T.; Spiering, W.; Starr, J.M.; Stott, D.J.; Stram, D.O.; Sugiyama, T.; Szymczak, S.; Tang, W.H.; Tong, L.; Trompet, S.; Turjanmaa, V.; Ueshima, H.; Uitterlinden, A.G.; Umemura, S.; Vaarasmaki, M.; van Dam, R.M.; van Gilst, W.H.; van Veldhuisen, D.J.; Viikari, J.S.; Waldenberger, M.; Wang, Y.; Wang, A.; Wilson, R.; Wong, T.Y.; Xiang, Y.B.; Yamaguchi, S.; Ye, X.; Young, R.D.; Young, T.L.; Yuan, J.M.; Zhou, X.; Asselbergs, F.W.; Ciullo, M.; Clarke, R.; Deloukas, P.; Franke, A.; Franks, P.W.; Franks, S.; Friedlander, Y.; Gross, M.D.; Guo, Z.; Hansen, T.; Jarvelin, M.R.; Jorgensen, T.; Jukema, J.W.; Kähönen, M.; Kajio, H.; Kivimaki, M.; Lee, J.Y.; Lehtimäki, T.; Linneberg, A.; Miki, T.; Pedersen, O.; Samani, N.J.; Sorensen, T.I.; Takayanagi, R.; Toniolo, D.; BIOS-consortium; CARDIo GRAMplusCD; LifeLines Cohort Study; InterAct Consortium; Ahsan, H.; Allayee, H.; Chen, Y.T.; Danesh, J.; Deary, I.J.; Franco, O.H.; Franke, L.; Heijman, B.T.; Holbrook, J.D.; Isaacs, A.; Kim, B.J.; Lin, X.; Liu, J.; März, W.; Metspalu, A.; Mohlke, K.L.; Sanghera, D.K.; Shu, X.O.; van Meurs, J.B.; Vithana, E.; Wickremasinghe, A.R.; Wijmenga, C.; Wolffenbuttel, B.H.; Yokota, M.; Zheng, W.; Zhu, D.; Vineis, P.; Kyrtopoulos, S.A.; Kleinjans, J.C.; McCarthy, M.I.; Soong, R.; Gieger, C.; Scott, J.; Teo, Y.Y.; He, J.; Elliott, P.; Tai, E.S.; van der Harst, P.; Kooner, J.S.; Chambers, J.C.
We carried out a trans-ancestry genome-wide association and replication study of blood pressurephenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNAmethylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNAmethylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.