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1. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Lagou, Vasiliki, Mägi, Reedik, Hottenga, Jouke- Jan, Grallert, Harald, Perry, John R. B., Bouatia-Naji, Nabila, Marullo, Letizia, Rybin, Denis, Jansen, Rick, Min, Josine L., Dimas, Antigone S., Ulrich, Anna, Zudina, Liudmila, Gådin, Jesper R., Jiang, Longda, Faggian, Alessia, Bonnefond, Amélie, Fadista, Joao, Stathopoulou, Maria G., Isaacs, Aaron, Willems, Sara M., Navarro, Pau, Tanaka, Toshiko, Jackson, Anne U., Montasser, May E., O’Connell, Jeff R., Bielak, Lawrence F., Webster, Rebecca J., Saxena, Richa, Stafford, Jeanette M., Pourcain, Beate St, Timpson, Nicholas J., Salo, Perttu, Shin, So-Youn, Amin, Najaf, Smith, Albert V., Li, Guo, Verweij, Niek, Goel, Anuj, Ford, Ian, Johnson, Paul C. D., Johnson, Toby, Kapur, Karen, Thorleifsson, Gudmar, Strawbridge, Rona J., Rasmussen-Torvik, Laura J., Esko, Tõnu, Mihailov, Evelin, Fall, Tove, Fraser, Ross M., Mahajan, Anubha, Kanoni, Stavroula, Giedraitis, Vilmantas, Kleber, Marcus E., Silbernagel, Günther, Meyer, Julia, Müller-Nurasyid, Martina, Ganna, Andrea, Sarin, Antti-Pekka, Yengo, Loic, Shungin, Dmitry, Luan, Jian’an, Horikoshi, Momoko, An, Ping, Sanna, Serena, Boettcher, Yvonne, Rayner, N. William, Nolte, Ilja M., Zemunik, Tatijana, Iperen, Erik van, Kovacs, Peter, Hastie, Nicholas D., Wild, Sarah H., McLachlan, Stela, Campbell, Susan, Polasek, Ozren, Carlson, Olga, Egan, Josephine, Kiess, Wieland, Willemsen, Gonneke, Kuusisto, Johanna, Laakso, Markku, Dimitriou, Maria, Hicks, Andrew A., Rauramaa, Rainer, Bandinelli, Stefania, Thorand, Barbara, Liu, Yongmei, Miljkovic, Iva, Lind, Lars, Doney, Alex, Perola, Markus, Hingorani, Aroon, Kivimaki, Mika, Kumari, Meena, Bennett, Amanda J., Groves, Christopher J., Herder, Christian, Koistinen, Heikki A., Kinnunen, Leena, Faire, Ulf de, Bakker, Stephan J. L., Uusitupa, Matti, Palmer, Colin N. A., Jukema, J. Wouter, Sattar, Naveed, Pouta, Anneli, Snieder, Harold, Boerwinkle, Eric, Pankow, James S., Magnusson, Patrik K., Krus, Ulrika, Scapoli, Chiara, de Geus, Eco J. C. N., Blüher, Matthias, Wolffenbuttel, Bruce H. R., Province, Michael A., Abecasis, Goncalo R., Meigs, James B., Hovingh, G. Kees, Lindström, Jaana, Wilson, James F., Wright, Alan F., Dedoussis, George V., Bornstein, Stefan R., Schwarz, Peter E. H., Tönjes, Anke, Winkelmann, Bernhard R., Boehm, Bernhard O., März, Winfried, Metspalu, Andres, Price, Jackie F., Deloukas, Panos, Körner, Antje, Lakka, Timo A., Keinanen-Kiukaanniemi, Sirkka M., Saaristo, Timo E., Bergman, Richard N., Tuomilehto, Jaakko, Wareham, Nicholas J., Langenberg, Claudia, Männistö, Satu, Franks, Paul W., Hayward, Caroline, Vitart, Veronique, Kaprio, Jaakko, Visvikis-Siest, Sophie, Balkau, Beverley, Altshuler, David, Rudan, Igor, Stumvoll, Michael, Campbell, Harry, van Duijn, Cornelia M., Gieger, Christian, Illig, Thomas, Ferrucci, Luigi, Pedersen, Nancy L., Pramstaller, Peter P., Boehnke, Michael, Frayling, Timothy M., Shuldiner, Alan R., Peyser, Patricia A., Kardia, Sharon L. R., Palmer, Lyle J., Penninx, Brenda W., Meneton, Pierre, Harris, Tamara B., Navis, Gerjan, Harst, Pim van der, Smith, George Davey, Forouhi, Nita G., Loos, Ruth J. F., Salomaa, Veikko, Soranzo, Nicole, Boomsma, Dorret I., Groop, Leif, Tuomi, Tiinamaija, Hofman, Albert, Munroe, Patricia B., Gudnason, Vilmundur, Siscovick, David S., Watkins, Hugh, Lecoeur, Cecile, Vollenweider, Peter, Franco-Cereceda, Anders, Eriksson, Per, Jarvelin, Marjo-Riitta, Stefansson, Kari, Hamsten, Anders, Nicholson, George, Karpe, Fredrik, Dermitzakis, Emmanouil T., Lindgren, Cecilia M., McCarthy, Mark I., Froguel, Philippe, Kaakinen, Marika A., Lyssenko, Valeriya, Watanabe, Richard M., Ingelsson, Erik, Florez, Jose C., Dupuis, Josée, Barroso, Inês, Morris, Andrew P., and Prokopenko, Inga

Published
2021
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3. Genetic insights into biological mechanisms governing human ovarian ageing

Author

Ruth, Katherine S, Day, Felix R, Hussain, Jazib, Martínez-Marchal, Ana, Aiken, Catherine E, Azad, Ajuna, Thompson, Deborah J, Knoblochova, Lucie, Abe, Hironori, Tarry-Adkins, Jane L, Gonzalez, Javier Martin, Fontanillas, Pierre, Claringbould, Annique, Bakker, Olivier B, Sulem, Patrick, Walters, Robin G, Terao, Chikashi, Turon, Sandra, Horikoshi, Momoko, Lin, Kuang, Onland-Moret, N Charlotte, Sankar, Aditya, Hertz, Emil Peter Thrane, Timshel, Pascal N, Shukla, Vallari, Borup, Rehannah, Olsen, Kristina W, Aguilera, Paula, Ferrer-Roda, Mònica, Huang, Yan, Stankovic, Stasa, Timmers, Paul R H J, Ahearn, Thomas U, Alizadeh, Behrooz Z, Naderi, Elnaz, Andrulis, Irene L, Arnold, Alice M, Aronson, Kristan J, Augustinsson, Annelie, Bandinelli, Stefania, Barbieri, Caterina M, Beaumont, Robin N, Becher, Heiko, Beckmann, Matthias W, Benonisdottir, Stefania, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E, Bolla, Manjeet K, Boomsma, Dorret I, Bowker, Nicholas, Brody, Jennifer A, Broer, Linda, Buring, Julie E, Campbell, Archie, Campbell, Harry, Castelao, Jose E, Catamo, Eulalia, Chanock, Stephen J, Chenevix-Trench, Georgia, Ciullo, Marina, Corre, Tanguy, Couch, Fergus J, Cox, Angela, Crisponi, Laura, Cross, Simon S, Cucca, Francesco, Czene, Kamila, Smith, George Davey, de Geus, Eco J C N, de Mutsert, Renée, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Dunning, Alison M, Dwek, Miriam, Eriksson, Mikael, Esko, Tõnu, Fasching, Peter A, Faul, Jessica D, Ferrucci, Luigi, Franceschini, Nora, Frayling, Timothy M, Gago-Dominguez, Manuela, Mezzavilla, Massimo, García-Closas, Montserrat, Gieger, Christian, Giles, Graham G, Grallert, Harald, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Guénel, Pascal, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hayward, Caroline, He, Chunyan, He, Wei, Heiss, Gerardo, Høffding, Miya K, Hopper, John L, Hottenga, Jouke J, Hu, Frank, Hunter, David, Ikram, Mohammad A, Jackson, Rebecca D, Joaquim, Micaella D R, John, Esther M, Joshi, Peter K, Karasik, David, Kardia, Sharon L R, Kartsonaki, Christiana, Karlsson, Robert, Kitahara, Cari M, Kolcic, Ivana, Kooperberg, Charles, Kraft, Peter, Kurian, Allison W, Kutalik, Zoltan, La Bianca, Martina, LaChance, Genevieve, Langenberg, Claudia, Launer, Lenore J, Laven, Joop S E, Lawlor, Deborah A, Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lindstrom, Sara, Lindstrom, Tricia, Linet, Martha, Liu, YongMei, Liu, Simin, Luan, Jian'an, Mägi, Reedik, Magnusson, Patrik K E, Mangino, Massimo, Mannermaa, Arto, Marco, Brumat, Marten, Jonathan, Martin, Nicholas G, Mbarek, Hamdi, McKnight, Barbara, Medland, Sarah E, Meisinger, Christa, Meitinger, Thomas, Menni, Cristina, Metspalu, Andres, Milani, Lili, Milne, Roger L, Montgomery, Grant W, Mook-Kanamori, Dennis O, Mulas, Antonella, Mulligan, Anna M, Murray, Alison, Nalls, Mike A, Newman, Anne, Noordam, Raymond, Nutile, Teresa, Nyholt, Dale R, Olshan, Andrew F, Olsson, Håkan, Painter, Jodie N, Patel, Alpa V, Pedersen, Nancy L, Perjakova, Natalia, Peters, Annette, Peters, Ulrike, Pharoah, Paul D P, Polasek, Ozren, Porcu, Eleonora, Psaty, Bruce M, Rahman, Iffat, Rennert, Gad, Rennert, Hedy S, Ridker, Paul M, Ring, Susan M, Robino, Antonietta, Rose, Lynda M, Rosendaal, Frits R, Rossouw, Jacques, Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Sala, Cinzia F, Saloustros, Emmanouil, Sandler, Dale P, Sanna, Serena, Sawyer, Elinor J, Sarnowski, Chloé, Schlessinger, David, Schmidt, Marjanka K, Schoemaker, Minouk J, Schraut, Katharina E, Scott, Christopher, Shekari, Saleh, Shrikhande, Amruta, Smith, Albert V, Smith, Blair H, Smith, Jennifer A, Sorice, Rossella, Southey, Melissa C, Spector, Tim D, Spinelli, John J, Stampfer, Meir, Stöckl, Doris, van Meurs, Joyce B J, Strauch, Konstantin, Styrkarsdottir, Unnur, Swerdlow, Anthony J, Tanaka, Toshiko, Teras, Lauren R, Teumer, Alexander, Þorsteinsdottir, Unnur, Timpson, Nicholas J, Toniolo, Daniela, Traglia, Michela, Troester, Melissa A, Truong, Thérèse, Tyrrell, Jessica, Uitterlinden, André G, Ulivi, Sheila, Vachon, Celine M, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Völzke, Henry, Wang, Qin, Wareham, Nicholas J, Weinberg, Clarice R, Weir, David R, Wilcox, Amber N, van Dijk, Ko Willems, Willemsen, Gonneke, Wilson, James F, Wolffenbuttel, Bruce H R, Wolk, Alicja, Wood, Andrew R, Zhao, Wei, Zygmunt, Marek, Chen, Zhengming, Li, Liming, Franke, Lude, Burgess, Stephen, Deelen, Patrick, Pers, Tune H, Grøndahl, Marie Louise, Andersen, Claus Yding, Pujol, Anna, Ruth, Katherine S, Day, Felix R, Hussain, Jazib, Martínez-Marchal, Ana, Aiken, Catherine E, Azad, Ajuna, Thompson, Deborah J, Knoblochova, Lucie, Abe, Hironori, Tarry-Adkins, Jane L, Gonzalez, Javier Martin, Fontanillas, Pierre, Claringbould, Annique, Bakker, Olivier B, Sulem, Patrick, Walters, Robin G, Terao, Chikashi, Turon, Sandra, Horikoshi, Momoko, Lin, Kuang, Onland-Moret, N Charlotte, Sankar, Aditya, Hertz, Emil Peter Thrane, Timshel, Pascal N, Shukla, Vallari, Borup, Rehannah, Olsen, Kristina W, Aguilera, Paula, Ferrer-Roda, Mònica, Huang, Yan, Stankovic, Stasa, Timmers, Paul R H J, Ahearn, Thomas U, Alizadeh, Behrooz Z, Naderi, Elnaz, Andrulis, Irene L, Arnold, Alice M, Aronson, Kristan J, Augustinsson, Annelie, Bandinelli, Stefania, Barbieri, Caterina M, Beaumont, Robin N, Becher, Heiko, Beckmann, Matthias W, Benonisdottir, Stefania, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E, Bolla, Manjeet K, Boomsma, Dorret I, Bowker, Nicholas, Brody, Jennifer A, Broer, Linda, Buring, Julie E, Campbell, Archie, Campbell, Harry, Castelao, Jose E, Catamo, Eulalia, Chanock, Stephen J, Chenevix-Trench, Georgia, Ciullo, Marina, Corre, Tanguy, Couch, Fergus J, Cox, Angela, Crisponi, Laura, Cross, Simon S, Cucca, Francesco, Czene, Kamila, Smith, George Davey, de Geus, Eco J C N, de Mutsert, Renée, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Dunning, Alison M, Dwek, Miriam, Eriksson, Mikael, Esko, Tõnu, Fasching, Peter A, Faul, Jessica D, Ferrucci, Luigi, Franceschini, Nora, Frayling, Timothy M, Gago-Dominguez, Manuela, Mezzavilla, Massimo, García-Closas, Montserrat, Gieger, Christian, Giles, Graham G, Grallert, Harald, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Guénel, Pascal, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hayward, Caroline, He, Chunyan, He, Wei, Heiss, Gerardo, Høffding, Miya K, Hopper, John L, Hottenga, Jouke J, Hu, Frank, Hunter, David, Ikram, Mohammad A, Jackson, Rebecca D, Joaquim, Micaella D R, John, Esther M, Joshi, Peter K, Karasik, David, Kardia, Sharon L R, Kartsonaki, Christiana, Karlsson, Robert, Kitahara, Cari M, Kolcic, Ivana, Kooperberg, Charles, Kraft, Peter, Kurian, Allison W, Kutalik, Zoltan, La Bianca, Martina, LaChance, Genevieve, Langenberg, Claudia, Launer, Lenore J, Laven, Joop S E, Lawlor, Deborah A, Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lindstrom, Sara, Lindstrom, Tricia, Linet, Martha, Liu, YongMei, Liu, Simin, Luan, Jian'an, Mägi, Reedik, Magnusson, Patrik K E, Mangino, Massimo, Mannermaa, Arto, Marco, Brumat, Marten, Jonathan, Martin, Nicholas G, Mbarek, Hamdi, McKnight, Barbara, Medland, Sarah E, Meisinger, Christa, Meitinger, Thomas, Menni, Cristina, Metspalu, Andres, Milani, Lili, Milne, Roger L, Montgomery, Grant W, Mook-Kanamori, Dennis O, Mulas, Antonella, Mulligan, Anna M, Murray, Alison, Nalls, Mike A, Newman, Anne, Noordam, Raymond, Nutile, Teresa, Nyholt, Dale R, Olshan, Andrew F, Olsson, Håkan, Painter, Jodie N, Patel, Alpa V, Pedersen, Nancy L, Perjakova, Natalia, Peters, Annette, Peters, Ulrike, Pharoah, Paul D P, Polasek, Ozren, Porcu, Eleonora, Psaty, Bruce M, Rahman, Iffat, Rennert, Gad, Rennert, Hedy S, Ridker, Paul M, Ring, Susan M, Robino, Antonietta, Rose, Lynda M, Rosendaal, Frits R, Rossouw, Jacques, Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Sala, Cinzia F, Saloustros, Emmanouil, Sandler, Dale P, Sanna, Serena, Sawyer, Elinor J, Sarnowski, Chloé, Schlessinger, David, Schmidt, Marjanka K, Schoemaker, Minouk J, Schraut, Katharina E, Scott, Christopher, Shekari, Saleh, Shrikhande, Amruta, Smith, Albert V, Smith, Blair H, Smith, Jennifer A, Sorice, Rossella, Southey, Melissa C, Spector, Tim D, Spinelli, John J, Stampfer, Meir, Stöckl, Doris, van Meurs, Joyce B J, Strauch, Konstantin, Styrkarsdottir, Unnur, Swerdlow, Anthony J, Tanaka, Toshiko, Teras, Lauren R, Teumer, Alexander, Þorsteinsdottir, Unnur, Timpson, Nicholas J, Toniolo, Daniela, Traglia, Michela, Troester, Melissa A, Truong, Thérèse, Tyrrell, Jessica, Uitterlinden, André G, Ulivi, Sheila, Vachon, Celine M, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Völzke, Henry, Wang, Qin, Wareham, Nicholas J, Weinberg, Clarice R, Weir, David R, Wilcox, Amber N, van Dijk, Ko Willems, Willemsen, Gonneke, Wilson, James F, Wolffenbuttel, Bruce H R, Wolk, Alicja, Wood, Andrew R, Zhao, Wei, Zygmunt, Marek, Chen, Zhengming, Li, Liming, Franke, Lude, Burgess, Stephen, Deelen, Patrick, Pers, Tune H, Grøndahl, Marie Louise, Andersen, Claus Yding, and Pujol, Anna

