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37 results on '"Evans, David M"'

1. Genetic architecture reconciles linkage and association studies of complex traits

Author

Sidorenko, Julia, Couvy-Duchesne, Baptiste, Kemper, Kathryn E., Moen, Gunn-Helen, Bhatta, Laxmi, Åsvold, Bjørn Olav, Mägi, Reedik, Ani, Alireza, Wang, Rujia, Nolte, Ilja M., Gordon, Scott, Hayward, Caroline, Campbell, Archie, Benjamin, Daniel J., Cesarini, David, Evans, David M., Goddard, Michael E., Haley, Chris S., Porteous, David, Medland, Sarah E., Martin, Nicholas G., Snieder, Harold, Metspalu, Andres, Hveem, Kristian, Brumpton, Ben, Visscher, Peter M., and Yengo, Loic

Published
2024
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2. Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth

Author

Beaumont, Robin N., Flatley, Christopher, Vaudel, Marc, Wu, Xiaoping, Chen, Jing, Moen, Gunn-Helen, Skotte, Line, Helgeland, Øyvind, Solé-Navais, Pol, Banasik, Karina, Albiñana, Clara, Ronkainen, Justiina, Fadista, João, Stinson, Sara Elizabeth, Trajanoska, Katerina, Wang, Carol A., Westergaard, David, Srinivasan, Sundararajan, Sánchez-Soriano, Carlos, Bilbao, Jose Ramon, Allard, Catherine, Groleau, Marika, Kuulasmaa, Teemu, Leirer, Daniel J., White, Frédérique, Jacques, Pierre-Étienne, Cheng, Haoxiang, Hao, Ke, Andreassen, Ole A., Åsvold, Bjørn Olav, Atalay, Mustafa, Bhatta, Laxmi, Bouchard, Luigi, Brumpton, Ben Michael, Brunak, Søren, Bybjerg-Grauholm, Jonas, Ebbing, Cathrine, Elliott, Paul, Engelbrechtsen, Line, Erikstrup, Christian, Estarlich, Marisa, Franks, Stephen, Gaillard, Romy, Geller, Frank, Grove, Jakob, Hougaard, David M., Kajantie, Eero, Morgen, Camilla S., Nohr, Ellen A., Nyegaard, Mette, Palmer, Colin N. A., Pedersen, Ole Birger, Rivadeneira, Fernando, Sebert, Sylvain, Shields, Beverley M., Stoltenberg, Camilla, Surakka, Ida, Thørner, Lise Wegner, Ullum, Henrik, Vaarasmaki, Marja, Vilhjalmsson, Bjarni J., Willer, Cristen J., Lakka, Timo A., Gybel-Brask, Dorte, Bustamante, Mariona, Hansen, Torben, Pearson, Ewan R., Reynolds, Rebecca M., Ostrowski, Sisse R., Pennell, Craig E., Jaddoe, Vincent W. V., Felix, Janine F., Hattersley, Andrew T., Melbye, Mads, Lawlor, Deborah A., Hveem, Kristian, Werge, Thomas, Nielsen, Henriette Svarre, Magnus, Per, Evans, David M., Jacobsson, Bo, Järvelin, Marjo-Riitta, Zhang, Ge, Hivert, Marie-France, Johansson, Stefan, Freathy, Rachel M., Feenstra, Bjarke, and Njølstad, Pål R.

Published
2023
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3. Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects

