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1. Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk

Author

Brænne, I, Zeng, L, Willenborg, C, Tragante, V, Kessler, T, Willer, C, Laakso, M, Wallentin, L, Franks, P, Salomaa, V, Dehghan, A, Meitinger, T, Samani, N, Asselbergs, F, Erdmann, J, Schunkert, H, Deloukas, P, Kanoni, S, Farrall, M, Assimes, T, Thompson, J, Ingelsson, E, Saleheen, D, Goldstein, B, Absher, D, König, I, Cazier, J, Johansson, Å, Hall, A, Lee, J, Chambers, J, Esko, T, Folkersen, L, Goel, A, Grundberg, E, Havulinna, A, Ho, W, Hopewell, J, Eriksson, N, Kleber, M, Kristiansson, K, Lundmark, P, Lyytikäinen, L, Rafelt, S, Shun, D, Strawbridge, R, Thorleifsson, G, Tikkanen, E, Van Zuydam, N, Voight, B, Waite, L, Zhang, W, Zieg, A, Altshuler, D, Balmforth, A, Barroso, I, Braund, P, Burgdorf, C, Claudi-Boehm, S, Cox, D, Dimitriou, M, Do, R, Doney, A, El Mokhtari, N, Eriksson, P, Fischer, K, Fontanillas, P, Franco-Cereceda, A, Gigante, B, Groop, L, Gustafsson, S, Hager, J, Hallmans, G, Han, B, Ehunt, S, Kang, H, Illig, T, Knowles, J, Kolovou, G, Kuusisto, J, Langenberg, C, Langford, C, Leander, K, Lokki, M, Lundmark, A, Mccarthy, M, Meisinger, C, Melander, O, Mihailov, E, Maouche, S, Morris, A, Müller-Nurasyid, M, Nikus, K, Peden, J, Rayner, N, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schäfer, A, Sivananthan, M, Song, C, Stewart, A, Tan, S, Thorgeirsson, G, Van Der Schoot, C, Wagner, P, Wells, G, Wild, P, Yang, T, Amouyel, P, Arveiler, D, Basart, H, Boehnke, M, Boerwinkle, E, Brambilla, P, Cambien, F, Cupples, A, De Faire, U, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Ferrières, J, Gauguier, D, Go, A, Goodall, A, Gudnason, V, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kähönen, M, Kee, F, Kim, H, Klopp, N, Koenig, W, Kratzer, W, Kuulasmaa, K, Laaksonen, R, Lind, L, Ouwehand, W, Parish, S, Park, J, Pedersen, N, Peters, A, Quertermous, T, Rader, D, Schadt, E, Shah, S, Sinisalo, J, Stark, K, Stefansson, K, Trégouët, D, Virtamo, J, Wareham, N, Zimmermann, M, Nieminen, M, Hengsten, C, Sandhu, M, Pastinen, T, Syvänen, A, Hovingh, G, Dedoussis, G, Lehtimäki, T, Metspalu, A, Zalloua, P, Siegbahn, A, Schreiber, S, Ripatti, S, Blankenberg, S, Perola, M, Clarke, R, Oboehm, B, O’Donnell, C, Reilly, M, März, W, Collins, R, Kathiresan, S, Hamsten, A, Kooner, J, Thorsteinsdottir, U, Danesh, J, Palmer, C, Roberts, R, Watkins, H, Hengstenberg, C, Mcpherson, R, Ziegler, A, Brænne, Ingrid, Zeng, Lingyao, Willenborg, Christina, Tragante, Vinicius, Kessler, Thorsten, Willer, Cristen J., Laakso, Markku, Wallentin, Lars, Franks, Paul W., Salomaa, Veikko, Dehghan, Abbas, Meitinger, Thomas, Samani, Nilesh J., Asselbergs, Folkert W., Erdmann, Jeanette, Schunkert, Heribert, Deloukas, Panos, Kanoni, Stavroula, Farrall, Martin, Assimes, Themistocles L., Thompson, John R., Ingelsson, Erik, Saleheen, Danish, Goldstein, Benjamin A., Absher, Devin, König, Inke R., Cazier, Jean-Baptiste, Johansson, Åsa, Hall, Alistair S., Lee, Jong-Young, Chambers, John C., Esko, Tõnu, Folkersen, Lasse, Goel, Anuj, Grundberg, Elin, Havulinna, Aki S., Ho, Weang K., Hopewell, Jemma C., Eriksson, Niclas, Kleber, Marcus E., Kristiansson, Kati, Lundmark, Per, Lyytikäinen, Leo-Pekka, Rafelt, Suzanne, Shun, Dmitry, Strawbridge, Rona J., Thorleifsson, Gudmar, Tikkanen, Emmi, Van Zuydam, Natalie, Voight, Benjamin F., Waite, Lindsay L., Zhang, Weihua, Zieg, Andreas, Altshuler, David, Balmforth, Anthony J., Barroso, Inês, Braund, Peter S., Burgdorf, Christof, Claudi-Boehm, Simone, Cox, David, Dimitriou, Maria, Do, Ron, Doney, Alex S. F., El Mokhtari, Nour Eddine, Eriksson, Per, Fischer, Krista, Fontanillas, Pierre, Franco-Cereceda, Anders, Gigante, Bruna, Groop, Leif, Gustafsson, Stefan, Hager, Jörg, Hallmans, Göran, Han, Bok-Ghee, Ehunt, Sarah, Kang, Hyun M., Illig, Thomas, Knowles, Joshua W., Kolovou, Genovefa, Kuusisto, Johanna, Langenberg, Claudia, Langford, Cordelia, Leander, Karin, Lokki, Marja-Liisa, Lundmark, Anders, McCarthy, Mark I., Meisinger, Christa, Melander, Olle, Mihailov, Evelin, Maouche, Seraya, Morris, Andrew D., Müller-Nurasyid, Martina, Nikus, Kjell, Peden, John F., Rayner, N. William, Rasheed, Asif, Rosinger, Silke, Rubin, Diana, Rumpf, Moritz P., Schäfer, Arne, Sivananthan, Mohan, Song, Ci, Stewart, Alexandre F. R., Tan, Sian-Tsung, Thorgeirsson, Gudmundur, Van Der Schoot, C. Ellen, Wagner, Peter J., Wells, George A., Wild, Philipp S., Yang, Tsun-Po, Amouyel, Philippe, Arveiler, Dominique, Basart, Hanneke, Boehnke, Michael, Boerwinkle, Eric, Brambilla, Paolo, Cambien, Francois, Cupples, Adrienne L., De Faire, Ulf, Diemert, Patrick, Epstein, Stephen E., Evans, Alun, Ferrario, Marco M., Ferrières, Jean, Gauguier, Dominique, Go, Alan S., Goodall, Alison H., Gudnason, Villi, Hazen, Stanley L., Holm, Hilma, Iribarren, Carlos, Jang, Yangsoo, Kähönen, Mika, Kee, Frank, Kim, Hyo-Soo, Klopp, Norman, Koenig, Wolfgang, Kratzer, Wolfgang, Kuulasmaa, Kari, Laaksonen, Reijo, Lee, Ji-Young, Lind, Lars, Ouwehand, Willem H., Parish, Sarah, Park, Jeong E., Pedersen, Nancy L., Peters, Annette, Quertermous, Thomas, Rader, Daniel J., Schadt, Eric, Shah, Svati H., Sinisalo, Juha, Stark, Klaus, Stefansson, Kari, Trégouët, David-Alexandre, Virtamo, Jarmo, Wareham, Nicholas, Zimmermann, Martina E., Nieminen, Markku S., Hengsten, Christian, Sandhu, Manjinder S., Pastinen, Tomi, Syvänen, Ann-Christine, Hovingh, G. Kees, Dedoussis, George, Lehtimäki, Terho, Metspalu, Andres, Zalloua, Pierre A., Siegbahn, Agneta, Schreiber, Stefan, Ripatti, Samuli, Blankenberg, Stefan S., Perola, Markus, Clarke, Robert, Oboehm, Bernhard, O’Donnell, Christopher, Reilly, Muredach P., März, Winfried, Collins, Rory, Kathiresan, Sekar, Hamsten, Anders, Kooner, Jaspal S., Thorsteinsdottir, Unnur, Danesh, John, Palmer, Colin