Abstract

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Published
2021

4. Genome-wide associations for birth weight and correlations with adult disease

Author

Horikoshi, Momoko, Beaumont, Robin N., Day, Felix R., Warrington, Nicole M., Kooijman, Marjolein N., Fernandez-Tajes, Juan, Feenstra, Bjarke, van Zuydam, Natalie R., Gaulton, Kyle J., Grarup, Niels, Bradfield, Jonathan P., Strachan, David P., Li-Gao, Ruifang, Ahluwalia, Tarunveer S., Kreiner, Eskil, Rueedi, Rico, Lyytikinen, Leo-Pekka, Cousminer, Diana L., Wu, Ying, Thiering, Elisabeth, Wang, Carol A., Have, Christian T., Hottenga, Jouke-Jan, Vilor-Tejedor, Natalia, Joshi, Peter K., Boh, Eileen Tai Hui, Ntalla, Ioanna, Pitknen, Niina, Mahajan, Anubha, van Leeuwen, Elisabeth M., Joro, Raimo, Lagou, Vasiliki, Nodzenski, Michael, Diver, Louise A., Zondervan, Krina T., Bustamante, Mariona, Marques-Vidal, Pedro, Mercader, Josep M., Bennett, Amanda J., Rahmioglu, Nilufer, Nyholt, Dale R., Ma, Ronald C. W., Tam, Claudia H. T., Tam, Wing Hung, Ganesh, Santhi K., van Rooij, Frank J. A., Jones, Samuel E., Loh, Po-Ru, Ruth, Katherine S., Tuke, Marcus A., Tyrrell, Jessica, Wood, Andrew R., Yaghootkar, Hanieh, Scholtens, Denise M., Paternoster, Lavinia, Prokopenko, Inga, Kovacs, Peter, Atalay, Mustafa, Willems, Sara M., Panoutsopoulou, Kalliope, Wang, Xu, Carstensen, Lisbeth, Geller, Frank, Schraut, Katharina E., Murcia, Mario, van Beijsterveldt, Catharina E. M., Willemsen, Gonneke, Appel, Emil V. R., Fonvig, Cilius E., Trier, Caecilie, Tiesler, Carla M. T., Standl, Marie, Kutalik, Zoltn, Bons-Guarch, Slvia, Hougaard, David M., Snchez, Friman, Torrents, David, Waage, Johannes, Hollegaard, Mads V., de Haan, Hugoline G., Rosendaal, Frits R., Medina-Gomez, Carolina, Ring, Susan M., Hemani, Gibran, McMahon, George, Robertson, Neil R., Groves, Christopher J., Langenberg, Claudia, Luan, Jianan, Scott, Robert A., Zhao, Jing Hua, Mentch, Frank D., MacKenzie, Scott M., Reynolds, Rebecca M., Lowe, William L., Tnjes, Anke, Stumvoll, Michael, Lindi, Virpi, Lakka, Timo A., van Duijn, Cornelia M., Kiess, Wieland, Krner, Antje, Srensen, Thorkild I. A., Niinikoski, Harri, Pahkala, Katja, Raitakari, Olli T., Zeggini, Eleftheria, Dedoussis, George V., Teo, Yik-Ying, Saw, Seang-Mei, Melbye, Mads, Campbell, Harry, Wilson, James F., Vrijheid, Martine, de Geus, Eco J. C. N., Boomsma, Dorret I., Kadarmideen, Haja N., Holm, Jens-Christian, Hansen, Torben, Sebert, Sylvain, Hattersley, Andrew T., Beilin, Lawrence J., Newnham, John P., Pennell, Craig E., Heinrich, Joachim, Adair, Linda S., Borja, Judith B., Mohlke, Karen L., Eriksson, Johan G., Widn, Elisabeth, Khnen, Mika, Viikari, Jorma S., Lehtimki, Terho, Vollenweider, Peter, Bnnelykke, Klaus, Bisgaard, Hans, Mook-Kanamori, Dennis O., Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andr G., Pisinger, Charlotta, Pedersen, Oluf, Power, Christine, Hyppnen, Elina, Wareham, Nicholas J., Hakonarson, Hakon, Davies, Eleanor, Walker, Brian R., Jaddoe, Vincent W. V., Jrvelin, Marjo-Riitta, Grant, Struan F. A., Vaag, Allan A., Lawlor, Debbie A., Frayling, Timothy M., Smith, George Davey, Morris, Andrew P., Ong, Ken K., Felix, Janine F., Timpson, Nicholas J., Perry, John R. B., Evans, David M., McCarthy, Mark I., and Freathy, Rachel M.

Subjects
Genome-wide association studies, Birth weight -- Genetic aspects -- Health aspects, Metabolic diseases -- Risk factors -- Genetic aspects, Cardiovascular diseases -- Risk factors -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Momoko Horikoshi [1, 2]; Robin N. Beaumont [3]; Felix R. Day [4]; Nicole M. Warrington [5, 6]; Marjolein N. Kooijman [7, 8, 9]; Juan Fernandez-Tajes [1]; Bjarke Feenstra [10]; [...]

Published
2016
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5. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Author

Warrington, Nicole M, Beaumont, Robin N, Horikoshi, Momoko, Day, Felix R, Helgeland, Øyvind, Laurin, Charles, Bacelis, Jonas, Peng, Shouneng, Hao, Ke, Feenstra, Bjarke, Wood, Andrew R, Mahajan, Anubha, Tyrrell, Jessica, Robertson, Neil R, Rayner, N William, Qiao, Zhen, Moen, Gunn-Helen, Vaudel, Marc, Marsit, Carmen J, Chen, Jia Jue Johannes, Nodzenski, Michael, Schnurr, Theresia M, Zafarmand, Mohammad H, Bradfield, Jonathan P, Grarup, Niels, Kooijman, Marjolein N, Li-Gao, Ruifang, Geller, Frank, Ahluwalia, Tarunveer S, Paternoster, Lavinia, Rueedi, Rico, Huikari, Ville, Hottenga, Jouke-Jan, Lyytikäinen, Leo-Pekka, Cavadino, Alana, Metrustry, Sarah, Cousminer, Diana L, Wu, Ying, Thiering, Elisabeth, Wang, Carol A, Have, Christian T, Vilor-Tejedor, Natalia, Joshi, Peter K, Painter, Jodie N, Ntalla, Ioanna, Myhre, Ronny, Pitkänen, Niina, van Leeuwen, Elisabeth M, Joro, Raimo, Lagou, Vasiliki, Richmond, Rebecca C, Espinosa, Ana, Barton, Sheila J, Inskip, Hazel M, Holloway, John W, Santa-Marina, Loreto, Estivill, Xavier, Ang, Wei, Marsh, Julie A, Reichetzeder, Christoph, Marullo, Letizia, Hocher, Berthold, Lunetta, Kathryn L, Murabito, Joanne M, Relton, Caroline L, Kogevinas, Manolis, Chatzi, Leda, Allard, Catherine, Bouchard, Luigi, Hivert, Marie-France, Zhang, Ge, Muglia, Louis J, Heikkinen, Jani, Consortium, EGG, Morgen, Camilla S, van Kampen, Antoine H C, van Schaik, Barbera D C, Mentch, Frank D, Langenberg, Claudia, Luan, Jian'an, Scott, Robert A, Zhao, Jing Hua, Hemani, Gibran, Ring, Susan M, Bennett, Amanda J, Gaulton, Kyle J, Fernandez-Tajes, Juan, van Zuydam, Natalie R, Medina-Gomez, Carolina, de Haan, Hugoline G, Rosendaal, Frits R, Kutalik, Zoltán, Marques-Vidal, Pedro, Das, Shikta, Willemsen, Gonneke, Mbarek, Hamdi, Müller-Nurasyid, Martina, Standl, Marie, Appel, Emil V R, Fonvig, Cilius E, Trier, Caecilie, van Beijsterveldt, Catharina E M, Murcia, Mario, Bustamante, Mariona, Bonas-Guarch, Sílvia, Hougaard, David M, Mercader, Josep M, Linneberg, Allan, Schraut, Katharina E, Lind, Penelope A, Medland, Sarah E, Shields, Beverley M, Knight, Bridget A, Chai, Jin-Fang, Panoutsopoulou, Kalliope, Bartels, Meike, Sánchez, Friman, Stokholm, Jakob, Torrents, David, Vinding, Rebecca K, Willems, Sara M, Atalay, Mustafa, Chawes, Bo L, Kovacs, Peter, Prokopenko, Inga, Tuke, Marcus A, Yaghootkar, Hanieh, Ruth, Katherine S, Jones, Samuel E, Loh, Po-Ru, Murray, Anna, Weedon, Michael N, Tönjes, Anke, Stumvoll, Michael, Michaelsen, Kim F, Eloranta, Aino-Maija, Lakka, Timo A, van Duijn, Cornelia M, Kiess, Wieland, Körner, Antje, Niinikoski, Harri, Pahkala, Katja, Raitakari, Olli T, Jacobsson, Bo, Zeggini, Eleftheria, Dedoussis, George V, Teo, Yik-Ying, Saw, Seang-Mei, Montgomery, Grant W, Campbell, Harry, Wilson, James F, Vrijkotte, Tanja G M, Vrijheid, Martine, de Geus, Eco J C N, Hayes, M Geoffrey, Kadarmideen, Haja N, Holm, Jens-Christian, Beilin, Lawrence J, Pennell, Craig E, Heinrich, Joachim, Adair, Linda S, Borja, Judith B, Mohlke, Karen L, Eriksson, Johan G, Widén, Elisabeth E, Hattersley, Andrew T, Spector, Tim D, Kähönen, Mika, Viikari, Jorma S, Lehtimäki, Terho, Boomsma, Dorret I, Sebert, Sylvain, Vollenweider, Peter, Sørensen, Thorkild I A, Bisgaard, Hans Flinker, Bønnelykke, Klaus, Murray, Jeffrey C, Melbye, Mads, Nohr, Ellen A, Mook-Kanamori, Dennis O, Rivadeneira, Fernando, Hofman, Albert, Felix, Janine F, Jaddoe, Vincent W V, Hansen, Torben, Pisinger, Charlotta, Vaag, Allan A, Pedersen, Oluf, Uitterlinden, André G, Järvelin, Marjo-Riitta, Power, Christine, Hyppönen, Elina, Scholtens, Denise M, Lowe, William L, Davey Smith, George, Timpson, Nicholas J, Morris, Andrew P, Wareham, Nicholas J, Hakonarson, Hakon, Grant, Struan F A, Frayling, Timothy M, Lawlor, Debbie A, Njølstad, Pål R, Johansson, Stefan, Ong, Ken K, McCarthy, Mark I, Perry, John R B, Evans, David M, Freathy, Rachel M, Warrington, Nicole M, Beaumont, Robin N, Horikoshi, Momoko, Day, Felix R, Helgeland, Øyvind, Laurin, Charles, Bacelis, Jonas, Peng, Shouneng, Hao, Ke, Feenstra, Bjarke, Wood, Andrew R, Mahajan, Anubha, Tyrrell, Jessica, Robertson, Neil R, Rayner, N William, Qiao, Zhen, Moen, Gunn-Helen, Vaudel, Marc, Marsit, Carmen J, Chen, Jia Jue Johannes, Nodzenski, Michael, Schnurr, Theresia M, Zafarmand, Mohammad H, Bradfield, Jonathan P, Grarup, Niels, Kooijman, Marjolein N, Li-Gao, Ruifang, Geller, Frank, Ahluwalia, Tarunveer S, Paternoster, Lavinia, Rueedi, Rico, Huikari, Ville, Hottenga, Jouke-Jan, Lyytikäinen, Leo-Pekka, Cavadino, Alana, Metrustry, Sarah, Cousminer, Diana L, Wu, Ying, Thiering, Elisabeth, Wang, Carol A, Have, Christian T, Vilor-Tejedor, Natalia, Joshi, Peter K, Painter, Jodie N, Ntalla, Ioanna, Myhre, Ronny, Pitkänen, Niina, van Leeuwen, Elisabeth M, Joro, Raimo, Lagou, Vasiliki, Richmond, Rebecca C, Espinosa, Ana, Barton, Sheila J, Inskip, Hazel M, Holloway, John W, Santa-Marina, Loreto, Estivill, Xavier, Ang, Wei, Marsh, Julie A, Reichetzeder, Christoph, Marullo, Letizia, Hocher, Berthold, Lunetta, Kathryn L, Murabito, Joanne M, Relton, Caroline L, Kogevinas, Manolis, Chatzi, Leda, Allard, Catherine, Bouchard, Luigi, Hivert, Marie-France, Zhang, Ge, Muglia, Louis J, Heikkinen, Jani, Consortium, EGG, Morgen, Camilla S, van Kampen, Antoine H C, van Schaik, Barbera D C, Mentch, Frank D, Langenberg, Claudia, Luan, Jian'an, Scott, Robert A, Zhao, Jing Hua, Hemani, Gibran, Ring, Susan M, Bennett, Amanda J, Gaulton, Kyle J, Fernandez-Tajes, Juan, van Zuydam, Natalie R, Medina-Gomez, Carolina, de Haan, Hugoline G, Rosendaal, Frits R, Kutalik, Zoltán, Marques-Vidal, Pedro, Das, Shikta, Willemsen, Gonneke, Mbarek, Hamdi, Müller-Nurasyid, Martina, Standl, Marie, Appel, Emil V R, Fonvig, Cilius E, Trier, Caecilie, van Beijsterveldt, Catharina E M, Murcia, Mario, Bustamante, Mariona, Bonas-Guarch, Sílvia, Hougaard, David M, Mercader, Josep M, Linneberg, Allan, Schraut, Katharina E, Lind, Penelope A, Medland, Sarah E, Shields, Beverley M, Knight, Bridget A, Chai, Jin-Fang, Panoutsopoulou, Kalliope, Bartels, Meike, Sánchez, Friman, Stokholm, Jakob, Torrents, David, Vinding, Rebecca K, Willems, Sara M, Atalay, Mustafa, Chawes, Bo L, Kovacs, Peter, Prokopenko, Inga, Tuke, Marcus A, Yaghootkar, Hanieh, Ruth, Katherine S, Jones, Samuel E, Loh, Po-Ru, Murray, Anna, Weedon, Michael N, Tönjes, Anke, Stumvoll, Michael, Michaelsen, Kim F, Eloranta, Aino-Maija, Lakka, Timo A, van Duijn, Cornelia M, Kiess, Wieland, Körner, Antje, Niinikoski, Harri, Pahkala, Katja, Raitakari, Olli T, Jacobsson, Bo, Zeggini, Eleftheria, Dedoussis, George V, Teo, Yik-Ying, Saw, Seang-Mei, Montgomery, Grant W, Campbell, Harry, Wilson, James F, Vrijkotte, Tanja G M, Vrijheid, Martine, de Geus, Eco J C N, Hayes, M Geoffrey, Kadarmideen, Haja N, Holm, Jens-Christian, Beilin, Lawrence J, Pennell, Craig E, Heinrich, Joachim, Adair, Linda S, Borja, Judith B, Mohlke, Karen L, Eriksson, Johan G, Widén, Elisabeth E, Hattersley, Andrew T, Spector, Tim D, Kähönen, Mika, Viikari, Jorma S, Lehtimäki, Terho, Boomsma, Dorret I, Sebert, Sylvain, Vollenweider, Peter, Sørensen, Thorkild I A, Bisgaard, Hans Flinker, Bønnelykke, Klaus, Murray, Jeffrey C, Melbye, Mads, Nohr, Ellen A, Mook-Kanamori, Dennis O, Rivadeneira, Fernando, Hofman, Albert, Felix, Janine F, Jaddoe, Vincent W V, Hansen, Torben, Pisinger, Charlotta, Vaag, Allan A, Pedersen, Oluf, Uitterlinden, André G, Järvelin, Marjo-Riitta, Power, Christine, Hyppönen, Elina, Scholtens, Denise M, Lowe, William L, Davey Smith, George, Timpson, Nicholas J, Morris, Andrew P, Wareham, Nicholas J, Hakonarson, Hakon, Grant, Struan F A, Frayling, Timothy M, Lawlor, Debbie A, Njølstad, Pål R, Johansson, Stefan, Ong, Ken K, McCarthy, Mark I, Perry, John R B, Evans, David M, and Freathy, Rachel M

Abstract

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.