Author

Howe, Laurence J, Nivard, Michel G, Morris, Tim T, Hansen, Ailin F, Rasheed, Humaira, Cho, Yoonsu, Chittoor, Geetha, Ahlskog, Rafael, Lind, Penelope A, Palviainen, Teemu, van der Zee, Matthijs D, Cheesman, Rosa, Mangino, Massimo, Wang, Yunzhang, Li, Shuai, Klaric, Lucija, Ratliff, Scott M, Bielak, Lawrence F, Nygaard, Marianne, Giannelis, Alexandros, Willoughby, Emily A, Reynolds, Chandra A, Balbona, Jared V, Andreassen, Ole A, Ask, Helga, Baras, Aris, Bauer, Christopher R, Boomsma, Dorret I, Campbell, Archie, Campbell, Harry, Chen, Zhengming, Christofidou, Paraskevi, Corfield, Elizabeth, Dahm, Christina C, Dokuru, Deepika R, Evans, Luke M, de Geus, Eco JC, Giddaluru, Sudheer, Gordon, Scott D, Harden, K Paige, Hill, W David, Hughes, Amanda, Kerr, Shona M, Kim, Yongkang, Kweon, Hyeokmoon, Latvala, Antti, Lawlor, Deborah A, Li, Liming, Lin, Kuang, Magnus, Per, Magnusson, Patrik KE, Mallard, Travis T, Martikainen, Pekka, Mills, Melinda C, Njølstad, Pål Rasmus, Overton, John D, Pedersen, Nancy L, Porteous, David J, Reid, Jeffrey, Silventoinen, Karri, Southey, Melissa C, Stoltenberg, Camilla, Tucker-Drob, Elliot M, Wright, Margaret J, Hewitt, John K, Keller, Matthew C, Stallings, Michael C, Lee, James J, Christensen, Kaare, Kardia, Sharon LR, Peyser, Patricia A, Smith, Jennifer A, Wilson, James F, Hopper, John L, Hägg, Sara, Spector, Tim D, Pingault, Jean-Baptiste, Plomin, Robert, Havdahl, Alexandra, Bartels, Meike, Martin, Nicholas G, Oskarsson, Sven, Justice, Anne E, Millwood, Iona Y, Hveem, Kristian, Naess, Øyvind, Willer, Cristen J, Åsvold, Bjørn Olav, Koellinger, Philipp D, Kaprio, Jaakko, Medland, Sarah E, Walters, Robin G, Benjamin, Daniel J, Turley, Patrick, Evans, David M, Davey Smith, George, Hayward, Caroline, Brumpton, Ben, Hemani, Gibran, and Davies, Neil M

Subjects
Human Genome, Genetics, Pediatric, 2.1 Biological and endogenous factors, Aetiology, Mental health, Generic health relevance, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, Social Science Genetic Association Consortium, Within Family Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.

Published
2022

5. A genome-wide association meta-analysis identifies new childhood obesity loci

Author

Bradfield, Jonathan P, Taal, H Rob, Timpson, Nicholas J, Scherag, Andre, Lecoeur, Cecile, Warrington, Nicole M, Hypponen, Elina, Holst, Claus, Valcarcel, Beatriz, Thiering, Elisabeth, Salem, Rany M, Schumacher, Fredrick R, Cousminer, Diana L, Sleiman, Patrick MA, Zhao, Jianhua, Berkowitz, Robert I, Vimaleswaran, Karani S, Jarick, Ivonne, Pennell, Craig E, Evans, David M, St Pourcain, Beate, Berry, Diane J, Mook-Kanamori, Dennis O, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andre G, van Duijn, Cornelia M, van der Valk, Ralf JP, de Jongste, Johan C, Postma, Dirkje S, Boomsma, Dorret I, Gauderman, W James, Hassanein, Mohamed T, Lindgren, Cecilia M, Magi, Reedik, Boreham, Colin AG, Neville, Charlotte E, Moreno, Luis A, Elliott, Paul, Pouta, Anneli, Hartikainen, Anna-Liisa, Li, Mingyao, Raitakari, Olli, Lehtimaki, Terho, Eriksson, Johan G, Palotie, Aarno, Dallongeville, Jean, Das, Shikta, Deloukas, Panos, McMahon, George, Ring, Susan M, Kemp, John P, Buxton, Jessica L, Blakemore, Alexandra IF, Bustamante, Mariona, Guxens, Monica, Hirschhorn, Joel N, Gillman, Matthew W, Kreiner-Moller, Eskil, Bisgaard, Hans, Gilliland, Frank D, Heinrich, Joachim, Wheeler, Eleanor, Barroso, Ines, O'Rahilly, Stephen, Meirhaeghe, Aline, Sorensen, Thorkild IA, Power, Chris, Palmer, Lyle J, Hinney, Anke, Widen, Elisabeth, Farooqi, I Sadaf, McCarthy, Mark I, Froguel, Philippe, Meyre, David, Hebebrand, Johannes, Jarvelin, Marjo-Riitta, Jaddoe, Vincent WV, Smith, George Davey, Hakonarson, Hakon, and Grant, Struan FA