N. A., Roberts, Robert, Watkins, Hugh, Hall, Alistair, Hengstenberg, Christian, McPherson, Ruth, Ziegler, Andreas, Brænne, I, Zeng, L, Willenborg, C, Tragante, V, Kessler, T, Willer, C, Laakso, M, Wallentin, L, Franks, P, Salomaa, V, Dehghan, A, Meitinger, T, Samani, N, Asselbergs, F, Erdmann, J, Schunkert, H, Deloukas, P, Kanoni, S, Farrall, M, Assimes, T, Thompson, J, Ingelsson, E, Saleheen, D, Goldstein, B, Absher, D, König, I, Cazier, J, Johansson, Å, Hall, A, Lee, J, Chambers, J, Esko, T, Folkersen, L, Goel, A, Grundberg, E, Havulinna, A, Ho, W, Hopewell, J, Eriksson, N, Kleber, M, Kristiansson, K, Lundmark, P, Lyytikäinen, L, Rafelt, S, Shun, D, Strawbridge, R, Thorleifsson, G, Tikkanen, E, Van Zuydam, N, Voight, B, Waite, L, Zhang, W, Zieg, A, Altshuler, D, Balmforth, A, Barroso, I, Braund, P, Burgdorf, C, Claudi-Boehm, S, Cox, D, Dimitriou, M, Do, R, Doney, A, El Mokhtari, N, Eriksson, P, Fischer, K, Fontanillas, P, Franco-Cereceda, A, Gigante, B, Groop, L, Gustafsson, S, Hager, J, Hallmans, G, Han, B, Ehunt, S, Kang, H, Illig, T, Knowles, J, Kolovou, G, Kuusisto, J, Langenberg, C, Langford, C, Leander, K, Lokki, M, Lundmark, A, Mccarthy, M, Meisinger, C, Melander, O, Mihailov, E, Maouche, S, Morris, A, Müller-Nurasyid, M, Nikus, K, Peden, J, Rayner, N, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schäfer, A, Sivananthan, M, Song, C, Stewart, A, Tan, S, Thorgeirsson, G, Van Der Schoot, C, Wagner, P, Wells, G, Wild, P, Yang, T, Amouyel, P, Arveiler, D, Basart, H, Boehnke, M, Boerwinkle, E, Brambilla, P, Cambien, F, Cupples, A, De Faire, U, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Ferrières, J, Gauguier, D, Go, A, Goodall, A, Gudnason, V, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kähönen, M, Kee, F, Kim, H, Klopp, N, Koenig, W, Kratzer, W, Kuulasmaa, K, Laaksonen, R, Lind, L, Ouwehand, W, Parish, S, Park, J, Pedersen, N, Peters, A, Quertermous, T, Rader, D, Schadt, E, Shah, S, Sinisalo, J, Stark, K, Stefansson, K, Trégouët, D, Virtamo, J, Wareham, N, Zimmermann, M, Nieminen, M, Hengsten, C, Sandhu, M, Pastinen, T, Syvänen, A, Hovingh, G, Dedoussis, G, Lehtimäki, T, Metspalu, A, Zalloua, P, Siegbahn, A, Schreiber, S, Ripatti, S, Blankenberg, S, Perola, M, Clarke, R, Oboehm, B, O’Donnell, C, Reilly, M, März, W, Collins, R, Kathiresan, S, Hamsten, A, Kooner, J, Thorsteinsdottir, U, Danesh, J, Palmer, C, Roberts, R, Watkins, H, Hengstenberg, C, Mcpherson, R, Ziegler, A, Brænne, Ingrid, Zeng, Lingyao, Willenborg, Christina, Tragante, Vinicius, Kessler, Thorsten, Willer, Cristen J., Laakso, Markku, Wallentin, Lars, Franks, Paul W., Salomaa, Veikko, Dehghan, Abbas, Meitinger, Thomas, Samani, Nilesh J., Asselbergs, Folkert W., Erdmann, Jeanette, Schunkert, Heribert, Deloukas, Panos, Kanoni, Stavroula, Farrall, Martin, Assimes, Themistocles L., Thompson, John R., Ingelsson, Erik, Saleheen, Danish, Goldstein, Benjamin A., Absher, Devin, König, Inke R., Cazier, Jean-Baptiste, Johansson, Åsa, Hall, Alistair S., Lee, Jong-Young, Chambers, John C., Esko, Tõnu, Folkersen, Lasse, Goel, Anuj, Grundberg, Elin, Havulinna, Aki S., Ho, Weang K., Hopewell, Jemma C., Eriksson, Niclas, Kleber, Marcus E., Kristiansson, Kati, Lundmark, Per, Lyytikäinen, Leo-Pekka, Rafelt, Suzanne, Shun, Dmitry, Strawbridge, Rona J., Thorleifsson, Gudmar, Tikkanen, Emmi, Van Zuydam, Natalie, Voight, Benjamin F., Waite, Lindsay L., Zhang, Weihua, Zieg, Andreas, Altshuler, David, Balmforth, Anthony J., Barroso, Inês, Braund, Peter S., Burgdorf, Christof, Claudi-Boehm, Simone, Cox, David, Dimitriou, Maria, Do, Ron, Doney, Alex S. F., El Mokhtari, Nour Eddine, Eriksson, Per, Fischer, Krista, Fontanillas, Pierre, Franco-Cereceda, Anders, Gigante, Bruna, Groop, Leif, Gustafsson, Stefan, Hager, Jörg, Hallmans, Göran, Han, Bok-Ghee, Ehunt, Sarah, Kang, Hyun M., Illig, Thomas, Knowles, Joshua W., Kolovou, Genovefa, Kuusisto, Johanna, Langenberg, Claudia, Langford, Cordelia, Leander, Karin, Lokki, Marja-Liisa, Lundmark, Anders, McCarthy, Mark I., Meisinger, Christa, Melander, Olle, Mihailov, Evelin, Maouche, Seraya, Morris, Andrew D., Müller-Nurasyid, Martina, Nikus, Kjell, Peden, John F., Rayner, N. William, Rasheed, Asif, Rosinger, Silke, Rubin, Diana, Rumpf, Moritz P., Schäfer, Arne, Sivananthan, Mohan, Song, Ci, Stewart, Alexandre F. R., Tan, Sian-Tsung, Thorgeirsson, Gudmundur, Van Der Schoot, C. Ellen, Wagner, Peter J., Wells, George A., Wild, Philipp S., Yang, Tsun-Po, Amouyel, Philippe, Arveiler, Dominique, Basart, Hanneke, Boehnke, Michael, Boerwinkle, Eric, Brambilla, Paolo, Cambien, Francois, Cupples, Adrienne L., De Faire, Ulf, Diemert, Patrick, Epstein, Stephen E., Evans, Alun, Ferrario, Marco M., Ferrières, Jean, Gauguier, Dominique, Go, Alan S., Goodall, Alison H., Gudnason, Villi, Hazen, Stanley L., Holm, Hilma, Iribarren, Carlos, Jang, Yangsoo, Kähönen, Mika, Kee, Frank, Kim, Hyo-Soo, Klopp, Norman, Koenig, Wolfgang, Kratzer, Wolfgang, Kuulasmaa, Kari, Laaksonen, Reijo, Lee, Ji-Young, Lind, Lars, Ouwehand, Willem H., Parish, Sarah, Park, Jeong E., Pedersen, Nancy L., Peters, Annette, Quertermous, Thomas, Rader, Daniel J., Schadt, Eric, Shah, Svati H., Sinisalo, Juha, Stark, Klaus, Stefansson, Kari, Trégouët, David-Alexandre, Virtamo, Jarmo, Wareham, Nicholas, Zimmermann, Martina E., Nieminen, Markku S., Hengsten, Christian, Sandhu, Manjinder S., Pastinen, Tomi, Syvänen, Ann-Christine, Hovingh, G. Kees, Dedoussis, George, Lehtimäki, Terho, Metspalu, Andres, Zalloua, Pierre A., Siegbahn, Agneta, Schreiber, Stefan, Ripatti, Samuli, Blankenberg, Stefan S., Perola, Markus, Clarke, Robert, Oboehm, Bernhard, O’Donnell, Christopher, Reilly, Muredach P., März, Winfried, Collins, Rory, Kathiresan, Sekar, Hamsten, Anders, Kooner, Jaspal S., Thorsteinsdottir, Unnur, Danesh, John, Palmer, Colin N. A., Roberts, Robert, Watkins, Hugh, Hall, Alistair, Hengstenberg, Christian, McPherson, Ruth, and Ziegler, Andreas