Published
2019

6. Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

Author

Ligthart, Symen, Vaez, Ahmad, Võsa, Urmo, Stathopoulou, Maria G, de Vries, Paul S, Prins, Bram P, Van der Most, Peter J, Tanaka, Toshiko, Naderi, Elnaz, Rose, Lynda M, Wu, Ying, Karlsson, Robert, Barbalic, Maja, Lin, Honghuang, Pool, René, Zhu, Gu, Macé, Aurélien, Sidore, Carlo, Trompet, Stella, Mangino, Massimo, Sabater-Lleal, Maria, Kemp, John P, Abbasi, Ali, Kacprowski, Tim, Verweij, Niek, Smith, Albert V, Huang, Tao, Marzi, Carola, Feitosa, Mary F, Lohman, Kurt K, Kleber, Marcus E, Milaneschi, Yuri, Mueller, Christian, Huq, Mahmudul, Vlachopoulou, Efthymia, Lyytikäinen, Leo-Pekka, Oldmeadow, Christopher, Deelen, Joris, Perola, Markus, Zhao, Jing Hua, Feenstra, Bjarke, Amini, Marzyeh, Lahti, Jari, Schraut, Katharina E, Fornage, Myriam, Suktitipat, Bhoom, Chen, Wei-Min, Li, Xiaohui, Nutile, Teresa, Malerba, Giovanni, Luan, Jian'an, Bak, Tom, Schork, Nicholas, Del Greco M, Fabiola, Thiering, Elisabeth, Mahajan, Anubha, Marioni, Riccardo E, Mihailov, Evelin, Eriksson, Joel, Ozel, Ayse Bilge, Zhang, Weihua, Nethander, Maria, Cheng, Yu-Ching, Aslibekyan, Stella, Ang, Wei, Gandin, Ilaria, Yengo, Loïc, Portas, Laura, Kooperberg, Charles, Hofer, Edith, Rajan, Kumar B, Schurmann, Claudia, den Hollander, Wouter, Ahluwalia, Tarunveer S, Zhao, Jing, Draisma, Harmen H M, Ford, Ian, Timpson, Nicholas, Teumer, Alexander, Huang, Hongyan, Wahl, Simone, Liu, YongMei, Huang, Jie, Uh, Hae-Won, Geller, Frank, Joshi, Peter K, Yanek, Lisa R, Trabetti, Elisabetta, Lehne, Benjamin, Vozzi, Diego, Verbanck, Marie, Biino, Ginevra, Saba, Yasaman, Meulenbelt, Ingrid, O'Connell, Jeff R, Laakso, Markku, Giulianini, Franco, Magnusson, Patrik K E, Ballantyne, Christie M, Hottenga, Jouke Jan, Montgomery, Grant W, Rivadineira, Fernando, Rueedi, Rico, Steri, Maristella, Herzig, Karl-Heinz, Stott, David J, Menni, Cristina, Frånberg, Mattias, St Pourcain, Beate, Felix, Stephan B, Pers, Tune H, Bakker, Stephan J L, Kraft, Peter, Peters, Annette, Vaidya, Dhananjay, Delgado, Graciela, Smit, Johannes H, Großmann, Vera, Sinisalo, Juha, Seppälä, Ilkka, Williams, Stephen R, Holliday, Elizabeth G, Moed, Matthijs, Langenberg, Claudia, Räikkönen, Katri, Ding, Jingzhong, Campbell, Harry, Sale, Michele M, Chen, Yii-Der I, James, Alan L, Ruggiero, Daniela, Soranzo, Nicole, Hartman, Catharina A, Smith, Erin N, Berenson, Gerald S, Fuchsberger, Christian, Hernandez, Dena, Tiesler, Carla M T, Giedraitis, Vilmantas, Liewald, David, Fischer, Krista, Mellström, Dan, Larsson, Anders, Wang, Yunmei, Scott, William R, Lorentzon, Matthias, Beilby, John, Ryan, Kathleen A, Pennell, Craig E, Vuckovic, Dragana, Balkau, Beverly, Concas, Maria Pina, Schmidt, Reinhold, Mendes de Leon, Carlos F, Bottinger, Erwin P, Kloppenburg, Margreet, Paternoster, Lavinia, Boehnke, Michael, Musk, A W, Willemsen, Gonneke, Evans, David M, Madden, Pamela A F, Kähönen, Mika, Kutalik, Zoltán, Zoledziewska, Magdalena, Karhunen, Ville, Kritchevsky, Stephen B, Sattar, Naveed, Lachance, Genevieve, Clarke, Robert, Harris, Tamara B, Raitakari, Olli T, Attia, John R, van Heemst, Diana, Kajantie, Eero, Sorice, Rossella, Gambaro, Giovanni, Scott, Robert A, Hicks, Andrew A, Ferrucci, Luigi, Standl, Marie, Lindgren, Cecilia M, Starr, John M, Karlsson, Magnus, Lind, Lars, Li, Jun Z, Chambers, John C, Mori, Trevor A, de Geus, Eco J C N, Heath, Andrew C, Martin, Nicholas G, Auvinen, Juha, Buckley, Brendan M, de Craen, Anton J M, Waldenberger, Melanie, Strauch, Konstantin, Meitinger, Thomas, Scott, Rodney J, McEvoy, Mark, Beekman, Marian, Bombieri, Cristina, Ridker, Paul M, Mohlke, Karen L, Pedersen, Nancy L, Morrison, Alanna C, Boomsma, Dorret I, Whitfield, John B, Strachan, David P, Hofman, Albert, Vollenweider, Peter, Cucca, Francesco, Jarvelin, Marjo-Riitta, Jukema, J Wouter, Spector, Tim D, Hamsten, Anders, Zeller, Tanja, Uitterlinden, André G, Nauck, Matthias, Gudnason, Vilmundur, Qi, Lu, Grallert, Harald, Borecki, Ingrid B, Rotter, Jerome I, März, Winfried, Wild, Philipp S, Lokki, Marja-Liisa, Boyle, Michael, Salomaa, Veikko, Melbye, Mads, Eriksson, Johan G, Wilson, James F, Penninx, Brenda W J H, Becker, Diane M, Worrall, Bradford B, Gibson, Greg, Krauss, Ronald M, Ciullo, Marina, Zaza, Gianluigi, Wareham, Nicholas J, Oldehinkel, Albertine J, Palmer, Lyle J, Murray, Sarah S, Pramstaller, Peter P, Bandinelli, Stefania, Heinrich, Joachim, Ingelsson, Erik, Deary, Ian J, Mägi, Reedik, Vandenput, Liesbeth, van der Harst, Pim, Desch, Karl C, Kooner, Jaspal S, Ohlsson, Claes, Hayward, Caroline, Lehtimäki, Terho, Shuldiner, Alan R, Arnett, Donna K, Beilin, Lawrence J, Robino, Antonietta, Froguel, Philippe, Pirastu, Mario, Jess, Tine, Koenig, Wolfgang, Loos, Ruth J F, Evans, Denis A, Schmidt, Helena, Smith, George Davey, Slagboom, P Eline, Eiriksdottir, Gudny, Morris, Andrew P, Psaty, Bruce M, Tracy, Russell P, Nolte, Ilja M, Boerwinkle, Eric, Visvikis-Siest, Sophie, Reiner, Alex P, Gross, Myron, Bis, Joshua C, Franke, Lude, Franco, Oscar H, Benjamin, Emelia J, Chasman, Daniel I, Dupuis, Josée, Snieder, Harold, Dehghan, Abbas, Alizadeh, Behrooz Z, Ligthart, Symen, Vaez, Ahmad, Võsa, Urmo, Stathopoulou, Maria G, de Vries, Paul S, Prins, Bram P, Van der Most, Peter J, Tanaka, Toshiko, Naderi, Elnaz, Rose, Lynda M, Wu, Ying, Karlsson, Robert, Barbalic, Maja, Lin, Honghuang, Pool, René, Zhu, Gu, Macé, Aurélien, Sidore, Carlo, Trompet, Stella, Mangino, Massimo, Sabater-Lleal, Maria, Kemp, John P, Abbasi, Ali, Kacprowski, Tim, Verweij, Niek, Smith, Albert V, Huang, Tao, Marzi, Carola, Feitosa, Mary F, Lohman, Kurt K, Kleber, Marcus E, Milaneschi, Yuri, Mueller, Christian, Huq, Mahmudul, Vlachopoulou, Efthymia, Lyytikäinen, Leo-Pekka, Oldmeadow, Christopher, Deelen, Joris, Perola, Markus, Zhao, Jing Hua, Feenstra, Bjarke, Amini, Marzyeh, Lahti, Jari, Schraut, Katharina E, Fornage, Myriam, Suktitipat, Bhoom, Chen, Wei-Min, Li, Xiaohui, Nutile, Teresa, Malerba, Giovanni, Luan, Jian'an, Bak, Tom, Schork, Nicholas, Del Greco M, Fabiola, Thiering, Elisabeth, Mahajan, Anubha, Marioni, Riccardo E, Mihailov, Evelin, Eriksson, Joel, Ozel, Ayse Bilge, Zhang, Weihua, Nethander, Maria, Cheng, Yu-Ching, Aslibekyan, Stella, Ang, Wei, Gandin, Ilaria, Yengo, Loïc, Portas, Laura, Kooperberg, Charles, Hofer, Edith, Rajan, Kumar B, Schurmann, Claudia, den Hollander, Wouter, Ahluwalia, Tarunveer S, Zhao, Jing, Draisma, Harmen H M, Ford, Ian, Timpson, Nicholas, Teumer, Alexander, Huang, Hongyan, Wahl, Simone, Liu, YongMei, Huang, Jie, Uh, Hae-Won, Geller, Frank, Joshi, Peter K, Yanek, Lisa R, Trabetti, Elisabetta, Lehne, Benjamin, Vozzi, Diego, Verbanck, Marie, Biino, Ginevra, Saba, Yasaman, Meulenbelt, Ingrid, O'Connell, Jeff R, Laakso, Markku, Giulianini, Franco, Magnusson, Patrik K E, Ballantyne, Christie M, Hottenga, Jouke Jan, Montgomery, Grant W, Rivadineira, Fernando, Rueedi, Rico, Steri, Maristella, Herzig, Karl-Heinz, Stott, David J, Menni, Cristina, Frånberg, Mattias, St Pourcain, Beate, Felix, Stephan B, Pers, Tune H, Bakker, Stephan J L, Kraft, Peter, Peters, Annette, Vaidya, Dhananjay, Delgado, Graciela, Smit, Johannes H, Großmann, Vera, Sinisalo, Juha, Seppälä, Ilkka, Williams, Stephen R, Holliday, Elizabeth G, Moed, Matthijs, Langenberg, Claudia, Räikkönen, Katri, Ding, Jingzhong, Campbell, Harry, Sale, Michele M, Chen, Yii-Der I, James, Alan L, Ruggiero, Daniela, Soranzo, Nicole, Hartman, Catharina A, Smith, Erin N, Berenson, Gerald S, Fuchsberger, Christian, Hernandez, Dena, Tiesler, Carla M T, Giedraitis, Vilmantas, Liewald, David, Fischer, Krista, Mellström, Dan, Larsson, Anders, Wang, Yunmei, Scott, William R, Lorentzon, Matthias, Beilby, John, Ryan, Kathleen A, Pennell, Craig E, Vuckovic, Dragana, Balkau, Beverly, Concas, Maria Pina, Schmidt, Reinhold, Mendes de Leon, Carlos F, Bottinger, Erwin P, Kloppenburg, Margreet, Paternoster, Lavinia, Boehnke, Michael, Musk, A W, Willemsen, Gonneke, Evans, David M, Madden, Pamela A F, Kähönen, Mika, Kutalik, Zoltán, Zoledziewska, Magdalena, Karhunen, Ville, Kritchevsky, Stephen B, Sattar, Naveed, Lachance, Genevieve, Clarke, Robert, Harris, Tamara B, Raitakari, Olli T, Attia, John R, van Heemst, Diana, Kajantie, Eero, Sorice, Rossella, Gambaro, Giovanni, Scott, Robert A, Hicks, Andrew A, Ferrucci, Luigi, Standl, Marie, Lindgren, Cecilia M, Starr, John M, Karlsson, Magnus, Lind, Lars, Li, Jun Z, Chambers, John C, Mori, Trevor A, de Geus, Eco J C N, Heath, Andrew C, Martin, Nicholas G, Auvinen, Juha, Buckley, Brendan M, de Craen, Anton J M, Waldenberger, Melanie, Strauch, Konstantin, Meitinger, Thomas, Scott, Rodney J, McEvoy, Mark, Beekman, Marian, Bombieri, Cristina, Ridker, Paul M, Mohlke, Karen L, Pedersen, Nancy L, Morrison, Alanna C, Boomsma, Dorret I, Whitfield, John B, Strachan, David P, Hofman, Albert, Vollenweider, Peter, Cucca, Francesco, Jarvelin, Marjo-Riitta, Jukema, J Wouter, Spector, Tim D, Hamsten, Anders, Zeller, Tanja, Uitterlinden, André G, Nauck, Matthias, Gudnason, Vilmundur, Qi, Lu, Grallert, Harald, Borecki, Ingrid B, Rotter, Jerome I, März, Winfried, Wild, Philipp S, Lokki, Marja-Liisa, Boyle, Michael, Salomaa, Veikko, Melbye, Mads, Eriksson, Johan G, Wilson, James F, Penninx, Brenda W J H, Becker, Diane M, Worrall, Bradford B, Gibson, Greg, Krauss, Ronald M, Ciullo, Marina, Zaza, Gianluigi, Wareham, Nicholas J, Oldehinkel, Albertine J, Palmer, Lyle J, Murray, Sarah S, Pramstaller, Peter P, Bandinelli, Stefania, Heinrich, Joachim, Ingelsson, Erik, Deary, Ian J, Mägi, Reedik, Vandenput, Liesbeth, van der Harst, Pim, Desch, Karl C, Kooner, Jaspal S, Ohlsson, Claes, Hayward, Caroline, Lehtimäki, Terho, Shuldiner, Alan R, Arnett, Donna K, Beilin, Lawrence J, Robino, Antonietta, Froguel, Philippe, Pirastu, Mario, Jess, Tine, Koenig, Wolfgang, Loos, Ruth J F, Evans, Denis A, Schmidt, Helena, Smith, George Davey, Slagboom, P Eline, Eiriksdottir, Gudny, Morris, Andrew P, Psaty, Bruce M, Tracy, Russell P, Nolte, Ilja M, Boerwinkle, Eric, Visvikis-Siest, Sophie, Reiner, Alex P, Gross, Myron, Bis, Joshua C, Franke, Lude, Franco, Oscar H, Benjamin, Emelia J, Chasman, Daniel I, Dupuis, Josée, Snieder, Harold, Dehghan, Abbas, and Alizadeh, Behrooz Z