Subjects
Biological Sciences, Genetics, Pediatric, Nutrition, Obesity, Human Genome, Metabolic and endocrine, Oral and gastrointestinal, Stroke, Cancer, Cardiovascular, Adolescent, Adult, Body Mass Index, Case-Control Studies, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Young Adult, Early Growth Genetics Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (

Published
2012

7. Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability

Author

Hysi, Pirro G., Valdes, Ana M., Liu, Fan, Furlotte, Nicholas A., Evans, David M., Bataille, Veronique, Visconti, Alessia, Hemani, Gibran, McMahon, George, Ring, Susan M., Smith, George Davey, Duffy, David L., Zhu, Gu, Gordon, Scott D., Medland, Sarah E., Lin, Bochao D., Willemsen, Gonneke, Jan Hottenga, Jouke, Vuckovic, Dragana, Girotto, Giorgia, Gandin, Ilaria, Sala, Cinzia, Concas, Maria Pina, Brumat, Marco, Gasparini, Paolo, Toniolo, Daniela, Cocca, Massimiliano, Robino, Antonietta, Yazar, Seyhan, Hewitt, Alex W., Chen, Yan, Zeng, Changqing, Uitterlinden, Andre G., Ikram, M. Arfan, Hamer, Merel A., van Duijn, Cornelia M., Nijsten, Tamar, Mackey, David A., Falchi, Mario, Boomsma, Dorret I., Martin, Nicholas G., The International Visible Trait Genetics Consortium, Hinds, David A., Kayser, Manfred, and Spector, Timothy D.

Published
2018
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9. Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis

Author

Kemp, John P, Morris, John A, Medina-Gomez, Carolina, Forgetta, Vincenzo, Warrington, Nicole M, Youlten, Scott E, Zheng, Jie, Gregson, Celia L, Grundberg, Elin, Trajanoska, Katerina, Logan, John G, Pollard, Andrea S, Sparkes, Penny C, Ghirardello, Elena J, Allen, Rebecca, Leitch, Victoria D, Butterfield, Natalie C, Komla-Ebri, Davide, Adoum, Anne-Tounsia, Curry, Katharine F, White, Jacqueline K, Kussy, Fiona, Greenlaw, Keelin M, Xu, Changjiang, Harvey, Nicholas C, Cooper, Cyrus, Adams, David J, Greenwood, Celia M T, Maurano, Matthew T, Kaptoge, Stephen, Rivadeneira, Fernando, Tobias, Jonathan H, Croucher, Peter I, Ackert-Bicknell, Cheryl L, Bassett, J H Duncan, Williams, Graham R, Richards, J Brent, and Evans, David M

Published
2017
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10. Publisher Correction: Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability

Author

Hysi, Pirro G., Valdes, Ana M., Liu, Fan, Furlotte, Nicholas A., Evans, David M., Bataille, Veronique, Visconti, Alessia, Hemani, Gibran, McMahon, George, Ring, Susan M., Smith, George Davey, Duffy, David L., Zhu, Gu, Gordon, Scott D., Medland, Sarah E., Lin, Bochao D., Willemsen, Gonneke, Jan Hottenga, Jouke, Vuckovic, Dragana, Girotto, Giorgia, Gandin, Ilaria, Sala, Cinzia, Concas, Maria Pina, Brumat, Marco, Gasparini, Paolo, Toniolo, Daniela, Cocca, Massimiliano, Robino, Antonietta, Yazar, Seyhan, Hewitt, Alex W., Chen, Yan, Zeng, Changqing, Uitterlinden, Andre G., Ikram, M. Arfan, Hamer, Merel A., van Duijn, Cornelia M., Nijsten, Tamar, Mackey, David A., Falchi, Mario, Boomsma, Dorret I., Martin, Nicholas G., The International Visible Trait Genetics Consortium, Hinds, David A., Kayser, Manfred, and Spector, Timothy D.