Abstract

Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10−12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10−10 and 2.21 × 10−6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples.

Published
2017

2. Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk

Author

Brænne, Ingrid, Zeng, Lingyao, Willenborg, Christina, Tragante, Vinicius, Kessler, Thorsten, Willer, Cristen J., Laakso, Markku, Wallentin, Lars, Franks, Paul W., Salomaa, Veikko, Dehghan, Abbas, Meitinger, Thomas, Samani, Nilesh J., Asselbergs, Folkert W, Erdmann, Jeanette, Schunkert, Heribert, CARDIoGRAM Consortium, Brænne, Ingrid, Zeng, Lingyao, Willenborg, Christina, Tragante, Vinicius, Kessler, Thorsten, Willer, Cristen J., Laakso, Markku, Wallentin, Lars, Franks, Paul W., Salomaa, Veikko, Dehghan, Abbas, Meitinger, Thomas, Samani, Nilesh J., Asselbergs, Folkert W, Erdmann, Jeanette, Schunkert, Heribert, and CARDIoGRAM Consortium

Published
2017

3. Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk

Author

Circulatory Health, Experimentele Afd. Cardiologie 1, Onderzoek Precision medicine, Team Medisch, Cardiologie, Brænne, Ingrid, Zeng, Lingyao, Willenborg, Christina, Tragante, Vinicius, Kessler, Thorsten, Willer, Cristen J., Laakso, Markku, Wallentin, Lars, Franks, Paul W., Salomaa, Veikko, Dehghan, Abbas, Meitinger, Thomas, Samani, Nilesh J., Asselbergs, Folkert W, Erdmann, Jeanette, Schunkert, Heribert, CARDIoGRAM Consortium, Circulatory Health, Experimentele Afd. Cardiologie 1, Onderzoek Precision medicine, Team Medisch, Cardiologie, Brænne, Ingrid, Zeng, Lingyao, Willenborg, Christina, Tragante, Vinicius, Kessler, Thorsten, Willer, Cristen J., Laakso, Markku, Wallentin, Lars, Franks, Paul W., Salomaa, Veikko, Dehghan, Abbas, Meitinger, Thomas, Samani, Nilesh J., Asselbergs, Folkert W, Erdmann, Jeanette, Schunkert, Heribert, and CARDIoGRAM Consortium

Published
2017

4. Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.

Author

Horikoshi, Momoko, Mӓgi, Reedik, van de Bunt, Martijn, Surakka, Ida, Sarin, Antti-Pekka, Mahajan, Anubha, Marullo, Letizia, Thorleifsson, Gudmar, Hӓgg, Sara, Hottenga, Jouke-Jan, Ladenvall, Claes, Ried, Janina S, Winkler, Thomas W, Willems, Sara M, Pervjakova, Natalia, Esko, Tõnu, Beekman, Marian, Nelson, Christopher P, Willenborg, Christina, Wiltshire, Steven, Ferreira, Teresa, Fernandez, Juan, Gaulton, Kyle J, Steinthorsdottir, Valgerdur, Hamsten, Anders, Magnusson, Patrik K E, Willemsen, Gonneke, Milaneschi, Yuri, Robertson, Neil R, Groves, Christopher J, Bennett, Amanda J, Lehtimӓki, Terho, Viikari, Jorma S, Rung, Johan, Lyssenko, Valeriya, Perola, Markus, Heid, Iris M, Herder, Christian, Grallert, Harald, Müller-Nurasyid, Martina, Roden, Michael, Hypponen, Elina, Isaacs, Aaron, van Leeuwen, Elisabeth M, Karssen, Lennart C, Mihailov, Evelin, Houwing-Duistermaat, Jeanine J, de Craen, Anton J M, Deelen, Joris, Havulinna, Aki S, Blades, Matthew, Hengstenberg, Christian, Erdmann, Jeanette, Schunkert, Heribert, Kaprio, Jaakko, Tobin, Martin D, Samani, Nilesh J, Lind, Lars, Salomaa, Veikko, Lindgren, Cecilia M, Slagboom, P Eline, Metspalu, Andres, van Duijn, Cornelia M, Eriksson, Johan G, Peters, Annette, Gieger, Christian, Jula, Antti, Groop, Leif, Raitakari, Olli T, Power, Chris, Penninx, Brenda W J H, de Geus, Eco, Smit, Johannes H, Boomsma, Dorret I, Pedersen, Nancy L, Ingelsson, Erik, Thorsteinsdottir, Unnur, Stefansson, Kari, Ripatti, Samuli, Prokopenko, Inga, McCarthy, Mark I, Morris, Andrew P, Horikoshi, Momoko, Mӓgi, Reedik, van de Bunt, Martijn, Surakka, Ida, Sarin, Antti-Pekka, Mahajan, Anubha, Marullo, Letizia, Thorleifsson, Gudmar, Hӓgg, Sara, Hottenga, Jouke-Jan, Ladenvall, Claes, Ried, Janina S, Winkler, Thomas W, Willems, Sara M, Pervjakova, Natalia, Esko, Tõnu, Beekman, Marian, Nelson, Christopher P, Willenborg, Christina, Wiltshire, Steven, Ferreira, Teresa, Fernandez, Juan, Gaulton, Kyle J, Steinthorsdottir, Valgerdur, Hamsten, Anders, Magnusson, Patrik K E, Willemsen, Gonneke, Milaneschi, Yuri, Robertson, Neil R, Groves, Christopher J, Bennett, Amanda J, Lehtimӓki, Terho, Viikari, Jorma S, Rung, Johan, Lyssenko, Valeriya, Perola, Markus, Heid, Iris M, Herder, Christian, Grallert, Harald, Müller-Nurasyid, Martina, Roden, Michael, Hypponen, Elina, Isaacs, Aaron, van Leeuwen, Elisabeth M, Karssen, Lennart C, Mihailov, Evelin, Houwing-Duistermaat, Jeanine J, de Craen, Anton J M, Deelen, Joris, Havulinna, Aki S, Blades, Matthew, Hengstenberg, Christian, Erdmann, Jeanette, Schunkert, Heribert, Kaprio, Jaakko, Tobin, Martin D, Samani, Nilesh J, Lind, Lars, Salomaa, Veikko, Lindgren, Cecilia M, Slagboom, P Eline, Metspalu, Andres, van Duijn, Cornelia M, Eriksson, Johan G, Peters, Annette, Gieger, Christian, Jula, Antti, Groop, Leif, Raitakari, Olli T, Power, Chris, Penninx, Brenda W J H, de Geus, Eco, Smit, Johannes H, Boomsma, Dorret I, Pedersen, Nancy L, Ingelsson, Erik, Thorsteinsdottir, Unnur, Stefansson, Kari, Ripatti, Samuli, Prokopenko, Inga, McCarthy, Mark I, and Morris, Andrew P

Abstract

Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.

Published
2015

5. Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation

Author

University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Clinicum, Horikoshi, Momoko, Maegi, Reedik, van de Bunt, Martijn, Surakka, Ida, Sarin, Antti-Pekka, Mahajan, Anubha, Marullo, Letizia, Thorleifsson, Gudmar, Haegg, Sara, Hottenga, Jouke-Jan, Ladenvall, Claes, Ried, Janina S., Winkler, Thomas W., Willems, Sara M., Tsernikova, Natalia, Esko, Tonu, Beekman, Marian, Nelson, Christopher P., Willenborg, Christina, Wiltshire, Steven, Ferreira, Teresa, Fernandez, Juan, Gaulton, Kyle J., Steinthorsdottir, Valgerdur, Hamsten, Anders, Magnusson, Patrik K. E., Willemsen, Gonneke, Milaneschi, Yuri, Robertson, Neil R., Groves, Christopher J., Bennett, Amanda J., Lehtimaeki, Terho, Viikari, Jorma S., Rung, Johan, Lyssenko, Valeriya, Perola, Markus, Heid, Iris M., Herder, Christian, Grallert, Harald, Mueller-Nurasyid, Martina, Roden, Michael, Hypponen, Elina, Isaacs, Aaron, van Leeuwen, Elisabeth M., Karssen, Lennart C., Mihailov, Evelin, Houwing-Duistermaat, Jeanine J., de Craen, Anton J. M., Deelen, Joris, Havulinna, Aki S., Blades, Matthew, Hengstenberg, Christian, Erdmann, Jeanette, Schunkert, Heribert, Kaprio, Jaakko, Tobin, Martin D., Samani, Nilesh J., Lind, Lars, Salomaa, Veikko, Lindgren, Cecilia M., Slagboom, P. Eline, Metspalu, Andres, van Duijn, Cornelia M., Eriksson, Johan G., Peters, Annette, Gieger, Christian, Jula, Antti, Groop, Leif, Raitakari, Olli T., Power, Chris, Penninx, Brenda W. J. H., de Geus, Eco, Smit, Johannes H., Boomsma, Dorret I., Pedersen, Nancy L., Ingelsson, Erik, Thorsteinsdottir, Unnur, Stefansson, Kari, Ripatti, Samuli, Prokopenko, Inga, McCarthy, Mark I., Morris, Andrew P., Engage Consortium, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Clinicum, Horikoshi, Momoko, Maegi, Reedik, van de Bunt, Martijn, Surakka, Ida, Sarin, Antti-Pekka, Mahajan, Anubha, Marullo, Letizia, Thorleifsson, Gudmar, Haegg, Sara, Hottenga, Jouke-Jan, Ladenvall, Claes, Ried, Janina S., Winkler, Thomas W., Willems, Sara M., Tsernikova, Natalia, Esko, Tonu, Beekman, Marian, Nelson, Christopher P., Willenborg, Christina, Wiltshire, Steven, Ferreira, Teresa, Fernandez, Juan, Gaulton, Kyle J., Steinthorsdottir, Valgerdur, Hamsten, Anders, Magnusson, Patrik K. E., Willemsen, Gonneke, Milaneschi, Yuri, Robertson, Neil R., Groves, Christopher J., Bennett, Amanda J., Lehtimaeki, Terho, Viikari, Jorma S., Rung, Johan, Lyssenko, Valeriya, Perola, Markus, Heid, Iris M., Herder, Christian, Grallert, Harald, Mueller-Nurasyid, Martina, Roden, Michael, Hypponen, Elina, Isaacs, Aaron, van Leeuwen, Elisabeth M., Karssen, Lennart C., Mihailov, Evelin, Houwing-Duistermaat, Jeanine J., de Craen, Anton J. M., Deelen, Joris, Havulinna, Aki S., Blades, Matthew, Hengstenberg, Christian, Erdmann, Jeanette, Schunkert, Heribert, Kaprio, Jaakko, Tobin, Martin D., Samani, Nilesh J., Lind, Lars, Salomaa, Veikko, Lindgren, Cecilia M., Slagboom, P. Eline, Metspalu, Andres, van Duijn, Cornelia M., Eriksson, Johan G., Peters, Annette, Gieger, Christian, Jula, Antti, Groop, Leif, Raitakari, Olli T., Power, Chris, Penninx, Brenda W. J. H., de Geus, Eco, Smit, Johannes H., Boomsma, Dorret I., Pedersen, Nancy L., Ingelsson, Erik, Thorsteinsdottir, Unnur, Stefansson, Kari, Ripatti, Samuli, Prokopenko, Inga, McCarthy, Mark I., Morris, Andrew P., and Engage Consortium