Abstract

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

Published
2018
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7. Genetic insights into biological mechanisms governing human ovarian ageing

Author

Ruth, Katherine S., Day, Felix R., Hussain, Jazib, Martínez-Marchal, Ana, Aiken, Catherine E., Azad, Ajuna, Thompson, Deborah J., Knoblochova, Lucie, Abe, Hironori, Tarry-Adkins, Jane L., Gonzalez, Javier Martin, Fontanillas, Pierre, Claringbould, Annique, Bakker, Olivier B., Sulem, Patrick, Walters, Robin G., Terao, Chikashi, Turon, Sandra, Horikoshi, Momoko, Lin, Kuang, Onland-Moret, N. Charlotte, Sankar, Aditya, Hertz, Emil Peter Thrane, Timshel, Pascal N., Shukla, Vallari, Borup, Rehannah, Olsen, Kristina W., Aguilera, Paula, Ferrer-Roda, Mònica, Huang, Yan, Stankovic, Stasa, Timmers, Paul R. H. J., Ahearn, Thomas U., Alizadeh, Behrooz Z., Naderi, Elnaz, Andrulis, Irene L., Arnold, Alice M., Aronson, Kristan J., Augustinsson, Annelie, Bandinelli, Stefania, Barbieri, Caterina M., Beaumont, Robin N., Becher, Heiko, Beckmann, Matthias W., Benonisdottir, Stefania, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E., Bolla, Manjeet K., Boomsma, Dorret I., Bowker, Nicholas, Brody, Jennifer A., Broer, Linda, Buring, Julie E., Campbell, Archie, Campbell, Harry, Castelao, Jose E., Catamo, Eulalia, Chanock, Stephen J., Chenevix-Trench, Georgia, Ciullo, Marina, Corre, Tanguy, Couch, Fergus J., Cox, Angela, Crisponi, Laura, Cross, Simon S., Cucca, Francesco, Czene, Kamila, Smith, George Davey, de Geus, Eco J. C. N., de Mutsert, Renée, De Vivo, Immaculata, Demerath, Ellen W., Dennis, Joe, Dunning, Alison M., Dwek, Miriam, Eriksson, Mikael, Esko, Tõnu, Fasching, Peter A., Faul, Jessica D., Ferrucci, Luigi, Franceschini, Nora, Frayling, Timothy M., Gago-Dominguez, Manuela, Mezzavilla, Massimo, García-Closas, Montserrat, Gieger, Christian, Giles, Graham G., Grallert, Harald, Gudbjartsson, Daniel F., Gudnason, Vilmundur, Guénel, Pascal, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hayward, Caroline, He, Chunyan, He, Wei, Heiss, Gerardo, Høffding, Miya K., Hopper, John L., Hottenga, Jouke J., Hu, Frank, Hunter, David, Ikram, Mohammad A., Jackson, Rebecca D., Joaquim, Micaella D. R., John, Esther M., Joshi, Peter K., Karasik, David, Kardia, Sharon L. R., Kartsonaki, Christiana, Karlsson, Robert, Kitahara, Cari M., Kolcic, Ivana, Kooperberg, Charles, Kraft, Peter, Kurian, Allison W., Kutalik, Zoltan, La Bianca, Martina, LaChance, Genevieve, Langenberg, Claudia, Launer, Lenore J., Laven, Joop S. E., Lawlor, Deborah A., Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lindstrom, Sara, Lindstrom, Tricia, Linet, Martha, Liu, YongMei, Liu, Simin, Luan, Jian’an, Mägi, Reedik, Magnusson, Patrik K. E., Mangino, Massimo, Mannermaa, Arto, Marco, Brumat, Marten, Jonathan, Martin, Nicholas G., Mbarek, Hamdi, McKnight, Barbara, Medland, Sarah E., Meisinger, Christa, Meitinger, Thomas, Menni, Cristina, Metspalu, Andres, Milani, Lili, Milne, Roger L., Montgomery, Grant W., Mook-Kanamori, Dennis O., Mulas, Antonella, Mulligan, Anna M., Murray, Alison, Nalls, Mike A., Newman, Anne, Noordam, Raymond, Nutile, Teresa, Nyholt, Dale R., Olshan, Andrew F., Olsson, Håkan, Painter, Jodie N., Patel, Alpa V., Pedersen, Nancy L., Perjakova, Natalia, Peters, Annette, Peters, Ulrike, Pharoah, Paul D. P., Polasek, Ozren, Porcu, Eleonora, Psaty, Bruce M., Rahman, Iffat, Rennert, Gad, Rennert, Hedy S., Ridker, Paul M., Ring, Susan M., Robino, Antonietta, Rose, Lynda M., Rosendaal, Frits R., Rossouw, Jacques, Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Sala, Cinzia F., Saloustros, Emmanouil, Sandler, Dale P., Sanna, Serena, Sawyer, Elinor J., Sarnowski, Chloé, Schlessinger, David, Schmidt, Marjanka K., Schoemaker, Minouk J., Schraut, Katharina E., Scott, Christopher, Shekari, Saleh, Shrikhande, Amruta, Smith, Albert V., Smith, Blair H., Smith, Jennifer A., Sorice, Rossella, Southey, Melissa C., Spector, Tim D., Spinelli, John J., Stampfer, Meir, Stöckl, Doris, van Meurs, Joyce B. J., Strauch, Konstantin, Styrkarsdottir, Unnur, Swerdlow, Anthony J., Tanaka, Toshiko, Teras, Lauren R., Teumer, Alexander, Þorsteinsdottir, Unnur, Timpson, Nicholas J., Toniolo, Daniela, Traglia, Michela, Troester, Melissa A., Truong, Thérèse, Tyrrell, Jessica, Uitterlinden, André G., Ulivi, Sheila, Vachon, Celine M., Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Völzke, Henry, Wang, Qin, Wareham, Nicholas J., Weinberg, Clarice R., Weir, David R., Wilcox, Amber N., van Dijk, Ko Willems, Willemsen, Gonneke, Wilson, James F., Wolffenbuttel, Bruce H. R., Wolk, Alicja, Wood, Andrew R., Zhao, Wei, Zygmunt, Marek, Chen, Zhengming, Li, Liming, Franke, Lude, Burgess, Stephen, Deelen, Patrick, Pers, Tune H., Grøndahl, Marie Louise, Andersen, Claus Yding, Pujol, Anna, Lopez-Contreras, Andres J., Daniel, Jeremy A., Stefansson, Kari, Chang-Claude, Jenny, van der Schouw, Yvonne T., Lunetta, Kathryn L., Chasman, Daniel I., Easton, Douglas F., Visser, Jenny A., Ozanne, Susan E., Namekawa, Satoshi H., Solc, Petr, Murabito, Joanne M., Ong, Ken K., Hoffmann, Eva R., Murray, Anna, Roig, Ignasi, and Perry, John R. B.

Abstract

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Published
2021
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8. Heritability estimates for 361 blood metabolites across 40 genome-wide association studies.

Author

Hagenbeek, Fiona A., Pool, René, van Dongen, Jenny, Draisma, Harmen H. M., Jan Hottenga, Jouke, Willemsen, Gonneke, Abdellaoui, Abdel, Fedko, Iryna O., den Braber, Anouk, Visser, Pieter Jelle, de Geus, Eco J. C. N., Willems van Dijk, Ko, Verhoeven, Aswin, Suchiman, H. Eka, Beekman, Marian, Slagboom, P. Eline, van Duijn, Cornelia M., BBMRI Metabolomics Consortium, Barkey Wolf, J. J. H., and Cats, D.

Subjects
HERITABILITY, SMALL molecules, ORGANIC acids, ESTIMATES, BLOOD, METABOLOMICS, METABOLITES
Abstract

Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes. We perform a review of all genome-wide association and (exome-) sequencing studies published between November 2008 and October 2018, and identify >800 class-specific metabolite loci associated with metabolite levels. In a twin-family cohort (N = 5117), these metabolite loci are leveraged to simultaneously estimate total heritability (h2total), and the proportion of heritability captured by known metabolite loci (h2Metabolite-hits) for 309 lipids and 52 organic acids. Our study reveals significant differences in h2Metabolite-hits among different classes of lipids and organic acids. Furthermore, phosphatidylcholines with a high degree of unsaturation have higher h2Metabolite-hits estimates than phosphatidylcholines with low degrees of unsaturation. This study highlights the importance of common genetic variants for metabolite levels, and elucidates the genetic architecture of metabolite classes. Blood metabolite levels are under the influence of environmental and genetic factors. Here, Hagenbeek et al. perform heritability estimations for metabolite measures and determine the contribution of known metabolite loci to metabolite levels using data from 40 genome-wide association studies. [ABSTRACT FROM AUTHOR]

Published
2020
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9. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Author

Day, Felix R, Thompson, Deborah J, Helgason, Hannes, Chasman, Daniel I, Finucane, Hilary, Sulem, Patrick, Ruth, Katherine S, Whalen, Sean, Sarkar, Abhishek K, Albrecht, Eva, Altmaier, Elisabeth, Amini, Marzyeh, Barbieri, Caterina M, Boutin, Thibaud, Campbell, Archie, Demerath, Ellen, Giri, Ayush, He, Chunyan, Hottenga, Jouke J, Karlsson, Robert, Kolcic, Ivana, Loh, Po-Ru, Lunetta, Kathryn L, Mangino, Massimo, Marco, Brumat, McMahon, George, Medland, Sarah E, Nolte, Ilja M, Noordam, Raymond, Nutile, Teresa, Paternoster, Lavinia, Perjakova, Natalia, Porcu, Eleonora, Rose, Lynda M, Schraut, Katharina E, Segrè, Ayellet V, Smith, Albert V, Stolk, Lisette, Teumer, Alexander, Andrulis, Irene L, Bandinelli, Stefania, Beckmann, Matthias W, Benitez, Javier, Bergmann, Sven, Bochud, Murielle, de Geus, Eco J C N, Mbarek, Hamdi, Willemsen, Gonneke, Boomsma, Dorret I, Visser, Jenny A, LifeLines Cohort Study, Day, Felix R, Thompson, Deborah J, Helgason, Hannes, Chasman, Daniel I, Finucane, Hilary, Sulem, Patrick, Ruth, Katherine S, Whalen, Sean, Sarkar, Abhishek K, Albrecht, Eva, Altmaier, Elisabeth, Amini, Marzyeh, Barbieri, Caterina M, Boutin, Thibaud, Campbell, Archie, Demerath, Ellen, Giri, Ayush, He, Chunyan, Hottenga, Jouke J, Karlsson, Robert, Kolcic, Ivana, Loh, Po-Ru, Lunetta, Kathryn L, Mangino, Massimo, Marco, Brumat, McMahon, George, Medland, Sarah E, Nolte, Ilja M, Noordam, Raymond, Nutile, Teresa, Paternoster, Lavinia, Perjakova, Natalia, Porcu, Eleonora, Rose, Lynda M, Schraut, Katharina E, Segrè, Ayellet V, Smith, Albert V, Stolk, Lisette, Teumer, Alexander, Andrulis, Irene L, Bandinelli, Stefania, Beckmann, Matthias W, Benitez, Javier, Bergmann, Sven, Bochud, Murielle, de Geus, Eco J C N, Mbarek, Hamdi, Willemsen, Gonneke, Boomsma, Dorret I, Visser, Jenny A, and LifeLines Cohort Study

Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10(-8)) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

Published
2017
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10. Biological Stress Systems, Adverse Life Events, and the Improvement of Chronic Multisite Musculoskeletal Pain Across a 6-Year Follow-Up

Author

Generaal, Ellen, Vogelzangs, Nicole, Macfarlane, Gary J, Geenen, Rinie, Smit, Johannes H, de Geus, Eco J C N, Dekker, Joost, Penninx, Brenda W J H, Generaal, Ellen, Vogelzangs, Nicole, Macfarlane, Gary J, Geenen, Rinie, Smit, Johannes H, de Geus, Eco J C N, Dekker, Joost, and Penninx, Brenda W J H

Abstract

Dysfunction of biological stress systems and adverse life events, independently and in interaction, have been hypothesized to predict chronic pain persistence. Conversely, these factors may hamper the improvement of chronic pain. Longitudinal evidence is currently lacking. We examined whether: 1) function of biological stress systems, 2) adverse life events, and 3) their combination predict the improvement of chronic multisite musculoskeletal pain. Subjects of the Netherlands Study of Depression and Anxiety (NESDA) with chronic multisite musculoskeletal pain at baseline (N = 665) were followed-up 2, 4, and 6 years later. The Chronic Pain Grade Questionnaire was used to determine improvement (not meeting the criteria) of chronic multisite musculoskeletal pain at follow-up. Baseline assessment of biological stress systems included function of hypothalamic-pituitary-adrenal axis (1-hour cortisol awakening response, evening level, and post dexamethasone level), the immune system (basal and lipopolysaccharide-stimulated inflammatory markers), the autonomic nervous system (heart rate, pre-ejection period, SD of the normal-to-normal interval, and respiratory sinus arrhythmia). The number of adverse life events were assessed at baseline and 2-year follow-up using the List of Threatening Events Questionnaire. We showed that hypothalamic-pituitary-adrenal axis, immune system, and autonomic nervous system functioning and adverse life events were not associated with the improvement of chronic multisite musculoskeletal pain, either as a main effect or in interaction. This longitudinal study could not confirm that biological stress system dysfunction and adverse life events affect the course of chronic multisite musculoskeletal pain.PERSPECTIVE: Biological stress systems and adverse life events are not associated with the improvement of chronic multisite musculoskeletal pain over 6 years of follow-up. Other determinants should thus be considered in future research to id

Published
2017
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11. Consistency of biological networks inferred from microarray and sequencing data

Author

Vinciotti, Veronica, Wit, Ernst C, Jansen, Rick, de Geus, Eco J C N, Penninx, Brenda W J H, Boomsma, Dorret I, 't Hoen, Peter A C, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, EMGO - Mental health, and Stochastic Studies and Statistics

Subjects
Biochemistry, Molecular Biology, Computer Science Applications
Abstract

BackgroundSparse Gaussian graphical models are popular for inferring biological networks, such as gene regulatory networks. In this paper, we investigate the consistency of these models across different data platforms, such as microarray and next generation sequencing, on the basis of a rich dataset containing samples that are profiled under both techniques as well as a large set of independent samples.ResultsOur analysis shows that individual node variances can have a remarkable effect on the connectivity of the resulting network. Their inconsistency across platforms and the fact that the variability level of a node may not be linked to its regulatory role mean that, failing to scale the data prior to the network analysis, leads to networks that are not reproducible across different platforms and that may be misleading. Moreover, we show how the reproducibility of networks across different platforms is significantly higher if networks are summarised in terms of enrichment amongst functional groups of interest, such as pathways, rather than at the level of individual edges.ConclusionsCareful pre-processing of transcriptional data and summaries of networks beyond individual edges can improve the consistency of network inference across platforms. However, caution is needed at this stage in the (over)interpretation of gene regulatory networks inferred from biological data.