Published
2019
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11. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Author

Scott, Robert A, Lagou, Vasiliki, Welch, Ryan P, Wheeler, Eleanor, Montasser, May E, Luan, Jian'an, Mägi, Reedik, Strawbridge, Rona J, Rehnberg, Emil, Gustafsson, Stefan, Kanoni, Stavroula, Rasmussen-Torvik, Laura J, Yengo, Loïc, Lecoeur, Cecile, Shungin, Dmitry, Sanna, Serena, Sidore, Carlo, Johnson, Paul C D, Jukema, J Wouter, Johnson, Toby, Mahajan, Anubha, Verweij, Niek, Thorleifsson, Gudmar, Hottenga, Jouke-Jan, Shah, Sonia, Smith, Albert V, Sennblad, Bengt, Gieger, Christian, Salo, Perttu, Perola, Markus, Timpson, Nicholas J, Evans, David M, Pourcain, Beate St, Wu, Ying, Andrews, Jeanette S, Hui, Jennie, Bielak, Lawrence F, Zhao, Wei, Horikoshi, Momoko, Navarro, Pau, Isaacs, Aaron, O'Connell, Jeffrey R, Stirrups, Kathleen, Vitart, Veronique, Hayward, Caroline, Esko, Tõnu, Mihailov, Evelin, Fraser, Ross M, Fall, Tove, Voight, Benjamin F, Raychaudhuri, Soumya, Chen, Han, Lindgren, Cecilia M, Morris, Andrew P, Rayner, Nigel W, Robertson, Neil, Rybin, Denis, Liu, Ching-Ti, Beckmann, Jacques S, Willems, Sara M, Chines, Peter S, Jackson, Anne U, Kang, Hyun Min, Stringham, Heather M, Song, Kijoung, Tanaka, Toshiko, Peden, John F, Goel, Anuj, Hicks, Andrew A, An, Ping, Müller-Nurasyid, Martina, Franco-Cereceda, Anders, Folkersen, Lasse, Marullo, Letizia, Jansen, Hanneke, Oldehinkel, Albertine J, Bruinenberg, Marcel, Pankow, James S, North, Kari E, Forouhi, Nita G, Loos, Ruth J F, Edkins, Sarah, Varga, Tibor V, Hallmans, Göran, Oksa, Heikki, Antonella, Mulas, Nagaraja, Ramaiah, Trompet, Stella, Ford, Ian, Bakker, Stephan J L, Kong, Augustine, Kumari, Meena, Gigante, Bruna, Herder, Christian, Munroe, Patricia B, Caulfield, Mark, Antti, Jula, Mangino, Massimo, Small, Kerrin, Miljkovic, Iva, Liu, Yongmei, Atalay, Mustafa, Kiess, Wieland, James, Alan L, Rivadeneira, Fernando, Uitterlinden, Andre G, Palmer, Colin N A, Doney, Alex S F, Willemsen, Gonneke, Smit, Johannes H, Campbell, Susan, Polasek, Ozren, Bonnycastle, Lori L, Hercberg, Serge, Dimitriou, Maria, Bolton, Jennifer L, Fowkes, Gerard R, Kovacs, Peter, Lindström, Jaana, Zemunik, Tatijana, Bandinelli, Stefania, Wild, Sarah H, Basart, Hanneke V, Rathmann, Wolfgang, Grallert, Harald, Maerz, Winfried, Kleber, Marcus E, Boehm, Bernhard O, Peters, Annette, Pramstaller, Peter P, Province, Michael A, Borecki, Ingrid B, Hastie, Nicholas D, Rudan, Igor, Campbell, Harry, Watkins, Hugh, Farrall, Martin, Stumvoll, Michael, Ferrucci, Luigi, Waterworth, Dawn M, Bergman, Richard N, Collins, Francis S, Tuomilehto, Jaakko, Watanabe, Richard M, de Geus, Eco J C, Penninx, Brenda W, Hofman, Albert, Oostra, Ben A, Psaty, Bruce M, Vollenweider, Peter, Wilson, James F, Wright, Alan F, Hovingh, G Kees, Metspalu, Andres, Uusitupa, Matti, Magnusson, Patrik K E, Kyvik, Kirsten O, Kaprio, Jaakko, Price, Jackie F, Dedoussis, George V, Deloukas, Panos, Meneton, Pierre, Lind, Lars, Boehnke, Michael, Shuldiner, Alan R, van Duijn, Cornelia M, Morris, Andrew D, Toenjes, Anke, Peyser, Patricia A, Beilby, John P, Körner, Antje, Kuusisto, Johanna, Laakso, Markku, Bornstein, Stefan R, Schwarz, Peter E H, Lakka, Timo A, Rauramaa, Rainer, Adair, Linda S, Smith, George Davey, Spector, Tim D, Illig, Thomas, de Faire, Ulf, Hamsten, Anders, Gudnason, Vilmundur, Kivimaki, Mika, Hingorani, Aroon, Keinanen-Kiukaanniemi, Sirkka M, Saaristo, Timo E, Boomsma, Dorret I, Stefansson, Kari, van der Harst, Pim, Dupuis, Josée, Pedersen, Nancy L, Sattar, Naveed, Harris, Tamara B, Cucca, Francesco, Ripatti, Samuli, Salomaa, Veikko, Mohlke, Karen L, Balkau, Beverley, Froguel, Philippe, Pouta, Anneli, Jarvelin, Marjo-Riitta, Wareham, Nicholas J, Bouatia-Naji, Nabila, McCarthy, Mark I, Franks, Paul W, Meigs, James B, Teslovich, Tanya M, Florez, Jose C, Langenberg, Claudia, Ingelsson, Erik, Prokopenko, Inga, and Barroso, Inês