Abstract

Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency >= 0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.

Published
2015

6. Integrative Genomics Reveals Novel Molecular Pathways and Gene Networks for Coronary Artery Disease.

Author

Mäkinen, Ville-Petteri, Civelek, Mete, Meng, Qingying, Zhang, Bin, Zhu, Jun, Levian, Candace, Huan, Tianxiao, Segrè, Ayellet V., Ghosh, Sujoy, Vivar, Juan, Nikpay, Majid, Stewart, Alexandre F. R., Nelson, Christopher P., Willenborg, Christina, Erdmann, Jeanette, Blakenberg, Stefan, O'Donnell, Christopher J., März, Winfried, Laaksonen, Reijo, and Epstein, Stephen E.

Subjects
CORONARY disease, HERITABILITY, GENE regulatory networks, MYOCARDIAL infarction treatment, GENOMICS
Abstract

The majority of the heritability of coronary artery disease (CAD) remains unexplained, despite recent successes of genome-wide association studies (GWAS) in identifying novel susceptibility loci. Integrating functional genomic data from a variety of sources with a large-scale meta-analysis of CAD GWAS may facilitate the identification of novel biological processes and genes involved in CAD, as well as clarify the causal relationships of established processes. Towards this end, we integrated 14 GWAS from the CARDIoGRAM Consortium and two additional GWAS from the Ottawa Heart Institute (25,491 cases and 66,819 controls) with 1) genetics of gene expression studies of CAD-relevant tissues in humans, 2) metabolic and signaling pathways from public databases, and 3) data-driven, tissue-specific gene networks from a multitude of human and mouse experiments. We not only detected CAD-associated gene networks of lipid metabolism, coagulation, immunity, and additional networks with no clear functional annotation, but also revealed key driver genes for each CAD network based on the topology of the gene regulatory networks. In particular, we found a gene network involved in antigen processing to be strongly associated with CAD. The key driver genes of this network included glyoxalase I (GLO1) and peptidylprolyl isomerase I (PPIL1), which we verified as regulatory by siRNA experiments in human aortic endothelial cells. Our results suggest genetic influences on a diverse set of both known and novel biological processes that contribute to CAD risk. The key driver genes for these networks highlight potential novel targets for further mechanistic studies and therapeutic interventions. [ABSTRACT FROM AUTHOR]

Published
2014
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7. Genetic Variants from Lipid-Related Pathways and Risk for Incident Myocardial Infarction.

Author

Song, Ci, Pedersen, Nancy L., Reynolds, Chandra A., Sabater-Lleal, Maria, Kanoni, Stavroula, Willenborg, Christina, Syvänen, Ann-Christine, Watkins, Hugh, Hamsten, Anders, Prince, Jonathan A., and Ingelsson, Erik

Subjects
MYOCARDIAL infarction risk factors, DISEASE incidence, ATHEROSCLEROSIS, DISEASE progression, LIPID metabolism disorders, SINGLE nucleotide polymorphisms, CARDIOVASCULAR diseases
Abstract

Background: Circulating lipids levels, as well as several familial lipid metabolism disorders, are strongly associated with initiation and progression of atherosclerosis and incidence of myocardial infarction (MI). Objectives: We hypothesized that genetic variants associated with circulating lipid levels would also be associated with MI incidence, and have tested this in three independent samples. Setting and Subjects: Using age- and sex-adjusted additive genetic models, we analyzed 554 single nucleotide polymorphisms (SNPs) in 41 candidate gene regions proposed to be involved in lipid-related pathways potentially predisposing to incidence of MI in 2,602 participants of the Swedish Twin Register (STR; 57% women). All associations with nominal P<0.01 were further investigated in the Uppsala Longitudinal Study of Adult Men (ULSAM; N = 1,142). Results: In the present study, we report associations of lipid-related SNPs with incident MI in two community-based longitudinal studies with in silico replication in a meta-analysis of genome-wide association studies. Overall, there were 9 SNPs in STR with nominal P-value <0.01 that were successfully genotyped in ULSAM. rs4149313 located in ABCA1 was associated with MI incidence in both longitudinal study samples with nominal significance (hazard ratio, 1.36 and 1.40; P-value, 0.004 and 0.015 in STR and ULSAM, respectively). In silico replication supported the association of rs4149313 with coronary artery disease in an independent meta-analysis including 173,975 individuals of European descent from the CARDIoGRAMplusC4D consortium (odds ratio, 1.03; P-value, 0.048). Conclusions: rs4149313 is one of the few amino acid changing variants in ABCA1 known to associate with reduced cholesterol efflux. Our results are suggestive of a weak association between this variant and the development of atherosclerosis and MI. [ABSTRACT FROM AUTHOR]

Published
2013
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8. Genetic Markers Enhance Coronary Risk Prediction in Men: The MORGAM Prospective Cohorts.

Author

Hughes, Maria F., Saarela, Olli, Stritzke, Jan, Kee, Frank, Silander, Kaisa, Klopp, Norman, Kontto, Jukka, Karvanen, Juha, Willenborg, Christina, Salomaa, Veikko, Virtamo, Jarmo, Amouyel, Phillippe, Arveiler, Dominique, Ferrières, Jean, Wiklund, Per-Gunner, Baumert, Jens, Thorand, Barbara, Diemert, Patrick, Trégouët, David-Alexandre, and Hengstenberg, Christian

Subjects
CORONARY disease, GENETICS, COHORT analysis, HAPLOTYPES, MIDDLE-aged men, DISEASE risk factors
Abstract

Background: More accurate coronary heart disease (CHD) prediction, specifically in middle-aged men, is needed to reduce the burden of disease more effectively. We hypothesised that a multilocus genetic risk score could refine CHD prediction beyond classic risk scores and obtain more precise risk estimates using a prospective cohort design. Methods: Using data from nine prospective European cohorts, including 26,221 men, we selected in a case-cohort setting 4,818 healthy men at baseline, and used Cox proportional hazards models to examine associations between CHD and risk scores based on genetic variants representing 13 genomic regions. Over follow-up (range: 5-18 years), 1,736 incident CHD events occurred. Genetic risk scores were validated in men with at least 10 years of follow-up (632 cases, 1361 non-cases). Genetic risk score 1 (GRS1) combined 11 SNPs and two haplotypes, with effect estimates from previous genome-wide association studies. GRS2 combined 11 SNPs plus 4 SNPs from the haplotypes with coefficients estimated from these prospective cohorts using 10-fold cross-validation. Scores were added to a model adjusted for classic risk factors comprising the Framingham risk score and 10-year risks were derived. Results: Both scores improved net reclassification (NRI) over the Framingham score (7.5%, p = 0.017 for GRS1, 6.5%, p = 0.044 for GRS2) but GRS2 also improved discrimination (c-index improvement 1.11%, p = 0.048). Subgroup analysis on men aged 50-59 (436 cases, 603 non-cases) improved net reclassification for GRS1 (13.8%) and GRS2 (12.5%). Net reclassification improvement remained significant for both scores when family history of CHD was added to the baseline model for this male subgroup improving prediction of early onset CHD events. Conclusions: Genetic risk scores add precision to risk estimates for CHD and improve prediction beyond classic risk factors, particularly for middle aged men. [ABSTRACT FROM AUTHOR]

Published
2012
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9. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author