Published
2016

12. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Author

Warrington, Nicole M., Beaumont, Robin N., Horikoshi, Momoko, Day, Felix R., Helgeland, Øyvind, Laurin, Charles, Bacelis, Jonas, Peng, Shouneng, Hao, Ke, Feenstra, Bjarke, Wood, Andrew R., Mahajan, Anubha, Tyrrell, Jessica, Robertson, Neil R., Rayner, N. William, Qiao, Zhen, Moen, Gunn-Helen, Vaudel, Marc, Marsit, Carmen J., Chen, Jia, Nodzenski, Michael, Schnurr, Theresia M., Zafarmand, Mohammad H., Bradfield, Jonathan P., Grarup, Niels, Kooijman, Marjolein N., Li-Gao, Ruifang, Geller, Frank, Ahluwalia, Tarunveer S., Paternoster, Lavinia, Rueedi, Rico, Huikari, Ville, Hottenga, Jouke-Jan, Lyytikäinen, Leo-Pekka, Cavadino, Alana, Metrustry, Sarah, Cousminer, Diana L., Wu, Ying, Thiering, Elisabeth, Wang, Carol A., Have, Christian T., Vilor-Tejedor, Natalia, Joshi, Peter K., Painter, Jodie N., Ntalla, Ioanna, Myhre, Ronny, Pitkänen, Niina, van Leeuwen, Elisabeth M., Joro, Raimo, Lagou, Vasiliki, Richmond, Rebecca C., Espinosa, Ana, Barton, Sheila J., Inskip, Hazel M., Holloway, John W., Santa-Marina, Loreto, Estivill, Xavier, Ang, Wei, Marsh, Julie A., Reichetzeder, Christoph, Marullo, Letizia, Hocher, Berthold, Lunetta, Kathryn L., Murabito, Joanne M., Relton, Caroline L., Kogevinas, Manolis, Chatzi, Leda, Allard, Catherine, Bouchard, Luigi, Hivert, Marie-France, Zhang, Ge, Muglia, Louis J., Heikkinen, Jani, Morgen, Camilla S., van Kampen, Antoine H. C., van Schaik, Barbera D. C., Mentch, Frank D., Langenberg, Claudia, Luan, Jian’an, Scott, Robert A., Zhao, Jing Hua, Hemani, Gibran, Ring, Susan M., Bennett, Amanda J., Gaulton, Kyle J., Fernandez-Tajes, Juan, van Zuydam, Natalie R., Medina-Gomez, Carolina, de Haan, Hugoline G., Rosendaal, Frits R., Kutalik, Zoltán, Marques-Vidal, Pedro, Das, Shikta, Willemsen, Gonneke, Mbarek, Hamdi, Müller-Nurasyid, Martina, Standl, Marie, Appel, Emil V. R., Fonvig, Cilius E., Trier, Caecilie, van Beijsterveldt, Catharina E. M., Murcia, Mario, Bustamante, Mariona, Bonas-Guarch, Sílvia, Hougaard, David M., Mercader, Josep M., Linneberg, Allan, Schraut, Katharina E., Lind, Penelope A., Medland, Sarah E., Shields, Beverley M., Knight, Bridget A., Chai, Jin-Fang, Panoutsopoulou, Kalliope, Bartels, Meike, Sánchez, Friman, Stokholm, Jakob, Torrents, David, Vinding, Rebecca K., Willems, Sara M., Atalay, Mustafa, Chawes, Bo L., Kovacs, Peter, Prokopenko, Inga, Tuke, Marcus A., Yaghootkar, Hanieh, Ruth, Katherine S., Jones, Samuel E., Loh, Po-Ru, Murray, Anna, Weedon, Michael N., Tönjes, Anke, Stumvoll, Michael, Michaelsen, Kim F., Eloranta, Aino-Maija, Lakka, Timo A., van Duijn, Cornelia M., Kiess, Wieland, Körner, Antje, Niinikoski, Harri, Pahkala, Katja, Raitakari, Olli T., Jacobsson, Bo, Zeggini, Eleftheria, Dedoussis, George V., Teo, Yik-Ying, Saw, Seang-Mei, Montgomery, Grant W., Campbell, Harry, Wilson, James F., Vrijkotte, Tanja G. M., Vrijheid, Martine, de Geus, Eco J. C. N., Hayes, M. Geoffrey, Kadarmideen, Haja N., Holm, Jens-Christian, Beilin, Lawrence J., Pennell, Craig E., Heinrich, Joachim, Adair, Linda S., Borja, Judith B., Mohlke, Karen L., Eriksson, Johan G., Widén, Elisabeth E., Hattersley, Andrew T., Spector, Tim D., Kähönen, Mika, Viikari, Jorma S., Lehtimäki, Terho, Boomsma, Dorret I., Sebert, Sylvain, Vollenweider, Peter, Sørensen, Thorkild I. A., Bisgaard, Hans, Bønnelykke, Klaus, Murray, Jeffrey C., Melbye, Mads, Nohr, Ellen A., Mook-Kanamori, Dennis O., Rivadeneira, Fernando, Hofman, Albert, Felix, Janine F., Jaddoe, Vincent W. V., Hansen, Torben, Pisinger, Charlotta, Vaag, Allan A., Pedersen, Oluf, Uitterlinden, André G., Järvelin, Marjo-Riitta, Power, Christine, Hyppönen, Elina, Scholtens, Denise M., Lowe, William L., Davey Smith, George, Timpson, Nicholas J., Morris, Andrew P., Wareham, Nicholas J., Hakonarson, Hakon, Grant, Struan F. A., Frayling, Timothy M., Lawlor, Debbie A., Njølstad, Pål R., Johansson, Stefan, Ong, Ken K., McCarthy, Mark I., Perry, John R. B., Evans, David M., and Freathy, Rachel M.

Abstract

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n= 321,223) and offspring birth weight (n= 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight–blood pressure association is attributable to genetic effects, and not to intrauterine programming.

Published
2019
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14. Author Correction: Heritability estimates for 361 blood metabolites across 40 genome-wide association studies.

Author

Hagenbeek, Fiona A., Pool, René, van Dongen, Jenny, Draisma, H. M., Jan Hottenga, Jouke, Willemsen, Gonneke, Abdellaoui, Abdel, Fedko, Iryna O., den Braber, Anouk, Visser, Pieter Jelle, de Geus, Eco J. C. N., Willems van Dijk, Ko, Verhoeven, Aswin, Suchiman, H. Eka, Beekman, Marian, Slagboom, P. Eline, van Duijn, Cornelia M., BBMRI Metabolomics Consortium, Barkey Wolf, J. J. H., and Cats, D.

Subjects
HERITABILITY, METABOLITES, BLOOD, ESTIMATES, AUTHORS
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Published
2020
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15. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Lagou, Vasiliki, Mägi, Reedik, Hottenga, Jouke- Jan, Grallert, Harald, Perry, John R. B., Bouatia-Naji, Nabila, Marullo, Letizia, Rybin, Denis, Jansen, Rick, Min, Josine L., Dimas, Antigone S., Ulrich, Anna, Zudina, Liudmila, Gådin, Jesper R., Jiang, Longda, Faggian, Alessia, Bonnefond, Amélie, Fadista, Joao, Stathopoulou, Maria G., Isaacs, Aaron, Willems, Sara M., Navarro, Pau, Tanaka, Toshiko, Jackson, Anne U., Montasser, May E., O’Connell, Jeff R., Bielak, Lawrence F., Webster, Rebecca J., Saxena, Richa, Stafford, Jeanette M., Pourcain, Beate St, Timpson, Nicholas J., Salo, Perttu, Shin, So-Youn, Amin, Najaf, Smith, Albert V., Li, Guo, Verweij, Niek, Goel, Anuj, Ford, Ian, Johnson, Paul C. D., Johnson, Toby, Kapur, Karen, Thorleifsson, Gudmar, Strawbridge, Rona J., Rasmussen-Torvik, Laura J., Esko, Tõnu, Mihailov, Evelin, Fall, Tove, Fraser, Ross M., Mahajan, Anubha, Kanoni, Stavroula, Giedraitis, Vilmantas, Kleber, Marcus E., Silbernagel, Günther, Meyer, Julia, Müller-Nurasyid, Martina, Ganna, Andrea, Sarin, Antti-Pekka, Yengo, Loic, Shungin, Dmitry, Luan, Jian’an, Horikoshi, Momoko, An, Ping, Sanna, Serena, Boettcher, Yvonne, Rayner, N. William, Nolte, Ilja M., Zemunik, Tatijana, Iperen, Erik Van, Kovacs, Peter, Hastie, Nicholas D., Wild, Sarah H., McLachlan, Stela, Campbell, Susan, Polasek, Ozren, Carlson, Olga, Egan, Josephine, Kiess, Wieland, Willemsen, Gonneke, Kuusisto, Johanna, Laakso, Markku, Dimitriou, Maria, Hicks, Andrew A., Rauramaa, Rainer, Bandinelli, Stefania, Thorand, Barbara, Liu, Yongmei, Miljkovic, Iva, Lind, Lars, Doney, Alex, Perola, Markus, Hingorani, Aroon, Kivimaki, Mika, Kumari, Meena, Bennett, Amanda J., Groves, Christopher J., Herder, Christian, Koistinen, Heikki A., Kinnunen, Leena, Faire, Ulf De, Bakker, Stephan J. L., Uusitupa, Matti, Palmer, Colin N. A., Jukema, J. Wouter, Sattar, Naveed, Pouta, Anneli, Snieder, Harold, Boerwinkle, Eric, Pankow, James S., Magnusson, Patrik K., Krus, Ulrika, Scapoli, Chiara, De Geus, Eco J. C. N., Blüher, Matthias, Wolffenbuttel, Bruce H. R., Province, Michael A., Abecasis, Goncalo R., Meigs, James B., Hovingh, G. Kees, Lindström, Jaana, Wilson, James F., Wright, Alan F., Dedoussis, George V., Bornstein, Stefan R., Schwarz, Peter E. H., Tönjes, Anke, Winkelmann, Bernhard R., Boehm, Bernhard O., März, Winfried, Metspalu, Andres, Price, Jackie F., Deloukas, Panos, Körner, Antje, Lakka, Timo A., Keinanen-Kiukaanniemi, Sirkka M., Saaristo, Timo E., Bergman, Richard N., Tuomilehto, Jaakko, Wareham, Nicholas J., Langenberg, Claudia, Männistö, Satu, Franks, Paul W., Hayward, Caroline, Vitart, Veronique, Kaprio, Jaakko, Visvikis-Siest, Sophie, Balkau, Beverley, Altshuler, David, Rudan, Igor, Stumvoll, Michael, Campbell, Harry, Van Duijn, Cornelia M., Gieger, Christian, Illig, Thomas, Ferrucci, Luigi, Pedersen, Nancy L., Pramstaller, Peter P., Boehnke, Michael, Frayling, Timothy M., Shuldiner, Alan R., Peyser, Patricia A., Kardia, Sharon L. R., Palmer, Lyle J., Penninx, Brenda W., Meneton, Pierre, Harris, Tamara B., Navis, Gerjan, Harst, Pim Van Der, Smith, George Davey, Forouhi, Nita G., Loos, Ruth J. F., Salomaa, Veikko, Soranzo, Nicole, Boomsma, Dorret I., Groop, Leif, Tuomi, Tiinamaija, Hofman, Albert, Munroe, Patricia B., Gudnason, Vilmundur, Siscovick, David S., Watkins, Hugh, Lecoeur, Cecile, Vollenweider, Peter, Franco-Cereceda, Anders, Eriksson, Per, Jarvelin, Marjo-Riitta, Stefansson, Kari, Hamsten, Anders, Nicholson, George, Karpe, Fredrik, Dermitzakis, Emmanouil T., Lindgren, Cecilia M., McCarthy, Mark I., Froguel, Philippe, Kaakinen, Marika A., Lyssenko, Valeriya, Watanabe, Richard M., Ingelsson, Erik, Florez, Jose C., Dupuis, Josée, Barroso, Inês, Morris, Andrew P., and Prokopenko, Inga

Subjects
692/699/2743/2815, 631/208/205/2138, 692/53/2421, 45/43, article, 631/208/480, 692/163/2743/137/773, 3. Good health
Abstract

Funder: EU H2020, Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.

16. Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

Author

Ligthart, Symen, Vaez, Ahmad, Võsa, Urmo, Stathopoulou, Maria G, De Vries, Paul S, Prins, Bram P, Van Der Most, Peter J, Tanaka, Toshiko, Naderi, Elnaz, Rose, Lynda M, Wu, Ying, Karlsson, Robert, Barbalic, Maja, Lin, Honghuang, Pool, René, Zhu, Gu, Macé, Aurélien, Sidore, Carlo, Trompet, Stella, Mangino, Massimo, Sabater-Lleal, Maria, Kemp, John P, Abbasi, Ali, Kacprowski, Tim, Verweij, Niek, Smith, Albert V, Huang, Tao, Marzi, Carola, Feitosa, Mary F, Lohman, Kurt K, Kleber, Marcus E, Milaneschi, Yuri, Mueller, Christian, Huq, Mahmudul, Vlachopoulou, Efthymia, Lyytikäinen, Leo-Pekka, Oldmeadow, Christopher, Deelen, Joris, Perola, Markus, Zhao, Jing Hua, Feenstra, Bjarke, Amini, Marzyeh, Lahti, Jari, Schraut, Katharina E, Fornage, Myriam, Suktitipat, Bhoom, Chen, Wei-Min, Li, Xiaohui, Nutile, Teresa, Malerba, Giovanni, Luan, Jian'an, Bak, Tom, Schork, Nicholas, Del Greco M, Fabiola, Thiering, Elisabeth, Mahajan, Anubha, Marioni, Riccardo E, Mihailov, Evelin, Eriksson, Joel, Ozel, Ayse Bilge, Zhang, Weihua, Nethander, Maria, Cheng, Yu-Ching, Aslibekyan, Stella, Ang, Wei, Gandin, Ilaria, Yengo, Loïc, Portas, Laura, Kooperberg, Charles, Hofer, Edith, Rajan, Kumar B, Schurmann, Claudia, Den Hollander, Wouter, Ahluwalia, Tarunveer S, Zhao, Jing, Draisma, Harmen H M, Ford, Ian, Timpson, Nicholas, Teumer, Alexander, Huang, Hongyan, Wahl, Simone, Liu, YongMei, Huang, Jie, Uh, Hae-Won, Geller, Frank, Joshi, Peter K, Yanek, Lisa R, Trabetti, Elisabetta, Lehne, Benjamin, Vozzi, Diego, Verbanck, Marie, Biino, Ginevra, Saba, Yasaman, Meulenbelt, Ingrid, O'Connell, Jeff R, Laakso, Markku, Giulianini, Franco, Magnusson, Patrik K E, Ballantyne, Christie M, Hottenga, Jouke Jan, Montgomery, Grant W, Rivadineira, Fernando, Rueedi, Rico, Steri, Maristella, Herzig, Karl-Heinz, Stott, David J, Menni, Cristina, Frånberg, Mattias, St Pourcain, Beate, Felix, Stephan B, Pers, Tune H, Bakker, Stephan J L, Kraft, Peter, Peters, Annette, Vaidya, Dhananjay, Delgado, Graciela, Smit, Johannes H, Großmann, Vera, Sinisalo, Juha, Seppälä, Ilkka, Williams, Stephen R, Holliday, Elizabeth G, Moed, Matthijs, Langenberg, Claudia, Räikkönen, Katri, Ding, Jingzhong, Campbell, Harry, Sale, Michele M, Chen, Yii-Der I, James, Alan L, Ruggiero, Daniela, Soranzo, Nicole, Hartman, Catharina A, Smith, Erin N, Berenson, Gerald S, Fuchsberger, Christian, Hernandez, Dena, Tiesler, Carla M T, Giedraitis, Vilmantas, Liewald, David, Fischer, Krista, Mellström, Dan, Larsson, Anders, Wang, Yunmei, Scott, William R, Lorentzon, Matthias, Beilby, John, Ryan, Kathleen A, Pennell, Craig E, Vuckovic, Dragana, Balkau, Beverly, Concas, Maria Pina, Schmidt, Reinhold, Mendes De Leon, Carlos F, Bottinger, Erwin P, Kloppenburg, Margreet, Paternoster, Lavinia, Boehnke, Michael, Musk, A W, Willemsen, Gonneke, Evans, David M, Madden, Pamela A F, Kähönen, Mika, Kutalik, Zoltán, Zoledziewska, Magdalena, Karhunen, Ville, Kritchevsky, Stephen B, Sattar, Naveed, Lachance, Genevieve, Clarke, Robert, Harris, Tamara B, Raitakari, Olli T, Attia, John R, Van Heemst, Diana, Kajantie, Eero, Sorice, Rossella, Gambaro, Giovanni, Scott, Robert A, Hicks, Andrew A, Ferrucci, Luigi, Standl, Marie, Lindgren, Cecilia M, Starr, John M, Karlsson, Magnus, Lind, Lars, Li, Jun Z, Chambers, John C, Mori, Trevor A, De Geus, Eco J C N, Heath, Andrew C, Martin, Nicholas G, Auvinen, Juha, Buckley, Brendan M, De Craen, Anton J M, Waldenberger, Melanie, Strauch, Konstantin, Meitinger, Thomas, Scott, Rodney J, McEvoy, Mark, Beekman, Marian, Bombieri, Cristina, Ridker, Paul M, Mohlke, Karen L, Pedersen, Nancy L, Morrison, Alanna C, Boomsma, Dorret I, Whitfield, John B, Strachan, David P, Hofman, Albert, Vollenweider, Peter, Cucca, Francesco, Jarvelin, Marjo-Riitta, Jukema, J Wouter, Spector, Tim D, Hamsten, Anders, Zeller, Tanja, Uitterlinden, André G, Nauck, Matthias, Gudnason, Vilmundur, Qi, Lu, Grallert, Harald, Borecki, Ingrid B, Rotter, Jerome I, März, Winfried, Wild, Philipp S, Lokki, Marja-Liisa, Boyle, Michael, Salomaa, Veikko, Melbye, Mads, Eriksson, Johan G, Wilson, James F, Penninx, Brenda W J H, Becker, Diane M, Worrall, Bradford B, Gibson, Greg, Krauss, Ronald M, Ciullo, Marina, Zaza, Gianluigi, Wareham, Nicholas J, Oldehinkel, Albertine J, Palmer, Lyle J, Murray, Sarah S, Pramstaller, Peter P, Bandinelli, Stefania, Heinrich, Joachim, Ingelsson, Erik, Deary, Ian J, Mägi, Reedik, Vandenput, Liesbeth, Van Der Harst, Pim, Desch, Karl C, Kooner, Jaspal S, Ohlsson, Claes, Hayward, Caroline, Lehtimäki, Terho, Shuldiner, Alan R, Arnett, Donna K, Beilin, Lawrence J, Robino, Antonietta, Froguel, Philippe, Pirastu, Mario, Jess, Tine, Koenig, Wolfgang, Loos, Ruth J F, Evans, Denis A, Schmidt, Helena, Smith, George Davey, Slagboom, P Eline, Eiriksdottir, Gudny, Morris, Andrew P, Psaty, Bruce M, Tracy, Russell P, Nolte, Ilja M, Boerwinkle, Eric, Visvikis-Siest, Sophie, Reiner, Alex P, Gross, Myron, Bis, Joshua C, Franke, Lude, Franco, Oscar H, Benjamin, Emelia J, Chasman, Daniel I, Dupuis, Josée, Snieder, Harold, Dehghan, Abbas, and Alizadeh, Behrooz Z