Published
2012
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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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13. An atlas of genetic influences on osteoporosis in humans and mice

Author

Morris, John A., Kemp, John P., Youlten, Scott E., Laurent, Laetitia, Logan, John G., Chai, Ryan C., Vulpescu, Nicholas A., Forgetta, Vincenzo, Kleinman, Aaron, Mohanty, Sindhu T., Sergio, C. Marcelo, Quinn, Julian, Nguyen-Yamamoto, Loan, Luco, Aimee-Lee, Vijay, Jinchu, Simon, Marie-Michelle, Pramatarova, Albena, Medina-Gomez, Carolina, Trajanoska, Katerina, Ghirardello, Elena J., Butterfield, Natalie C., Curry, Katharine F., Leitch, Victoria D., Sparkes, Penny C., Adoum, Anne-Tounsia, Mannan, Naila S., Komla-Ebri, Davide S. K., Pollard, Andrea S., Dewhurst, Hannah F., Hassall, Thomas A. D., Beltejar, Michael-John G., Adams, Douglas J., Vaillancourt, Suzanne M., Kaptoge, Stephen, Baldock, Paul, Cooper, Cyrus, Reeve, Jonathan, Ntzani, Evangelia E., Evangelou, Evangelos, Ohlsson, Claes, Karasik, David, Rivadeneira, Fernando, Kiel, Douglas P., Tobias, Jonathan H., Gregson, Celia L., Harvey, Nicholas C., Grundberg, Elin, Goltzman, David, Adams, David J., Lelliott, Christopher J., Hinds, David A., Ackert-Bicknell, Cheryl L., Hsu, Yi-Hsiang, Maurano, Matthew T., Croucher, Peter I., Williams, Graham R., Bassett, J. H. Duncan, Evans, David M., and Richards, J. Brent

Abstract

Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P= 1 × 10−75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P< 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.