Winkler, Thomas W., Justice, Anne E., Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F., Chu, Su, Czajkowski, Jacek, Esko, Tõnu, Fall, Tove, Kilpeläinen, Tuomas O., Lu, Yingchang, Mägi, Reedik, Mihailov, Evelin, Pers, Tune H., Rüeger, Sina, Teumer, Alexander, Ehret, Georg B., Ferreira, Teresa, Heard-Costa, Nancy L., Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D., Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M., Jansen, Rick, Westra, Harm-Jan, White, Charles C., Absher, Devin, Ahluwalia, Tarunveer S., Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L., de Craen, Anton J. M., Bis, Joshua C., Bonnefond, Amélie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston W. K., Delgado, Graciela, Demirkan, Ayse, Dueker, Nicole, Eklund, Niina, Eiriksdottir, Gudny, Eriksson, Joel, Feenstra, Bjarke, Fischer, Krista, Frau, Francesca, Galesloot, Tessel E., Geller, Frank, Goel, Anuj, Gorski, Mathias, Grammer, Tanja B., Gustafsson, Stefan, Haitjema, Saskia, Hottenga, Jouke-Jan, Huffman, Jennifer E., Jackson, Anne U., Jacobs, Kevin B., Johansson, Åsa, Kaakinen, Marika, Kleber, Marcus E., Lahti, Jari, Leach, Irene Mateo, Lehne, Benjamin, Liu, Youfang, Lo, Ken Sin, Lorentzon, Mattias, Luan, Jian'an, Madden, Pamela A. F., Mangino, Massimo, McKnight, Barbara, Medina-Gomez, Carolina, Monda, Keri L., Montasser, May E., Müller, Gabriele, Müller-Nurasyid, Martina, Nolte, Ilja M., Panoutsopoulou, Kalliope, Pascoe, Laura, Paternoster, Lavinia, Rayner, Nigel W., Renström, Frida, Rizzi, Federica, Rose, Lynda M., Ryan, Kathy A., Salo, Perttu, Sanna, Serena, Scharnagl, Hubert, Shi, Jianxin, Smith, Albert Vernon, Southam, Lorraine, Stančáková, Alena, Steinthorsdottir, Valgerdur, Strawbridge, Rona J., Sung, Yun Ju, Tachmazidou, Ioanna, Tanaka, Toshiko, Thorleifsson, Gudmar, Trompet, Stella, Pervjakova, Natalia, Tyrer, Jonathan P., Vandenput, Liesbeth, van der Laan, Sander W, van der Velde, Nathalie, van Setten, Jessica, van Vliet-Ostaptchouk, Jana V., Verweij, Niek, Vlachopoulou, Efthymia, Waite, Lindsay L., Wang, Sophie R., Wang, Zhaoming, Wild, Sarah H., Willenborg, Christina, Wilson, James F., Wong, Andrew, Yang, Jian, Yengo, Loïc, Yerges-Armstrong, Laura M., Yu, Lei, Zhang, Weihua, Zhao, Jing Hua, Andersson, Ehm A., Bakker, Stephan J. L., Baldassarre, Damiano, Banasik, Karina, Barcella, Matteo, Barlassina, Cristina, Bellis, Claire, Benaglio, Paola, Blangero, John, Blüher, Matthias, Bonnet, Fabrice, Bonnycastle, Lori L., Boyd, Heather A., Bruinenberg, Marcel, Buchman, Aron S, Campbell, Harry, Chen, Yii-Der Ida, Chines, Peter S., Claudi-Boehm, Simone, Cole, John, Collins, Francis S., de Geus, Eco J. C., de Groot, Lisette C. P. G. M., Dimitriou, Maria, Duan, Jubao, Enroth, Stefan, Eury, Elodie, Farmaki, Aliki-Eleni, Forouhi, Nita G., Friedrich, Nele, Gejman, Pablo V., Gigante, Bruna, Glorioso, Nicola, Go, Alan S., Gottesman, Omri, Gräßler, Jürgen, Grallert, Harald, Grarup, Niels, Gu, Yu-Mei, Broer, Linda, Ham, Annelies C., Hansen, Torben, Harris, Tamara B., Hartman, Catharina A., Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew T., Heath, Andrew C., Henders, Anjali K., Hernandez, Dena, Hillege, Hans, Holmen, Oddgeir, Hovingh, Kees G, Hui, Jennie, Husemoen, Lise L., Hutri-Kähönen, Nina, Hysi, Pirro G., Illig, Thomas, De Jager, Philip L., Jalilzadeh, Shapour, Jørgensen, Torben, Jukema, J. Wouter, Juonala, Markus, Kanoni, Stavroula, Karaleftheri, Maria, Khaw, Kay Tee, Kinnunen, Leena, Kittner, Steven J., Koenig, Wolfgang, Kolcic, Ivana, Kovacs, Peter, Krarup, Nikolaj T., Kratzer, Wolfgang, Krüger, Janine, Kuh, Diana, Kumari, Meena, Kyriakou, Theodosios, Langenberg, Claudia, Lannfelt, Lars, Lanzani, Chiara, Lotay, Vaneet, Launer, Lenore J., Leander, Karin, Lindström, Jaana, Linneberg, Allan, Liu, Yan-Ping, Lobbens, Stéphane, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Magnusson, Patrik K., McArdle, Wendy L., Menni, Cristina, Merger, Sigrun, Milani, Lili, Montgomery, Grant W., Morris, Andrew P., Narisu, Narisu, Nelis, Mari, Ong, Ken K., Palotie, Aarno, Pérusse, Louis, Pichler, Irene, Pilia, Maria G., Pouta, Anneli, Rheinberger, Myriam, Ribel-Madsen, Rasmus, Richards, Marcus, Rice, Kenneth M., Rice, Treva K., Rivolta, Carlo, Salomaa, Veikko, Sanders, Alan R., Sarzynski, Mark A., Scholtens, Salome, Scott, Robert A., Scott, William R., Sebert, Sylvain, Sengupta, Sebanti, Sennblad, Bengt, Seufferlein, Thomas, Silveira, Angela, Slagboom, P. Eline, Smit, Jan H., Sparsø, Thomas H., Stirrups, Kathleen, Stolk, Ronald P., Stringham, Heather M., Swertz, Morris A, Swift, Amy J., Syvänen, Ann-Christine, Tan, Sian-Tsung, Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Tsafantakis, Emmanouil, van der Most, Peter J., Völker, Uwe, Vohl, Marie-Claude, Vonk, Judith M., Waldenberger, Melanie, Walker, Ryan W., Wennauer, Roman, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Wright, Alan F., Zillikens, M. Carola, van Dijk, Suzanne C., van Schoor, Natasja M., Asselbergs, Folkert W., de Bakker, Paul I. W., Beckmann, Jacques S., Beilby, John, Bennett, David A., Bergman, Richard N., Bergmann, Sven, Böger, Carsten A., Boehm, Bernhard O., Boerwinkle, Eric, Boomsma, Dorret I., Bornstein, Stefan R., Bottinger, Erwin P., Bouchard, Claude, Chambers, John C., Chanock, Stephen J., Chasman, Daniel I., Cucca, Francesco, Cusi, Daniele, Dedoussis, George, Erdmann, Jeanette, Eriksson, Johan G., Evans, Denis A., de Faire, Ulf, Farrall, Martin, Ferrucci, Luigi, Ford, Ian, Franke, Lude, Franks, Paul W., Froguel, Philippe, Gansevoort, Ron T., Gieger, Christian, Grönberg, Henrik, Gudnason, Vilmundur, Gyllensten, Ulf, Hall, Per, Hamsten, Anders, van der Harst, Pim, Hayward, Caroline, Heliövaara, Markku, Hengstenberg, Christian, Hicks, Andrew A, Hingorani, Aroon, Hofman, Albert, Hu, Frank, Huikuri, Heikki V., Hveem, Kristian, James, Alan L., Jordan, Joanne M., Jula, Antti, Kähönen, Mika, Kajantie, Eero, Kathiresan, Sekar, Kiemeney, Lambertus A. L. M., Kivimaki, Mika, Knekt, Paul B., Koistinen, Heikki A., Kooner, Jaspal S., Koskinen, Seppo, Kuusisto, Johanna, Maerz, Winfried, Martin, Nicholas G, Laakso, Markku, Lakka, Timo A., Lehtimäki, Terho, Lettre, Guillaume, Levinson, Douglas F., Lind, Lars, Lokki, Marja-Liisa, Mäntyselkä, Pekka, Melbye, Mads, Metspalu, Andres, Mitchell, Braxton D., Moll, Frans L., Murray, Jeffrey C., Musk, Arthur W., Nieminen, Markku S., Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J., Oostra, Ben A., Palmer, Lyle J, Pankow, James S., Pasterkamp, Gerard, Pedersen, Nancy L., Pedersen, Oluf, Penninx, Brenda W., Perola, Markus, Peters, Annette, Polašek, Ozren, Pramstaller, Peter P., Psaty, Bruce M., Qi, Lu, Quertermous, Thomas, Raitakari, Olli T., Rankinen, Tuomo, Rauramaa, Rainer, Ridker, Paul M., Rioux, John D., Rivadeneira, Fernando, Rotter, Jerome I., Rudan, Igor, den Ruijter, Hester M., Saltevo, Juha, Sattar, Naveed, Schunkert, Heribert, Schwarz, Peter E. H., Shuldiner, Alan R., Sinisalo, Juha, Snieder, Harold, Sørensen, Thorkild I. A., Spector, Tim D., Staessen, Jan A., Stefania, Bandinelli, Thorsteinsdottir, Unnur, Stumvoll, Michael, Tardif, Jean-Claude, Tremoli, Elena, Tuomilehto, Jaakko, Uitterlinden, André G., Uusitupa, Matti, Verbeek, André L. M., Vermeulen, Sita H., Viikari, Jorma S., Vitart, Veronique, Völzke, Henry, Vollenweider, Peter, Waeber, Gérard, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J., Watkins, Hugh, Zeggini, Eleftheria, Chakravarti, Aravinda, Clegg, Deborah J., Cupples, L. Adrienne, Gordon-Larsen, Penny, Jaquish, Cashell E., Rao, D. C., Abecasis, Goncalo R., Assimes, Themistocles L., Barroso, Inês, Berndt, Sonja I., Boehnke, Michael, Deloukas, Panos, Fox, Caroline S., Groop, Leif C., Hunter, David J., Ingelsson, Erik, Kaplan, Robert C., McCarthy, Mark I., Mohlke, Karen L., O'Connell, Jeffrey R., Schlessinger, David, Strachan, David P., Stefansson, Kari, van Duijn, Cornelia M., Hirschhorn, Joel N., Lindgren, Cecilia M., Heid, Iris M., North, Kari E., Borecki, Ingrid B., Kutalik, Zoltán, and Loos, Ruth J. F.