Subjects
2. Zero hunger, 610 Medicine & health, 360 Social problems & social services, 3. Good health
Abstract

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

17. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Lagou, Vasiliki, Mägi, Reedik, Hottenga, Jouke- Jan, Grallert, Harald, Perry, John R. B., Bouatia-Naji, Nabila, Marullo, Letizia, Rybin, Denis, Jansen, Rick, Min, Josine L., Dimas, Antigone S., Ulrich, Anna, Zudina, Liudmila, Gådin, Jesper R., Jiang, Longda, Faggian, Alessia, Bonnefond, Amélie, Fadista, Joao, Stathopoulou, Maria G., Isaacs, Aaron, Willems, Sara M., Navarro, Pau, Tanaka, Toshiko, Jackson, Anne U., Montasser, May E., O’Connell, Jeff R., Bielak, Lawrence F., Webster, Rebecca J., Saxena, Richa, Stafford, Jeanette M., Pourcain, Beate St, Timpson, Nicholas J., Salo, Perttu, Shin, So-Youn, Amin, Najaf, Smith, Albert V., Li, Guo, Verweij, Niek, Goel, Anuj, Ford, Ian, Johnson, Paul C. D., Johnson, Toby, Kapur, Karen, Thorleifsson, Gudmar, Strawbridge, Rona J., Rasmussen-Torvik, Laura J., Esko, Tõnu, Mihailov, Evelin, Fall, Tove, Fraser, Ross M., Mahajan, Anubha, Kanoni, Stavroula, Giedraitis, Vilmantas, Kleber, Marcus E., Silbernagel, Günther, Meyer, Julia, Müller-Nurasyid, Martina, Ganna, Andrea, Sarin, Antti-Pekka, Yengo, Loic, Shungin, Dmitry, Luan, Jian’an, Horikoshi, Momoko, An, Ping, Sanna, Serena, Boettcher, Yvonne, Rayner, N. William, Nolte, Ilja M., Zemunik, Tatijana, Iperen, Erik Van, Kovacs, Peter, Hastie, Nicholas D., Wild, Sarah H., McLachlan, Stela, Campbell, Susan, Polasek, Ozren, Carlson, Olga, Egan, Josephine, Kiess, Wieland, Willemsen, Gonneke, Kuusisto, Johanna, Laakso, Markku, Dimitriou, Maria, Hicks, Andrew A., Rauramaa, Rainer, Bandinelli, Stefania, Thorand, Barbara, Liu, Yongmei, Miljkovic, Iva, Lind, Lars, Doney, Alex, Perola, Markus, Hingorani, Aroon, Kivimaki, Mika, Kumari, Meena, Bennett, Amanda J., Groves, Christopher J., Herder, Christian, Koistinen, Heikki A., Kinnunen, Leena, Faire, Ulf De, Bakker, Stephan J. L., Uusitupa, Matti, Palmer, Colin N. A., Jukema, J. Wouter, Sattar, Naveed, Pouta, Anneli, Snieder, Harold, Boerwinkle, Eric, Pankow, James S., Magnusson, Patrik K., Krus, Ulrika, Scapoli, Chiara, De Geus, Eco J. C. N., Blüher, Matthias, Wolffenbuttel, Bruce H. R., Province, Michael A., Abecasis, Goncalo R., Meigs, James B., Hovingh, G. Kees, Lindström, Jaana, Wilson, James F., Wright, Alan F., Dedoussis, George V., Bornstein, Stefan R., Schwarz, Peter E. H., Tönjes, Anke, Winkelmann, Bernhard R., Boehm, Bernhard O., März, Winfried, Metspalu, Andres, Price, Jackie F., Deloukas, Panos, Körner, Antje, Lakka, Timo A., Keinanen-Kiukaanniemi, Sirkka M., Saaristo, Timo E., Bergman, Richard N., Tuomilehto, Jaakko, Wareham, Nicholas J., Langenberg, Claudia, Männistö, Satu, Franks, Paul W., Hayward, Caroline, Vitart, Veronique, Kaprio, Jaakko, Visvikis-Siest, Sophie, Balkau, Beverley, Altshuler, David, Rudan, Igor, Stumvoll, Michael, Campbell, Harry, Van Duijn, Cornelia M., Gieger, Christian, Illig, Thomas, Ferrucci, Luigi, Pedersen, Nancy L., Pramstaller, Peter P., Boehnke, Michael, Frayling, Timothy M., Shuldiner, Alan R., Peyser, Patricia A., Kardia, Sharon L. R., Palmer, Lyle J., Penninx, Brenda W., Meneton, Pierre, Harris, Tamara B., Navis, Gerjan, Harst, Pim Van Der, Smith, George Davey, Forouhi, Nita G., Loos, Ruth J. F., Salomaa, Veikko, Soranzo, Nicole, Boomsma, Dorret I., Groop, Leif, Tuomi, Tiinamaija, Hofman, Albert, Munroe, Patricia B., Gudnason, Vilmundur, Siscovick, David S., Watkins, Hugh, Lecoeur, Cecile, Vollenweider, Peter, Franco-Cereceda, Anders, Eriksson, Per, Jarvelin, Marjo-Riitta, Stefansson, Kari, Hamsten, Anders, Nicholson, George, Karpe, Fredrik, Dermitzakis, Emmanouil T., Lindgren, Cecilia M., McCarthy, Mark I., Froguel, Philippe, Kaakinen, Marika A., Lyssenko, Valeriya, Watanabe, Richard M., Ingelsson, Erik, Florez, Jose C., Dupuis, Josée, Barroso, Inês, Morris, Andrew P., and Prokopenko, Inga

Subjects
692/699/2743/2815, 631/208/205/2138, 692/53/2421, 45/43, article, 631/208/480, 692/163/2743/137/773, 3. Good health
Abstract

Funder: EU H2020, Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.

18. Genome-wide associations for birth weight and correlations with adult disease

Author

Standl, Marie, Grarup, Niels, Mercader, Josep M., Nodzenski, Michael, Warrington, Nicole M., Felix, Janine F., Tuke, Marcus A., Hofman, Albert, Mohlke, Karen L., Strachan, David P., Kadarmideen, Haja N., Bonàs-Guarch, Sílvia, Scholtens, Denise M., Panoutsopoulou, Kalliope, Kovacs, Peter, Li-Gao, Ruifang, Langenberg, Claudia, Bønnelykke, Klaus, Morris, Andrew P., Reynolds, Rebecca M., Sørensen, Thorkild I. A., Day, Felix R., Freathy, Rachel M., Schraut, Katharina E., Feenstra, Bjarke, Bisgaard, Hans, Torrents, David, Carstensen, Lisbeth, De Haan, Hugoline G., Newnham, John P., Ruth, Katherine S., Ring, Susan M., Sánchez, Friman, Pisinger, Charlotta, Bustamante, Mariona, Robertson, Neil R., Rahmioglu, Nilufer, Kutalik, Zoltán, Rueedi, Rico, Boomsma, Dorret I., Horikoshi, Momoko, Rosendaal, Frits R., Van Beijsterveldt, Catharina E. M., Campbell, Harry, Mentch, Frank D., Kreiner, Eskil, Stumvoll, Michael, Fonvig, Cilius E., Willems, Sara M., Willemsen, Gonneke, Prokopenko, Inga, Beaumont, Robin N., Wu, Ying, Geller, Frank, Smith, George Davey, Bennett, Amanda J., Pitkänen, Niina, Dedoussis, George V., Vilor-Tejedor, Natalia, Lindi, Virpi, Jones, Samuel E., Trier, Caecilie, Tam, Claudia H. T., Vrijheid, Martine, Pedersen, Oluf, Tyrrell, Jessica, Widén, Elisabeth, Wareham, Nicholas J., Boh, Eileen Tai Hui, Uitterlinden, André G., De Geus, Eco J. C. N., Mahajan, Anubha, Kiess, Wieland, Vaag, Allan A., Wang, Carol A., Ganesh, Santhi K., Eriksson, Johan G., Van Leeuwen, Elisabeth M., Ong, Ken K., Timpson, Nicholas J., Luan, Jian'An, Murcia, Mario, Hottenga, Jouke-Jan, Van Rooij, Frank J. A., Thiering, Elisabeth, Mook-Kanamori, Dennis O., Davies, Eleanor, Van Zuydam, Natalie R., Ntalla, Ioanna, Vollenweider, Peter, Zhao, Jing Hua, Sebert, Sylvain, Hakonarson, Hakon, Walker, Brian R., Appel, Emil V. R., Joshi, Peter K., Tönjes, Anke, Adair, Linda S., Lakka, Timo A., Have, Christian T., Körner, Antje, Nyholt, Dale R., McMahon, George, Jaddoe, Vincent W. V., Tam, Wing Hung, Tiesler, Carla M. T., Teo, Yik-Ying, Atalay, Mustafa, Raitakari, Olli T., Niinikoski, Harri, Paternoster, Lavinia, Melbye, Mads, Rivadeneira, Fernando, Kähönen, Mika, Bradfield, Jonathan P., Beilin, Lawrence J., Hyppönen, Elina, Loh, Po-Ru, Wood, Andrew R., Ma, Ronald C. W., Scott, Robert A., Viikari, Jorma S., Medina-Gomez, Carolina, Pahkala, Katja, Hansen, Torben, Wilson, James F., Zeggini, Eleftheria, Kooijman, Marjolein N., Joro, Raimo, Cousminer, Diana L., Borja, Judith B., Frayling, Timothy M., Järvelin, Marjo-Riitta, Perry, John R. B., Holm, Jens-Christian, Lagou, Vasiliki, MacKenzie, Scott M., Fernandez-Tajes, Juan, Evans, David M., Pennell, Craig E., McCarthy, Mark I., Waage, Johannes, Heinrich, Joachim, Ahluwalia, Tarunveer S., Grant, Struan F. A., Hemani, Gibran, Lawlor, Debbie A., Lehtimäki, Terho, Van Duijn, Cornelia M., Gaulton, Kyle J., Zondervan, Krina T., Lyytikaïnen, Leo-Pekka, Hollegaard, Mads V., Wang, Xu, Lowe, William L., Yaghootkar, Hanieh, Diver, Louise A., Hattersley, Andrew T., Groves, Christopher J., Hougaard, David M., Power, Christine, Marques-Vidal, Pedro, and Saw, Seang-Mei

Subjects
3. Good health
Abstract

Birth weight (BW) is influenced by both foetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease1. These lifecourse associations have often been attributed to the impact of an adverse early life environment. We performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where foetal genotype was associated with BW (P

19. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Author

Emmi Tikkanen, Pascal Guénel, Rico Rueedi, Hamdi Mbarek, Gerardo Heiss, Hilary K. Finucane, Jing Hua Zhao, Peter K. Joshi, Mark I. McCarthy, Frank B. Hu, Stephen J. Chanock, Manjeet K. Bolla, Sandosh Padmanabhan, Vilmundur Gudnason, Chunyan He, Aarno Palotie, Reedik Mägi, Joe Dennis, Nicholas G. Martin, Behrooz Z. Alizadeh, Elisabeth Widen, Caroline Hayward, Penelope A. Lind, Magdalena Zoledziewska, Ayellet V. Segrè, Fergus J. Couch, Massimo Mangino, Melissa C. Southey, Immaculata De Vivo, Yongmei Liu, Ute Hamann, Angela Cox, Maartje J. Hooning, Iffat Rahman, Mitul Shah, Eric Boerwinkle, Matthias W. Beckmann, Catharina A. Hartman, Tanguy Corre, Kathryn L. Lunetta, Thérèse Truong, Anna Marie Mulligan, Caterina Barbieri, Robert Winqvist, Lili Milani, Cristina Menni, Frits R. Rosendaal, Pau Navarro, Christian Gieger, Ken K. Ong, Stig E. Bojesen, Susan M. Ring, Marjanka K. Schmidt, George McMahon, Deborah J. Thompson, Robert Karlsson, Nicholas J. Timpson, M. Arfan Ikram, Alexander Teumer, Jingmei Li, Christa Meisinger, Diana L. Cousminer, Doris Stöckl, Heli Nevanlinna, Teresa Nutile, Tim D. Spector, Eva Albrecht, Murielle Bochud, Linda Broer, Felix R. Day, Sven Bergmann, Renée de Mutsert, Nicholas J. Wareham, Marjo-Riitta Järvelin, Marzyeh Amini, Elisabeth Altmaier, Isabel dos-Santos-Silva, Peter Vollenweider, Douglas F. Easton, Tamara B. Harris, Ellen A. Nohr, Paul D.P. Pharoah, David J. Porteous, Jenny A. Visser, Ilja M. Nolte, Genevieve Lachance, Thomas Meitinger, Archie Campbell, Thomas Brüning, Graham G. Giles, Johan G. Eriksson, Nancy L. Pedersen, George Davey Smith, Gonneke Willemsen, Joanne M. Murabito, Francesco Cucca, Daniel I. Chasman, Eleonora Porcu, Nora Franceschini, Thibaud Boutin, Ulla Sovio, Roger L. Milne, Annette Peters, Lisette Stolk, Paul M. Ridker, Claudia Langenberg, Patrick Sulem, Toshiko Tanaka, Marike Gabrielson, Judith S. Brand, Unnur Thorsteindottir, Alison M. Dunning, Marina Ciullo, Julie E. Buring, Harold Snieder, Lude Franke, Meir J. Stampfer, Po-Ru Loh, Julian Peto, Ellen W. Demerath, Sheila Ulivi, Ivana Kolcic, Maristella Steri, Jouke J. Hottenga, Amanda B. Spurdle, Tõnu Esko, Katherine S. Pollard, Eulalia Catamo, Anneli Pouta, Kyriaki Michailidou, Dieter Flesch-Janys, James F. Wilson, Kamila Czene, Sean Whalen, Diether Lambrechts, Abhishek Sarkar, Laura Crisponi, Jonathan Tyrer, Antonietta Robino, Sara Lindström, Harald Grallert, Stefania Lenarduzzi, Peter Kraft, Patrik K. E. Magnusson, Lavinia Paternoster, Digna R. Velez Edwards, Mike A. Nalls, Per Hall, Joyce Y. Tung, Cinzia Sala, Lindsay Fernández-Rhodes, Ayush Giri, Hiltrud Brauch, André G. Uitterlinden, Alkes L. Price, Tracy A. O'Mara, Lynda M. Rose, John L. Hopper, David A. Hinds, Katherine S. Ruth, Arto Mannermaa, Uwe Völker, Rossella Sorice, Zoltán Kutalik, Debbie A Lawlor, Georgia Chenevix-Trench, Anna Murray, Albertine J. Oldehinkel, Bruce H. R. Wolffenbuttel, Hae Kyung Im, Dale R. Nyholt, Lenore J. Launer, Andres Metspalu, Irene L. Andrulis, Konstantin Strauch, Albert V. Smith, Daniela Toniolo, Eco J. C. de Geus, Jenny Chang-Claude, Marek Zygmunt, Dorret I. Boomsma, Harry Campbell, Peter Devilee, Henry Völzke, Daniela Ruggiero, Dennis O. Mook-Kanamori, John R. B. Perry, Javier Benitez, Grant W. Montgomery, David J. Hunter, David Karasik, Luigi Ferrucci, Emily Hallberg, Stefania Bandinelli, Hermann Brenner, Raymond Noordam, Sarah E. Medland, Peter A. Fasching, Qin Wang, Ilaria Gandin, Manolis Kellis, Hannes Helgason, Igor Rudan, Paolo Radice, Michela Traglia, Jian'an Luan, Robert A. Scott, Brumat Marco, Veronique Vitart, Kari Stefansson, Katharina E. Schraut, Ko Willems van Dijk, Ozren Polasek, Daniel F. Gudbjartsson, Natalia Perjakova, Joop S.E. Laven, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Art and Culture, History, Antiquity, Day, Felix R., Thompson, Deborah J., Helgason, Hanne, Chasman, Daniel I., Finucane, Hilary, Sulem, Patrick, Ruth, Katherine S., Whalen, Sean, Sarkar, Abhishek K., Albrecht, Eva, Altmaier, Elisabeth, Amini, Marzyeh, Barbieri, CATERINA MARIA, Boutin, Thibaud, Campbell, Archie, Demerath, Ellen, Giri, Ayush, He, Chunyan, Hottenga, Jouke J., Karlsson, Robert, Kolcic, Ivana, Loh, Po Ru, Lunetta, Kathryn L., Mangino, Massimo, Brumat, Marco, Mcmahon, George, Medland, Sarah E., Nolte, Ilja M., Noordam, Raymond, Nutile, Teresa, Paternoster, Lavinia, Perjakova, Natalia, Porcu, Eleonora, Rose, Lynda M., Schraut, Katharina E., Segrã¨, Ayellet V., Smith, Albert V., Stolk, Lisette, Teumer, Alexander, Andrulis, Irene L., Bandinelli, Stefania, Beckmann, Matthias W., Benitez, Javier, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E., Bolla, Manjeet K., Brand, Judith S., Brauch, Hiltrud, Brenner, Hermann, Broer, Linda, Brã¼ning, Thoma, Buring, Julie E., Campbell, Harry, Catamo, Eulalia, Chanock, Stephen, Chenevix Trench, Georgia, Corre, Tanguy, Couch, Fergus J., Cousminer, Diana L., Cox, Angela, Crisponi, Laura, Czene, Kamila, Davey Smith, George, De Geus, Eco J. C. N., De Mutsert, Renã©e, De Vivo, Immaculata, Dennis, Joe, Devilee, Peter, Dos Santos Silva, Isabel, Dunning, Alison M., Eriksson, Johan G., Fasching, Peter A., Fernández Rhodes, Lindsay, Ferrucci, Luigi, Flesch Janys, Dieter, Franke, Lude, Gabrielson, Marike, Gandin, Ilaria, Giles, Graham G., Grallert, Harald, Gudbjartsson, Daniel F., Guã©nel, Pascal, Hall, Per, Hallberg, Emily, Hamann, Ute, Harris, Tamara B., Hartman, Catharina A., Heiss, Gerardo, Hooning, Maartje J., Hopper, John L., Hu, Frank, Hunter, David J., Ikram, M. Arfan, Im, Hae Kyung, Jã¤rvelin, Marjo Riitta, Joshi, Peter K., Karasik, David, Kellis, Manoli, Kutalik, Zoltan, Lachance, Genevieve, Lambrechts, Diether, Langenberg, Claudia, Launer, Lenore J., Laven, Joop S. E., Lenarduzzi, Stefania, Li, Jingmei, Lind, Penelope A., Lindstrom, Sara, Liu, Yongmei, Luan, Jian'An, Mã¤gi, Reedik, Mannermaa, Arto, Mbarek, Hamdi, Mccarthy, Mark I., Meisinger, Christa, Meitinger, Thoma, Menni, Cristina, Metspalu, Andre, Michailidou, Kyriaki, Milani, Lili, Milne, Roger L., Montgomery, Grant W., Mulligan, Anna M., Nalls, Mike A., Navarro, Pau, Nevanlinna, Heli, Nyholt, Dale R., Oldehinkel, Albertine J., O'Mara, Tracy A., Padmanabhan, Sandosh, Palotie, Aarno, Pedersen, Nancy, Peters, Annette, Peto, Julian, Pharoah, Paul D. P., Pouta, Anneli, Radice, Paolo, Rahman, Iffat, Ring, Susan M., Robino, Antonietta, Rosendaal, Frits R., Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Sala, Cinzia F., Schmidt, Marjanka K., Scott, Robert A., Shah, Mitul, Sorice, Rossella, Southey, Melissa C., Sovio, Ulla, Stampfer, Meir, Steri, Maristella, Strauch, Konstantin, Tanaka, Toshiko, Tikkanen, Emmi, Timpson, Nicholas J., Traglia, Michela, Truong, Thã©rã¨se, Tyrer, Jonathan P., Uitterlinden, André G., Edwards, Digna R. Velez, Vitart, Veronique, Vã¶lker, Uwe, Vollenweider, Peter, Wang, Qin, Widen, Elisabeth, Van Dijk, Ko Willem, Willemsen, Gonneke, Winqvist, Robert, Wolffenbuttel, Bruce H. R., Zhao, Jing Hua, Zoledziewska, Magdalena, Zygmunt, Marek, Alizadeh, Behrooz Z., Boomsma, Dorret I., Ciullo, Marina, Cucca, Francesco, Esko, Tãµnu, Franceschini, Nora, Gieger, Christian, Gudnason, Vilmundur, Hayward, Caroline, Kraft, Peter, Lawlor, Debbie A., Magnusson, Patrik K. E., Martin, Nicholas G., Mook Kanamori, Dennis O., Nohr, Ellen A., Polasek, Ozren, Porteous, David, Price, Alkes L., Ridker, Paul M., Snieder, Harold, Spector, Tim D., Stã¶ckl, Dori, Toniolo, Daniela, Ulivi, Sheila, Visser, Jenny A., Vã¶lzke, Henry, Wareham, Nicholas J., Wilson, James F., LifeLines Cohort, Study, Interact, Consortium, Kconfab/aocs, Investigator, Endometrial Cancer Association, Consortium, Ovarian Cancer Association, Consortium, Practical, Consortium, Spurdle, Amanda B., Thorsteindottir, Unnur, Pollard, Katherine S., Easton, Douglas F., Tung, Joyce Y., Chang Claude, Jenny, Hinds, David, Murray, Anna, Murabito, Joanne M., Stefansson, Kari, Ong, Ken K., Perry, John R. B., Internal Medicine, Erasmus MC other, Medical Oncology, Epidemiology, Obstetrics & Gynecology, Day, Felix [0000-0003-3789-7651], Thompson, Deborah [0000-0003-1465-5799], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Pharoah, Paul [0000-0001-8494-732X], Sovio, Ulla [0000-0002-0799-1105], Tyrer, Jonathan [0000-0003-3724-4757], Zhao, Jing Hua [0000-0003-4930-3582], Wareham, Nicholas [0000-0003-1422-2993], Easton, Douglas [0000-0003-2444-3247], Ong, Kenneth [0000-0003-4689-7530], Perry, John [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Massachusetts Institute of Technology. Department of Mathematics, and Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory

Subjects
0301 basic medicine, Male, Netherlands Twin Register (NTR), Ovarian Cancer Association Consortium, LOCI, Genome-wide association study, cancer risk, Menarche/genetics, Bioinformatics, GWAS, menarche, puberty, Body Mass Index, Risk Factors, Neoplasms, Databases, Genetic, WIDE ASSOCIATION, Endometrial Cancer Association Consortium, Ribonucleoproteins/genetics, 2. Zero hunger, Genetics, Age Factors, Genetics GWAS menarche, reproductive disorders, Neoplasms/genetics, 3. Good health, Ribonucleoproteins, Menarche, MENDELIAN RANDOMIZATION, Intercellular Signaling Peptides and Proteins, GROWTH, Female, TRAITS, Population variance, Intercellular Signaling Peptides and Proteins/genetics, Adolescent, Ubiquitin-Protein Ligases, kConFab/AOCS Investigators, Quantitative Trait Loci, Quantitative trait locus, Biology, METABOLISM, INHERITANCE, Polymorphism, Single Nucleotide, PRACTICAL consortium, 03 medical and health sciences, Genomic Imprinting, SDG 3 - Good Health and Well-being, Mendelian randomization, REGRESSION, medicine, Journal Article, Humans, cancer, Genetic Predisposition to Disease, 1000 Genomes Project, Membrane Proteins/genetics, METAANALYSIS, Puberty, Calcium-Binding Proteins, Membrane Proteins, Cancer, InterAct Consortium, Heritability, medicine.disease, BODY-MASS INDEX, 030104 developmental biology, genome-wide association studies, Puberty/genetics, LifeLines Cohort Study, Genome-Wide Association Study
Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to similar to 370,000 women, we identify 389 independent signals (P

Published
2017

20. Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Author

Lagou V, Mägi R, Hottenga JJ, Grallert H, Perry JRB, Bouatia-Naji N, Marullo L, Rybin D, Jansen R, Min JL, Dimas AS, Ulrich A, Zudina L, Gådin JR, Jiang L, Faggian A, Bonnefond A, Fadista J, Stathopoulou MG, Isaacs A, Willems SM, Navarro P, Tanaka T, Jackson AU, Montasser ME, O'Connell JR, Bielak LF, Webster RJ, Saxena R, Stafford JM, Pourcain BS, Timpson NJ, Salo P, Shin SY, Amin N, Smith AV, Li G, Verweij N, Goel A, Ford I, Johnson PCD, Johnson T, Kapur K, Thorleifsson G, Strawbridge RJ, Rasmussen-Torvik LJ, Esko T, Mihailov E, Fall T, Fraser RM, Mahajan A, Kanoni S, Giedraitis V, Kleber ME, Silbernagel G, Meyer J, Müller-Nurasyid M, Ganna A, Sarin AP, Yengo L, Shungin D, Luan J, Horikoshi M, An P, Sanna S, Boettcher Y, Rayner NW, Nolte IM, Zemunik T, Iperen EV, Kovacs P, Hastie ND, Wild SH, McLachlan S, Campbell S, Polasek O, Carlson O, Egan J, Kiess W, Willemsen G, Kuusisto J, Laakso M, Dimitriou M, Hicks AA, Rauramaa R, Bandinelli S, Thorand B, Liu Y, Miljkovic I, Lind L, Doney A, Perola M, Hingorani A, Kivimaki M, Kumari M, Bennett AJ, Groves CJ, Herder C, Koistinen HA, Kinnunen L, Faire U, Bakker SJL, Uusitupa M, Palmer CNA, Jukema JW, Sattar N, Pouta A, Snieder H, Boerwinkle E, Pankow JS, Magnusson PK, Krus U, Scapoli C, de Geus EJCN, Blüher M, Wolffenbuttel BHR, Province MA, Abecasis GR, Meigs JB, Hovingh GK, Lindström J, Wilson JF, Wright AF, Dedoussis GV, Bornstein SR, Schwarz PEH, Tönjes A, Winkelmann BR, Boehm BO, März W, Metspalu A, Price JF, Deloukas P, Körner A, Lakka TA, Keinanen-Kiukaanniemi SM, Saaristo TE, Bergman RN, Tuomilehto J, Wareham NJ, Langenberg C, Männistö S, Franks PW, Hayward C, Vitart V, Kaprio J, Visvikis-Siest S, Balkau B, Altshuler D, Rudan I, Stumvoll M, Campbell H, van Duijn CM, Gieger C, Illig T, Ferrucci L, Pedersen NL, Pramstaller PP, Boehnke M, Frayling TM, Shuldiner AR, Peyser PA, Kardia SLR, Palmer LJ, Penninx BW, Meneton P, Harris TB, Navis G, Harst PV, Smith GD, Forouhi NG, Loos RJF, Salomaa V, Soranzo N, Boomsma DI, Groop L, Tuomi T, Hofman A, Munroe PB, Gudnason V, Siscovick DS, Watkins H, Lecoeur C, Vollenweider P, Franco-Cereceda A, Eriksson P, Jarvelin MR, Stefansson K, Hamsten A, Nicholson G, Karpe F, Dermitzakis ET, Lindgren CM, McCarthy MI, Froguel P, Kaakinen MA, Lyssenko V, Watanabe RM, Ingelsson E, Florez JC, Dupuis J, Barroso I, Morris AP, and Prokopenko I

Published
2021
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21. Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.