Published
2019
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14. A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci

Author

Hinds, David A, primary, McMahon, George, additional, Kiefer, Amy K, additional, Do, Chuong B, additional, Eriksson, Nicholas, additional, Evans, David M, additional, St Pourcain, Beate, additional, Ring, Susan M, additional, Mountain, Joanna L, additional, Francke, Uta, additional, Davey-Smith, George, additional, Timpson, Nicholas J, additional, and Tung, Joyce Y, additional

Published
2013
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15. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Author

Berndt, Sonja I, primary, Gustafsson, Stefan, additional, Mägi, Reedik, additional, Ganna, Andrea, additional, Wheeler, Eleanor, additional, Feitosa, Mary F, additional, Justice, Anne E, additional, Monda, Keri L, additional, Croteau-Chonka, Damien C, additional, Day, Felix R, additional, Esko, Tõnu, additional, Fall, Tove, additional, Ferreira, Teresa, additional, Gentilini, Davide, additional, Jackson, Anne U, additional, Luan, Jian'an, additional, Randall, Joshua C, additional, Vedantam, Sailaja, additional, Willer, Cristen J, additional, Winkler, Thomas W, additional, Wood, Andrew R, additional, Workalemahu, Tsegaselassie, additional, Hu, Yi-Juan, additional, Lee, Sang Hong, additional, Liang, Liming, additional, Lin, Dan-Yu, additional, Min, Josine L, additional, Neale, Benjamin M, additional, Thorleifsson, Gudmar, additional, Yang, Jian, additional, Albrecht, Eva, additional, Amin, Najaf, additional, Bragg-Gresham, Jennifer L, additional, Cadby, Gemma, additional, den Heijer, Martin, additional, Eklund, Niina, additional, Fischer, Krista, additional, Goel, Anuj, additional, Hottenga, Jouke-Jan, additional, Huffman, Jennifer E, additional, Jarick, Ivonne, additional, Johansson, Åsa, additional, Johnson, Toby, additional, Kanoni, Stavroula, additional, Kleber, Marcus E, additional, König, Inke R, additional, Kristiansson, Kati, additional, Kutalik, Zoltán, additional, Lamina, Claudia, additional, Lecoeur, Cecile, additional, Li, Guo, additional, Mangino, Massimo, additional, McArdle, Wendy L, additional, Medina-Gomez, Carolina, additional, Müller-Nurasyid, Martina, additional, Ngwa, Julius S, additional, Nolte, Ilja M, additional, Paternoster, Lavinia, additional, Pechlivanis, Sonali, additional, Perola, Markus, additional, Peters, Marjolein J, additional, Preuss, Michael, additional, Rose, Lynda M, additional, Shi, Jianxin, additional, Shungin, Dmitry, additional, Smith, Albert Vernon, additional, Strawbridge, Rona J, additional, Surakka, Ida, additional, Teumer, Alexander, additional, Trip, Mieke D, additional, Tyrer, Jonathan, additional, Van Vliet-Ostaptchouk, Jana V, additional, Vandenput, Liesbeth, additional, Waite, Lindsay L, additional, Zhao, Jing Hua, additional, Absher, Devin, additional, Asselbergs, Folkert W, additional, Atalay, Mustafa, additional, Attwood, Antony P, additional, Balmforth, Anthony J, additional, Basart, Hanneke, additional, Beilby, John, additional, Bonnycastle, Lori L, additional, Brambilla, Paolo, additional, Bruinenberg, Marcel, additional, Campbell, Harry, additional, Chasman, Daniel I, additional, Chines, Peter S, additional, Collins, Francis S, additional, Connell, John M, additional, Cookson, William O, additional, de Faire, Ulf, additional, de Vegt, Femmie, additional, Dei, Mariano, additional, Dimitriou, Maria, additional, Edkins, Sarah, additional, Estrada, Karol, additional, Evans, David M, additional, Farrall, Martin, additional, Ferrario, Marco M, additional, Ferrières, Jean, additional, Franke, Lude, additional, Frau, Francesca, additional, Gejman, Pablo V, additional, Grallert, Harald, additional, Grönberg, Henrik, additional, Gudnason, Vilmundur, additional, Hall, Alistair S, additional, Hall, Per, additional, Hartikainen, Anna-Liisa, additional, Hayward, Caroline, additional, Heard-Costa, Nancy