Abstract

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

Published
2015
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10. A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels

Author

Waterworth, Dawn, O'Rahilly, Stephen, Hivert, Marie-France, Loos, Ruth J. F., Tanaka, Toshiko, Timpson, Nicholas John, Semple, Robert K., Soranzo, Nicole, Song, Kijoung, Rocha, Nuno, Grundberg, Elin, Dupuis, Josée, Langenberg, Claudia, Prokopenko, Inga, Sladek, Robert, Aulchenko, Yurii, Waeber, Gerard, Erdmann, Jeanette, Burnett, Mary-Susan, Sattar, Naveed, Devaney, Joseph, Willenborg, Christina, Hingorani, Aroon, Witteman, Jaquelin C. M., Vollenweider, Peter, Glaser, Beate, Hengstenberg, Christian, Ferrucci, Luigi, Melzer, David, Stark, Klaus, Deanfield, John, Winogradow, Janina, Grassl, Martina, Hall, Alistair S., Egan, Josephine M., Ricketts, Sally L., König, Inke R., Reinhard, Wibke, Grundy, Scott, Wichmann, H-Erich, Barter, Phil, Mahley, Robert, Kesaniemi, Y. Antero, Rader, Daniel J., Reilly, Muredach P., Stewart, Alexandre F. R., Van Duijn, Cornelia M., Schunkert, Heribert, Burling, Keith, Deloukas, Panos, Pastinen, Tomi, Samani, Nilesh J., McPherson, Ruth, Davey Smith, George, Frayling, Timothy M., Wareham, Nicholas J., Mooser, Vincent, Spector, Tim D., Richards, J. Brent, Florez, Jose Carlos, Perry, John R.B., Saxena, Richa, Evans, David, Meigs, James Benjamin, Thompson, John R., and Epstein, Stephen E.

Subjects
cardiovascular disorders, congenital heart disease, diabetes and endocrinology, obesity, type 2 diabetes, genetics and genomics, genetics of disease
Abstract

The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10−8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10−19 for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10−8, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5×10−6, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2×10−3, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.

Published
2009
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11. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author