Author

Ligthart S, Vaez A, Võsa U, Stathopoulou MG, de Vries PS, Prins BP, Van der Most PJ, Tanaka T, Naderi E, Rose LM, Wu Y, Karlsson R, Barbalic M, Lin H, Pool R, Zhu G, Macé A, Sidore C, Trompet S, Mangino M, Sabater-Lleal M, Kemp JP, Abbasi A, Kacprowski T, Verweij N, Smith AV, Huang T, Marzi C, Feitosa MF, Lohman KK, Kleber ME, Milaneschi Y, Mueller C, Huq M, Vlachopoulou E, Lyytikäinen LP, Oldmeadow C, Deelen J, Perola M, Zhao JH, Feenstra B, Amini M, Lahti J, Schraut KE, Fornage M, Suktitipat B, Chen WM, Li X, Nutile T, Malerba G, Luan J, Bak T, Schork N, Del Greco M F, Thiering E, Mahajan A, Marioni RE, Mihailov E, Eriksson J, Ozel AB, Zhang W, Nethander M, Cheng YC, Aslibekyan S, Ang W, Gandin I, Yengo L, Portas L, Kooperberg C, Hofer E, Rajan KB, Schurmann C, den Hollander W, Ahluwalia TS, Zhao J, Draisma HHM, Ford I, Timpson N, Teumer A, Huang H, Wahl S, Liu Y, Huang J, Uh HW, Geller F, Joshi PK, Yanek LR, Trabetti E, Lehne B, Vozzi D, Verbanck M, Biino G, Saba Y, Meulenbelt I, O'Connell JR, Laakso M, Giulianini F, Magnusson PKE, Ballantyne CM, Hottenga JJ, Montgomery GW, Rivadineira F, Rueedi R, Steri M, Herzig KH, Stott DJ, Menni C, Frånberg M, St Pourcain B, Felix SB, Pers TH, Bakker SJL, Kraft P, Peters A, Vaidya D, Delgado G, Smit JH, Großmann V, Sinisalo J, Seppälä I, Williams SR, Holliday EG, Moed M, Langenberg C, Räikkönen K, Ding J, Campbell H, Sale MM, Chen YI, James AL, Ruggiero D, Soranzo N, Hartman CA, Smith EN, Berenson GS, Fuchsberger C, Hernandez D, Tiesler CMT, Giedraitis V, Liewald D, Fischer K, Mellström D, Larsson A, Wang Y, Scott WR, Lorentzon M, Beilby J, Ryan KA, Pennell CE, Vuckovic D, Balkau B, Concas MP, Schmidt R, Mendes de Leon CF, Bottinger EP, Kloppenburg M, Paternoster L, Boehnke M, Musk AW, Willemsen G, Evans DM, Madden PAF, Kähönen M, Kutalik Z, Zoledziewska M, Karhunen V, Kritchevsky SB, Sattar N, Lachance G, Clarke R, Harris TB, Raitakari OT, Attia JR, van Heemst D, Kajantie E, Sorice R, Gambaro G, Scott RA, Hicks AA, Ferrucci L, Standl M, Lindgren CM, Starr JM, Karlsson M, Lind L, Li JZ, Chambers JC, Mori TA, de Geus EJCN, Heath AC, Martin NG, Auvinen J, Buckley BM, de Craen AJM, Waldenberger M, Strauch K, Meitinger T, Scott RJ, McEvoy M, Beekman M, Bombieri C, Ridker PM, Mohlke KL, Pedersen NL, Morrison AC, Boomsma DI, Whitfield JB, Strachan DP, Hofman A, Vollenweider P, Cucca F, Jarvelin MR, Jukema JW, Spector TD, Hamsten A, Zeller T, Uitterlinden AG, Nauck M, Gudnason V, Qi L, Grallert H, Borecki IB, Rotter JI, März W, Wild PS, Lokki ML, Boyle M, Salomaa V, Melbye M, Eriksson JG, Wilson JF, Penninx BWJH, Becker DM, Worrall BB, Gibson G, Krauss RM, Ciullo M, Zaza G, Wareham NJ, Oldehinkel AJ, Palmer LJ, Murray SS, Pramstaller PP, Bandinelli S, Heinrich J, Ingelsson E, Deary IJ, Mägi R, Vandenput L, van der Harst P, Desch KC, Kooner JS, Ohlsson C, Hayward C, Lehtimäki T, Shuldiner AR, Arnett DK, Beilin LJ, Robino A, Froguel P, Pirastu M, Jess T, Koenig W, Loos RJF, Evans DA, Schmidt H, Smith GD, Slagboom PE, Eiriksdottir G, Morris AP, Psaty BM, Tracy RP, Nolte IM, Boerwinkle E, Visvikis-Siest S, Reiner AP, Gross M, Bis JC, Franke L, Franco OH, Benjamin EJ, Chasman DI, Dupuis J, Snieder H, Dehghan A, and Alizadeh BZ

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers metabolism, Bipolar Disorder genetics, Bipolar Disorder metabolism, Body Mass Index, C-Reactive Protein genetics, Child, Female, Genome-Wide Association Study methods, Humans, Inflammation metabolism, Liver metabolism, Liver pathology, Male, Mendelian Randomization Analysis methods, Middle Aged, Schizophrenia genetics, Schizophrenia metabolism, Young Adult, Genetic Loci genetics, Inflammation genetics, Metabolic Networks and Pathways genetics
Abstract

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10 -8 ). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences., (Copyright © 2018 American Society of Human Genetics. All rights reserved.)

Published
2018
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22. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.

Author

Day FR, Thompson DJ, Helgason H, Chasman DI, Finucane H, Sulem P, Ruth KS, Whalen S, Sarkar AK, Albrecht E, Altmaier E, Amini M, Barbieri CM, Boutin T, Campbell A, Demerath E, Giri A, He C, Hottenga JJ, Karlsson R, Kolcic I, Loh PR, Lunetta KL, Mangino M, Marco B, McMahon G, Medland SE, Nolte IM, Noordam R, Nutile T, Paternoster L, Perjakova N, Porcu E, Rose LM, Schraut KE, Segrè AV, Smith AV, Stolk L, Teumer A, Andrulis IL, Bandinelli S, Beckmann MW, Benitez J, Bergmann S, Bochud M, Boerwinkle E, Bojesen SE, Bolla MK, Brand JS, Brauch H, Brenner H, Broer L, Brüning T, Buring JE, Campbell H, Catamo E, Chanock S, Chenevix-Trench G, Corre T, Couch FJ, Cousminer DL, Cox A, Crisponi L, Czene K, Davey Smith G, de Geus EJCN, de Mutsert R, De Vivo I, Dennis J, Devilee P, Dos-Santos-Silva I, Dunning AM, Eriksson JG, Fasching PA, Fernández-Rhodes L, Ferrucci L, Flesch-Janys D, Franke L, Gabrielson M, Gandin I, Giles GG, Grallert H, Gudbjartsson DF, Guénel P, Hall P, Hallberg E, Hamann U, Harris TB, Hartman CA, Heiss G, Hooning MJ, Hopper JL, Hu F, Hunter DJ, Ikram MA, Im HK, Järvelin MR, Joshi PK, Karasik D, Kellis M, Kutalik Z, LaChance G, Lambrechts D, Langenberg C, Launer LJ, Laven JSE, Lenarduzzi S, Li J, Lind PA, Lindstrom S, Liu Y, Luan J, Mägi R, Mannermaa A, Mbarek H, McCarthy MI, Meisinger C, Meitinger T, Menni C, Metspalu A, Michailidou K, Milani L, Milne RL, Montgomery GW, Mulligan AM, Nalls MA, Navarro P, Nevanlinna H, Nyholt DR, Oldehinkel AJ, O'Mara TA, Padmanabhan S, Palotie A, Pedersen N, Peters A, Peto J, Pharoah PDP, Pouta A, Radice P, Rahman I, Ring SM, Robino A, Rosendaal FR, Rudan I, Rueedi R, Ruggiero D, Sala CF, Schmidt MK, Scott RA, Shah M, Sorice R, Southey MC, Sovio U, Stampfer M, Steri M, Strauch K, Tanaka T, Tikkanen E, Timpson NJ, Traglia M, Truong T, Tyrer JP, Uitterlinden AG, Edwards DRV, Vitart V, Völker U, Vollenweider P, Wang Q, Widen E, van Dijk KW, Willemsen G, Winqvist R, Wolffenbuttel BHR, Zhao JH, Zoledziewska M, Zygmunt M, Alizadeh BZ, Boomsma DI, Ciullo M, Cucca F, Esko T, Franceschini N, Gieger C, Gudnason V, Hayward C, Kraft P, Lawlor DA, Magnusson PKE, Martin NG, Mook-Kanamori DO, Nohr EA, Polasek O, Porteous D, Price AL, Ridker PM, Snieder H, Spector TD, Stöckl D, Toniolo D, Ulivi S, Visser JA, Völzke H, Wareham NJ, Wilson JF, Spurdle AB, Thorsteindottir U, Pollard KS, Easton DF, Tung JY, Chang-Claude J, Hinds D, Murray A, Murabito JM, Stefansson K, Ong KK, and Perry JRB

Subjects
Adolescent, Age Factors, Body Mass Index, Calcium-Binding Proteins, Databases, Genetic, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomic Imprinting, Humans, Male, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Ubiquitin-Protein Ligases, Intercellular Signaling Peptides and Proteins genetics, Membrane Proteins genetics, Menarche genetics, Neoplasms genetics, Puberty genetics, Ribonucleoproteins genetics
Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10 -8 ) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

Published
2017
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23. Biological Stress Systems, Adverse Life Events, and the Improvement of Chronic Multisite Musculoskeletal Pain Across a 6-Year Follow-Up.

Author

Generaal E, Vogelzangs N, Macfarlane GJ, Geenen R, Smit JH, de Geus EJ, Dekker J, and Penninx BW

Subjects
Adolescent, Adult, Aged, C-Reactive Protein metabolism, Chronic Pain, Cytokines metabolism, Female, Humans, Hydrocortisone metabolism, Longitudinal Studies, Male, Middle Aged, Netherlands, Risk Factors, Surveys and Questionnaires, Time Factors, Young Adult, Life Change Events, Musculoskeletal Pain physiopathology, Musculoskeletal Pain psychology, Stress, Physiological physiology
Abstract

Dysfunction of biological stress systems and adverse life events, independently and in interaction, have been hypothesized to predict chronic pain persistence. Conversely, these factors may hamper the improvement of chronic pain. Longitudinal evidence is currently lacking. We examined whether: 1) function of biological stress systems, 2) adverse life events, and 3) their combination predict the improvement of chronic multisite musculoskeletal pain. Subjects of the Netherlands Study of Depression and Anxiety (NESDA) with chronic multisite musculoskeletal pain at baseline (N = 665) were followed-up 2, 4, and 6 years later. The Chronic Pain Grade Questionnaire was used to determine improvement (not meeting the criteria) of chronic multisite musculoskeletal pain at follow-up. Baseline assessment of biological stress systems included function of hypothalamic-pituitary-adrenal axis (1-hour cortisol awakening response, evening level, and post dexamethasone level), the immune system (basal and lipopolysaccharide-stimulated inflammatory markers), the autonomic nervous system (heart rate, pre-ejection period, SD of the normal-to-normal interval, and respiratory sinus arrhythmia). The number of adverse life events were assessed at baseline and 2-year follow-up using the List of Threatening Events Questionnaire. We showed that hypothalamic-pituitary-adrenal axis, immune system, and autonomic nervous system functioning and adverse life events were not associated with the improvement of chronic multisite musculoskeletal pain, either as a main effect or in interaction. This longitudinal study could not confirm that biological stress system dysfunction and adverse life events affect the course of chronic multisite musculoskeletal pain., Perspective: Biological stress systems and adverse life events are not associated with the improvement of chronic multisite musculoskeletal pain over 6 years of follow-up. Other determinants should thus be considered in future research to identify in which persons pain symptoms will improve., (Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Published
2017
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24. Consistency of biological networks inferred from microarray and sequencing data.

Author

Vinciotti V, Wit EC, Jansen R, de Geus EJ, Penninx BW, Boomsma DI, and 't Hoen PA

Subjects
Anxiety genetics, Depression genetics, Female, Humans, Male, Reproducibility of Results, Twin Studies as Topic, Gene Regulatory Networks, High-Throughput Nucleotide Sequencing, Oligonucleotide Array Sequence Analysis, Sequence Analysis, RNA
Abstract

Background: Sparse Gaussian graphical models are popular for inferring biological networks, such as gene regulatory networks. In this paper, we investigate the consistency of these models across different data platforms, such as microarray and next generation sequencing, on the basis of a rich dataset containing samples that are profiled under both techniques as well as a large set of independent samples., Results: Our analysis shows that individual node variances can have a remarkable effect on the connectivity of the resulting network. Their inconsistency across platforms and the fact that the variability level of a node may not be linked to its regulatory role mean that, failing to scale the data prior to the network analysis, leads to networks that are not reproducible across different platforms and that may be misleading. Moreover, we show how the reproducibility of networks across different platforms is significantly higher if networks are summarised in terms of enrichment amongst functional groups of interest, such as pathways, rather than at the level of individual edges., Conclusions: Careful pre-processing of transcriptional data and summaries of networks beyond individual edges can improve the consistency of network inference across platforms. However, caution is needed at this stage in the (over)interpretation of gene regulatory networks inferred from biological data.

Published
2016
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25. Dysregulated physiological stress systems and accelerated cellular aging.

Author

Révész D, Verhoeven JE, Milaneschi Y, de Geus EJ, Wolkowitz OM, and Penninx BW

Subjects
Adolescent, Adult, Aged, Aging immunology, Aging metabolism, Autonomic Nervous System physiology, Cellular Senescence immunology, Cytokines metabolism, Female, Heart Rate physiology, Humans, Hydrocortisone metabolism, Hypothalamo-Hypophyseal System physiology, Inflammation Mediators metabolism, Leukocytes cytology, Linear Models, Male, Middle Aged, Pituitary-Adrenal System physiology, Saliva metabolism, Telomere Homeostasis, Young Adult, Aging physiology, Cellular Senescence physiology, Stress, Physiological physiology
Abstract

Exposure to chronic stressors is associated with accelerated biological aging as indicated by reduced leukocyte telomere length (LTL). This impact could be because of chronic overactivation of the body's physiological stress systems. This study examined the associations between LTL and the immune system, hypothalamic-pituitary-adrenal axis and autonomic nervous system. LTL was assessed in 2936 adults from the Netherlands Study of Depression and Anxiety. Inflammation markers (interleukin-6, c-reactive protein, tumor necrosis factor-alpha), hypothalamic-pituitary-adrenal-axis indicators (salivary cortisol awakening curve [area under the curve indicators, with respect to the ground and increase], evening levels, 0.5 mg dexamethasone cortisol suppression ratio), and autonomic nervous system measures (heart rate, respiratory sinus arrhythmia, pre-ejection period) were determined. Linear regression analyses were performed and adjusted for sociodemographic, lifestyle and clinical factors. Shorter LTL was significantly associated with higher c-reactive protein, interleukin-6, area under the curve with respect to increase, and heart rate. A cumulative index score was calculated based on the number of highest tertiles of these 4 stress markers. LTL demonstrated a significant gradient within subjects ranging from having zero (5528 base pairs) to having 4 elevated stress markers (5371 base pairs, p for trend = 0.002), corresponding to a difference of 10 years of accelerated biological aging. Contrary to the expectations, shorter LTL was also associated with longer pre-ejection period, indicating lower sympathetic tone. This large-scale study showed that inflammation, high awakening cortisol response, and increased heart rate are associated with shorter LTL, especially when they are dysregulated cumulatively., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Published
2014
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26. Facilitated defensive coping, silent ischaemia and ECG left-ventricular hypertrophy: the SABPA study.

Author

Malan L, Hamer M, Schlaich MP, Lambert GW, Harvey BH, Reimann M, Ziemssen T, de Geus EJ, Huisman HW, van Rooyen JM, Schutte R, Schutte AE, Fourie CM, Seedat YK, and Malan NT

Subjects
Adult, Black People, Humans, Hypertrophy, Left Ventricular pathology, Male, Middle Aged, Myocardial Ischemia metabolism, Myocardium pathology, South Africa epidemiology, Stress, Physiological, Stress, Psychological metabolism, White People, Adaptation, Psychological, Hypertrophy, Left Ventricular ethnology, Myocardial Ischemia ethnology, Receptors, Adrenergic metabolism, Stress, Psychological ethnology
Abstract

Background: Defensive active coping responses (being-in-control, acceptance of the stressor as reality) have been associated with vascular hyper-responsiveness in urban Africans. However, the association between active coping responses, blood pressure (BP), and ECG-derived left-ventricular hypertrophy (LVH) responses is unknown., Objectives and Methods: Associations between BP, silent ischaemia and ECG Cornell product LVH were assessed in 161 African and Caucasian men with active coping responses identified by the Amirkhan Coping Strategy Indicator. BP, ECG and silent ischaemia data were obtained from 24-h ambulatory monitoring. Beat-to-beat BP was continuously recorded during stress testing and fasting resting blood samples obtained for biochemical analyses., Results: Enhanced ß-adrenergic central cardiac responses were evident in active coping Caucasians as opposed to a predomination of α-adrenergic vascular responses in active coping Africans. Active coping African men displayed higher 24-h BP and prevalence of silent ischaemia events compared to the Caucasian men. Regression analyses revealed that α-adrenergic responses were associated with silent ischaemic events, adjusted R 0.21 [ß 1.07, 95% confidence interval (CI) 0.29-1.85] and that ischaemic events predicted LVH in active coping Africans (adjusted R 0.12, ß 0.35, 95% CI 0.11-0.59). Receiver-operated characteristic (ROC) analyses indicated a defensive pathway cut point of 16 in Africans as opposed to 32 in Caucasians predicting silent ischaemia with sensitivity/specificity 100/96%., Conclusions: A defensive pathway revealed disturbed vascular function showing dissociation between behavioural and physiological ß-adrenergic active coping responses in Africans. Vascular responsiveness facilitated silent ischaemia events and structural LVH changes which potentially explain the increased risk for incident ischaemic stroke in black Africans.

Published
2012
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