Winkler, Thomas W., Justice, Anne E., Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F., Chu, Su, Czajkowski, Jacek, Esko, Tõnu, Fall, Tove, Kilpeläinen, Tuomas O., Lu, Yingchang, Mägi, Reedik, Mihailov, Evelin, Pers, Tune H., Rüeger, Sina, Teumer, Alexander, Ehret, Georg B., Ferreira, Teresa, Heard-Costa, Nancy L., Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D., Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M., Jansen, Rick, Westra, Harm-Jan, White, Charles C., Absher, Devin, Ahluwalia, Tarunveer S., Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L., de Craen, Anton J. M., Bis, Joshua C., Bonnefond, Amélie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston W. K., Delgado, Graciela, Demirkan, Ayse, Dueker, Nicole, Eklund, Niina, Eiriksdottir, Gudny, Eriksson, Joel, Feenstra, Bjarke, Fischer, Krista, Frau, Francesca, Galesloot, Tessel E., Geller, Frank, Goel, Anuj, Gorski, Mathias, Grammer, Tanja B., Gustafsson, Stefan, Haitjema, Saskia, Hottenga, Jouke-Jan, Huffman, Jennifer E., Jackson, Anne U., Jacobs, Kevin B., Johansson, Åsa, Kaakinen, Marika, Kleber, Marcus E., Lahti, Jari, Mateo Leach, Irene, Lehne, Benjamin, Liu, Youfang, Lo, Ken Sin, Lorentzon, Mattias, Luan, Jian'an, Madden, Pamela A. F., Mangino, Massimo, McKnight, Barbara, Medina-Gomez, Carolina, Monda, Keri L., Montasser, May E., Müller, Gabriele, Müller-Nurasyid, Martina, Nolte, Ilja M., Panoutsopoulou, Kalliope, Pascoe, Laura, Paternoster, Lavinia, Rayner, Nigel W., Renström, Frida, Rizzi, Federica, Rose, Lynda M., Ryan, Kathy A., Salo, Perttu, Sanna, Serena, Scharnagl, Hubert, Shi, Jianxin, Smith, Albert Vernon, Southam, Lorraine, Stančáková, Alena, Steinthorsdottir, Valgerdur, Strawbridge, Rona J., Sung, Yun Ju, Tachmazidou, Ioanna, Tanaka, Toshiko, Thorleifsson, Gudmar, Trompet, Stella, Pervjakova, Natalia, Tyrer, Jonathan P., Vandenput, Liesbeth, van der Laan, Sander W., van der Velde, Nathalie, van Setten, Jessica, van Vliet-Ostaptchouk, Jana V., Verweij, Niek, Vlachopoulou, Efthymia, Waite, Lindsay L., Wang, Sophie R., Wang, Zhaoming, Wild, Sarah H., Willenborg, Christina, Wilson, James F., Wong, Andrew, Yang, Jian, Yengo, Loïc, Yerges-Armstrong, Laura M., Yu, Lei, Zhang, Weihua, Zhao, Jing Hua, Andersson, Ehm A., Bakker, Stephan J. L., Baldassarre, Damiano, Banasik, Karina, Barcella, Matteo, Barlassina, Cristina, Bellis, Claire, Benaglio, Paola, Blangero, John, Blüher, Matthias, Bonnet, Fabrice, Bonnycastle, Lori L., Boyd, Heather A., Bruinenberg, Marcel, Buchman, Aron S., Campbell, Harry, Chen, Yii-Der Ida, Chines, Peter S., Claudi-Boehm, Simone, Cole, John, Collins, Francis S., de Geus, Eco J. C., de Groot, Lisette C. P. G. M., Dimitriou, Maria, Duan, Jubao, Enroth, Stefan, Eury, Elodie, Farmaki, Aliki-Eleni, Forouhi, Nita G., Friedrich, Nele, Gejman, Pablo V., Gigante, Bruna, Glorioso, Nicola, Go, Alan S., Gottesman, Omri, Gräßler, Jürgen, Grallert, Harald, Grarup, Niels, Gu, Yu-Mei, Broer, Linda, Ham, Annelies C., Hansen, Torben, Harris, Tamara B., Hartman, Catharina A., Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew T., Heath, Andrew C., Henders, Anjali K., Hernandez, Dena, Hillege, Hans, Holmen, Oddgeir, Hovingh, Kees G., Hui, Jennie, Husemoen, Lise L., Hutri-Kähönen, Nina, Hysi, Pirro G., Illig, Thomas, De Jager, Philip L., Jalilzadeh, Shapour, Jørgensen, Torben, Jukema, J. Wouter, Juonala, Markus, Kanoni, Stavroula, Karaleftheri, Maria, Khaw, Kay Tee, Kinnunen, Leena, Kittner, Steven J., Koenig, Wolfgang, Kolcic, Ivana, Kovacs, Peter, Krarup, Nikolaj T., Kratzer, Wolfgang, Krüger, Janine, Kuh, Diana, Kumari, Meena, Kyriakou, Theodosios, Langenberg, Claudia, Lannfelt, Lars, Lanzani, Chiara, Lotay, Vaneet, Launer, Lenore J., Leander, Karin, Lindström, Jaana, Linneberg, Allan, Liu, Yan-Ping, Lobbens, Stéphane, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Magnusson, Patrik K., McArdle, Wendy L., Menni, Cristina, Merger, Sigrun, Milani, Lili, Montgomery, Grant W., Morris, Andrew P., Narisu, Narisu, Nelis, Mari, Ong, Ken K., Palotie, Aarno, Pérusse, Louis, Pichler, Irene, Pilia, Maria G., Pouta, Anneli, Rheinberger, Myriam, Ribel-Madsen, Rasmus, Richards, Marcus, Rice, Kenneth M., Rice, Treva K., Rivolta, Carlo, Salomaa, Veikko, Sanders, Alan R., Sarzynski, Mark A., Scholtens, Salome, Scott, Robert A., Scott, William R., Sebert, Sylvain, Sengupta, Sebanti, Sennblad, Bengt, Seufferlein, Thomas, Silveira, Angela, Slagboom, P. Eline, Smit, Jan H., Sparsø, Thomas H., Stirrups, Kathleen, Stolk, Ronald P., Stringham, Heather M., Swertz, Morris A., Swift, Amy J., Syvänen, Ann-Christine, Tan, Sian-Tsung, Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Tsafantakis, Emmanouil, van der Most, Peter J., Völker, Uwe, Vohl, Marie-Claude, Vonk, Judith M., Waldenberger, Melanie, Walker, Ryan W., Wennauer, Roman, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Wright, Alan F., Zillikens, M. Carola, van Dijk, Suzanne C., van Schoor, Natasja M., Asselbergs, Folkert W., de Bakker, Paul I. W., Beckmann, Jacques S., Beilby, John, Bennett, David A., Bergman, Richard N., Bergmann, Sven, Böger, Carsten A., Boehm, Bernhard O., Boerwinkle, Eric, Boomsma, Dorret I., Bornstein, Stefan R., Bottinger, Erwin P., Bouchard, Claude, Chambers, John C., Chanock, Stephen J., Chasman, Daniel I., Cucca, Francesco, Cusi, Daniele, Dedoussis, George, Erdmann, Jeanette, Eriksson, Johan G., Evans, Denis A., de Faire, Ulf, Farrall, Martin, Ferrucci, Luigi, Ford, Ian, Franke, Lude, Franks, Paul W., Froguel, Philippe, Gansevoort, Ron T., Gieger, Christian, Grönberg, Henrik, Gudnason, Vilmundur, Gyllensten, Ulf, Hall, Per, Hamsten, Anders, van der Harst, Pim, Hayward, Caroline, Heliövaara, Markku, Hengstenberg, Christian, Hicks, Andrew A., Hingorani, Aroon, Hofman, Albert, Hu, Frank, Huikuri, Heikki V., Hveem, Kristian, James, Alan L., Jordan, Joanne M., Jula, Antti, Kähönen, Mika, Kajantie, Eero, Kathiresan, Sekar, Kiemeney, Lambertus A. L. M., Kivimaki, Mika, Knekt, Paul B., Koistinen, Heikki A., Kooner, Jaspal S., Koskinen, Seppo, Kuusisto, Johanna, Maerz, Winfried, Martin, Nicholas G., Laakso, Markku, Lakka, Timo A., Lehtimäki, Terho, Lettre, Guillaume, Levinson, Douglas F., Lind, Lars, Lokki, Marja-Liisa, Mäntyselkä, Pekka, Melbye, Mads, Metspalu, Andres, Mitchell, Braxton D., Moll, Frans L., Murray, Jeffrey C., Musk, Arthur W., Nieminen, Markku S., Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J., Oostra, Ben A., Palmer, Lyle J., Pankow, James S., Pasterkamp, Gerard, Pedersen, Nancy L., Pedersen, Oluf, Penninx, Brenda W., Perola, Markus, Peters, Annette, Polašek, Ozren, Pramstaller, Peter P., Psaty, Bruce M., Qi, Lu, Quertermous, Thomas, Raitakari, Olli T., Rankinen, Tuomo, Rauramaa, Rainer, Ridker, Paul M., Rioux, John D., Rivadeneira, Fernando, Rotter, Jerome I., Rudan, Igor, den Ruijter, Hester M., Saltevo, Juha, Sattar, Naveed, Schunkert, Heribert, Schwarz, Peter E. H., Shuldiner, Alan R., Sinisalo, Juha, Snieder, Harold, Sørensen, Thorkild I. A., Spector, Tim D., Staessen, Jan A., Stefania, Bandinelli, Thorsteinsdottir, Unnur, Stumvoll, Michael, Tardif, Jean-Claude, Tremoli, Elena, Tuomilehto, Jaakko, Uitterlinden, André G., Uusitupa, Matti, Verbeek, André L. M., Vermeulen, Sita H., Viikari, Jorma S., Vitart, Veronique, Völzke, Henry, Vollenweider, Peter, Waeber, Gérard, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J., Watkins, Hugh, Zeggini, Eleftheria, Charge Consortium, Diagram Consortium, Glgc Consortium, Global-BPGen Consortium, Icbp Consortium, Magic Consortium, Chakravarti, Aravinda, Clegg, Deborah J., Cupples, L. Adrienne, Gordon-Larsen, Penny, Jaquish, Cashell E., Rao, D. C., Abecasis, Goncalo R., Assimes, Themistocles L., Barroso, Inês, Berndt, Sonja I., Boehnke, Michael, Deloukas, Panos, Fox, Caroline S., Groop, Leif C., Hunter, David J., Ingelsson, Erik, Kaplan, Robert C., McCarthy, Mark I., Mohlke, Karen L., O'Connell, Jeffrey R., Schlessinger, David, Strachan, David P., Stefansson, Kari, van Duijn, Cornelia M., Hirschhorn, Joel N., Lindgren, Cecilia M., Heid, Iris M., North, Kari E., Borecki, Ingrid B., Kutalik, Zoltán, and Loos, Ruth J. F.

Subjects
3. Good health

12. Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk.

Author

Brænne I, Zeng L, Willenborg C, Tragante V, Kessler T, Willer CJ, Laakso M, Wallentin L, Franks PW, Salomaa V, Dehghan A, Meitinger T, Samani NJ, Asselbergs FW, Erdmann J, and Schunkert H

Subjects
Cardiovascular Diseases chemically induced, Case-Control Studies, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Cardiovascular Diseases genetics, Genetic Predisposition to Disease, Glatiramer Acetate adverse effects
Abstract

Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10-12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10-10 and 2.21 × 10-6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples.

Published
2017
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13. Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author

Winkler TW, Justice AE, Graff M, Barata L, Feitosa MF, Chu S, Czajkowski J, Esko T, Fall T, Kilpeläinen TO, Lu Y, Mägi R, Mihailov E, Pers TH, Rüeger S, Teumer A, Ehret GB, Ferreira T, Heard-Costa NL, Karjalainen J, Lagou V, Mahajan A, Neinast MD, Prokopenko I, Simino J, Teslovich TM, Jansen R, Westra HJ, White CC, Absher D, Ahluwalia TS, Ahmad S, Albrecht E, Alves AC, Bragg-Gresham JL, de Craen AJ, Bis JC, Bonnefond A, Boucher G, Cadby G, Cheng YC, Chiang CW, Delgado G, Demirkan A, Dueker N, Eklund N, Eiriksdottir G, Eriksson J, Feenstra B, Fischer K, Frau F, Galesloot TE, Geller F, Goel A, Gorski M, Grammer TB, Gustafsson S, Haitjema S, Hottenga JJ, Huffman JE, Jackson AU, Jacobs KB, Johansson Å, Kaakinen M, Kleber ME, Lahti J, Mateo Leach I, Lehne B, Liu Y, Lo KS, Lorentzon M, Luan J, Madden PA, Mangino M, McKnight B, Medina-Gomez C, Monda KL, Montasser ME, Müller G, Müller-Nurasyid M, Nolte IM, Panoutsopoulou K, Pascoe L, Paternoster L, Rayner NW, Renström F, Rizzi F, Rose LM, Ryan KA, Salo P, Sanna S, Scharnagl H, Shi J, Smith AV, Southam L, Stančáková A, Steinthorsdottir V, Strawbridge RJ, Sung YJ, Tachmazidou I, Tanaka T, Thorleifsson G, Trompet S, Pervjakova N, Tyrer JP, Vandenput L, van der Laan SW, van der Velde N, van Setten J, van Vliet-Ostaptchouk JV, Verweij N, Vlachopoulou E, Waite LL, Wang SR, Wang Z, Wild SH, Willenborg C, Wilson JF, Wong A, Yang J, Yengo L, Yerges-Armstrong LM, Yu L, Zhang W, Zhao JH, Andersson EA, Bakker SJ, Baldassarre D, Banasik K, Barcella M, Barlassina C, Bellis C, Benaglio P, Blangero J, Blüher M, Bonnet F, Bonnycastle LL, Boyd HA, Bruinenberg M, Buchman AS, Campbell H, Chen YI, Chines PS, Claudi-Boehm S, Cole J, Collins FS, de Geus EJ, de Groot LC, Dimitriou M, Duan J, Enroth S, Eury E, Farmaki AE, Forouhi NG, Friedrich N, Gejman PV, Gigante B, Glorioso N, Go AS, Gottesman O, Gräßler J, Grallert H, Grarup N, Gu YM, Broer L, Ham AC, Hansen T, Harris TB, Hartman CA, Hassinen M, Hastie N, Hattersley AT, Heath AC, Henders AK, Hernandez D, Hillege H, Holmen O, Hovingh KG, Hui J, Husemoen LL, Hutri-Kähönen N, Hysi PG, Illig T, De Jager PL, Jalilzadeh S, Jørgensen T, Jukema JW, Juonala M, Kanoni S, Karaleftheri M, Khaw KT, Kinnunen L, Kittner SJ, Koenig W, Kolcic I, Kovacs P, Krarup NT, Kratzer W, Krüger J, Kuh D, Kumari M, Kyriakou T, Langenberg C, Lannfelt L, Lanzani C, Lotay V, Launer LJ, Leander K, Lindström J, Linneberg A, Liu YP, Lobbens S, Luben R, Lyssenko V, Männistö S, Magnusson PK, McArdle WL, Menni C, Merger S, Milani L, Montgomery GW, Morris AP, Narisu N, Nelis M, Ong KK, Palotie A, Pérusse L, Pichler I, Pilia MG, Pouta A, Rheinberger M, Ribel-Madsen R, Richards M, Rice KM, Rice TK, Rivolta C, Salomaa V, Sanders AR, Sarzynski MA, Scholtens S, Scott RA, Scott WR, Sebert S, Sengupta S, Sennblad B, Seufferlein T, Silveira A, Slagboom PE, Smit JH, Sparsø TH, Stirrups K, Stolk RP, Stringham HM, Swertz MA, Swift AJ, Syvänen AC, Tan ST, Thorand B, Tönjes A, Tremblay A, Tsafantakis E, van der Most PJ, Völker U, Vohl MC, Vonk JM, Waldenberger M, Walker RW, Wennauer R, Widén E, Willemsen G, Wilsgaard T, Wright AF, Zillikens MC, van Dijk SC, van Schoor NM, Asselbergs FW, de Bakker PI, Beckmann JS, Beilby J, Bennett DA, Bergman RN, Bergmann S, Böger CA, Boehm BO, Boerwinkle E, Boomsma DI, Bornstein SR, Bottinger EP, Bouchard C, Chambers JC, Chanock SJ, Chasman DI, Cucca F, Cusi D, Dedoussis G, Erdmann J, Eriksson JG, Evans DA, de Faire U, Farrall M, Ferrucci L, Ford I, Franke L, Franks PW, Froguel P, Gansevoort RT, Gieger C, Grönberg H, Gudnason V, Gyllensten U, Hall P, Hamsten A, van der Harst P, Hayward C, Heliövaara M, Hengstenberg C, Hicks AA, Hingorani A, Hofman A, Hu F, Huikuri HV, Hveem K, James AL, Jordan JM, Jula A, Kähönen M, Kajantie E, Kathiresan S, Kiemeney LA, Kivimaki M, Knekt PB, Koistinen HA, Kooner JS, Koskinen S, Kuusisto J, Maerz W, Martin NG, Laakso M, Lakka TA, Lehtimäki T, Lettre G, Levinson DF, Lind L, Lokki ML, Mäntyselkä P, Melbye M, Metspalu A, Mitchell BD, Moll FL, Murray JC, Musk AW, Nieminen MS, Njølstad I, Ohlsson C, Oldehinkel AJ, Oostra BA, Palmer LJ, Pankow JS, Pasterkamp G, Pedersen NL, Pedersen O, Penninx BW, Perola M, Peters A, Polašek O, Pramstaller PP, Psaty BM, Qi L, Quertermous T, Raitakari OT, Rankinen T, Rauramaa R, Ridker PM, Rioux JD, Rivadeneira F, Rotter JI, Rudan I, den Ruijter HM, Saltevo J, Sattar N, Schunkert H, Schwarz PE, Shuldiner AR, Sinisalo J, Snieder H, Sørensen TI, Spector TD, Staessen JA, Stefania B, Thorsteinsdottir U, Stumvoll M, Tardif JC, Tremoli E, Tuomilehto J, Uitterlinden AG, Uusitupa M, Verbeek AL, Vermeulen SH, Viikari JS, Vitart V, Völzke H, Vollenweider P, Waeber G, Walker M, Wallaschofski H, Wareham NJ, Watkins H, Zeggini E, Chakravarti A, Clegg DJ, Cupples LA, Gordon-Larsen P, Jaquish CE, Rao DC, Abecasis GR, Assimes TL, Barroso I, Berndt SI, Boehnke M, Deloukas P, Fox CS, Groop LC, Hunter DJ, Ingelsson E, Kaplan RC, McCarthy MI, Mohlke KL, O'Connell JR, Schlessinger D, Strachan DP, Stefansson K, van Duijn CM, Hirschhorn JN, Lindgren CM, Heid IM, North KE, Borecki IB, Kutalik Z, and Loos RJ

Abstract

[This corrects the article DOI: 10.1371/journal.pgen.1005378.].

Published
2016
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14. Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.

Author

Horikoshi M, Mӓgi R, van de Bunt M, Surakka I, Sarin AP, Mahajan A, Marullo L, Thorleifsson G, Hӓgg S, Hottenga JJ, Ladenvall C, Ried JS, Winkler TW, Willems SM, Pervjakova N, Esko T, Beekman M, Nelson CP, Willenborg C, Wiltshire S, Ferreira T, Fernandez J, Gaulton KJ, Steinthorsdottir V, Hamsten A, Magnusson PK, Willemsen G, Milaneschi Y, Robertson NR, Groves CJ, Bennett AJ, Lehtimӓki T, Viikari JS, Rung J, Lyssenko V, Perola M, Heid IM, Herder C, Grallert H, Müller-Nurasyid M, Roden M, Hypponen E, Isaacs A, van Leeuwen EM, Karssen LC, Mihailov E, Houwing-Duistermaat JJ, de Craen AJ, Deelen J, Havulinna AS, Blades M, Hengstenberg C, Erdmann J, Schunkert H, Kaprio J, Tobin MD, Samani NJ, Lind L, Salomaa V, Lindgren CM, Slagboom PE, Metspalu A, van Duijn CM, Eriksson JG, Peters A, Gieger C, Jula A, Groop L, Raitakari OT, Power C, Penninx BW, de Geus E, Smit JH, Boomsma DI, Pedersen NL, Ingelsson E, Thorsteinsdottir U, Stefansson K, Ripatti S, Prokopenko I, McCarthy MI, and Morris AP

Subjects
Body Mass Index, Gene Frequency genetics, Genome-Wide Association Study, Germinal Center Kinases, Glucose-6-Phosphatase genetics, Humans, Polymorphism, Single Nucleotide genetics, Protein Serine-Threonine Kinases genetics, Thrombospondins genetics, Chromosome Mapping, Genetic Predisposition to Disease, Glycemic Index genetics, Obesity genetics, Quantitative Trait Loci genetics
Abstract

Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.

Published
2015
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15. A genome-wide association study reveals variants in ARL15 that influence adiponectin levels.

Author

Richards JB, Waterworth D, O'Rahilly S, Hivert MF, Loos RJ, Perry JR, Tanaka T, Timpson NJ, Semple RK, Soranzo N, Song K, Rocha N, Grundberg E, Dupuis J, Florez JC, Langenberg C, Prokopenko I, Saxena R, Sladek R, Aulchenko Y, Evans D, Waeber G, Erdmann J, Burnett MS, Sattar N, Devaney J, Willenborg C, Hingorani A, Witteman JC, Vollenweider P, Glaser B, Hengstenberg C, Ferrucci L, Melzer D, Stark K, Deanfield J, Winogradow J, Grassl M, Hall AS, Egan JM, Thompson JR, Ricketts SL, König IR, Reinhard W, Grundy S, Wichmann HE, Barter P, Mahley R, Kesaniemi YA, Rader DJ, Reilly MP, Epstein SE, Stewart AF, Van Duijn CM, Schunkert H, Burling K, Deloukas P, Pastinen T, Samani NJ, McPherson R, Davey Smith G, Frayling TM, Wareham NJ, Meigs JB, Mooser V, and Spector TD

Subjects
Adiponectin genetics, Adiponectin physiology, Coronary Disease genetics, Diabetes Mellitus, Type 2 genetics, Female, Genetic Predisposition to Disease, Humans, Male, Polymorphism, Single Nucleotide, Adiponectin blood, Genome-Wide Association Study
Abstract

The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P< or =5x10(-8)). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P< or =0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2x10(-19) for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9x10(-8), n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5x10(-6), n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-3), n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk., Competing Interests: The authors have declared that no competing interests exist.

Published
2009
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