L, additional, Heath, Andrew C, additional, Hebebrand, Johannes, additional, Homuth, Georg, additional, Hu, Frank B, additional, Hunt, Sarah E, additional, Hyppönen, Elina, additional, Iribarren, Carlos, additional, Jacobs, Kevin B, additional, Jansson, John-Olov, additional, Jula, Antti, additional, Kähönen, Mika, additional, Kathiresan, Sekar, additional, Kee, Frank, additional, Khaw, Kay-Tee, additional, Kivimäki, Mika, additional, Koenig, Wolfgang, additional, Kraja, Aldi T, additional, Kumari, Meena, additional, Kuulasmaa, Kari, additional, Kuusisto, Johanna, additional, Laitinen, Jaana H, additional, Lakka, Timo A, additional, Langenberg, Claudia, additional, Launer, Lenore J, additional, Lind, Lars, additional, Lindström, Jaana, additional, Liu, Jianjun, additional, Liuzzi, Antonio, additional, Lokki, Marja-Liisa, additional, Lorentzon, Mattias, additional, Madden, Pamela A, additional, Magnusson, Patrik K, additional, Manunta, Paolo, additional, Marek, Diana, additional, März, Winfried, additional, Leach, Irene Mateo, additional, McKnight, Barbara, additional, Medland, Sarah E, additional, Mihailov, Evelin, additional, Milani, Lili, additional, Montgomery, Grant W, additional, Mooser, Vincent, additional, Mühleisen, Thomas W, additional, Munroe, Patricia B, additional, Musk, Arthur W, additional, Narisu, Narisu, additional, Navis, Gerjan, additional, Nicholson, George, additional, Nohr, Ellen A, additional, Ong, Ken K, additional, Oostra, Ben A, additional, Palmer, Colin N A, additional, Palotie, Aarno, additional, Peden, John F, additional, Pedersen, Nancy, additional, Peters, Annette, additional, Polasek, Ozren, additional, Pouta, Anneli, additional, Pramstaller, Peter P, additional, Prokopenko, Inga, additional, Pütter, Carolin, additional, Radhakrishnan, Aparna, additional, Raitakari, Olli, additional, Rendon, Augusto, additional, Rivadeneira, Fernando, additional, Rudan, Igor, additional, Saaristo, Timo E, additional, Sambrook, Jennifer G, additional, Sanders, Alan R, additional, Sanna, Serena, additional, Saramies, Jouko, additional, Schipf, Sabine, additional, Schreiber, Stefan, additional, Schunkert, Heribert, additional, Shin, So-Youn, additional, Signorini, Stefano, additional, Sinisalo, Juha, additional, Skrobek, Boris, additional, Soranzo, Nicole, additional, Stančáková, Alena, additional, Stark, Klaus, additional, Stephens, Jonathan C, additional, Stirrups, Kathleen, additional, Stolk, Ronald P, additional, Stumvoll, Michael, additional, Swift, Amy J, additional, Theodoraki, Eirini V, additional, Thorand, Barbara, additional, Tregouet, David-Alexandre, additional, Tremoli, Elena, additional, Van der Klauw, Melanie M, additional, van Meurs, Joyce B J, additional, Vermeulen, Sita H, additional, Viikari, Jorma, additional, Virtamo, Jarmo, additional, Vitart, Veronique, additional, Waeber, Gérard, additional, Wang, Zhaoming, additional, Widén, Elisabeth, additional, Wild, Sarah H, additional, Willemsen, Gonneke, additional, Winkelmann, Bernhard R, additional, Witteman, Jacqueline C M, additional, Wolffenbuttel, Bruce H R, additional, Wong, Andrew, additional, Wright, Alan F, additional, Zillikens, M Carola, additional, Amouyel, Philippe, additional, Boehm, Bernhard O, additional, Boerwinkle, Eric, additional, Boomsma, Dorret I, additional, Caulfield, Mark J, additional, Chanock, Stephen J, additional, Cupples, L Adrienne, additional, Cusi, Daniele, additional, Dedoussis, George V, additional, Erdmann, Jeanette, additional, Eriksson, Johan G, additional, Franks, Paul W, additional, Froguel, Philippe, additional, Gieger, Christian, additional, Gyllensten, Ulf, additional, Hamsten, Anders, additional, Harris, Tamara B, additional, Hengstenberg, Christian, additional, Hicks, Andrew A, additional, Hingorani, Aroon, additional, Hinney, Anke, additional, Hofman, Albert, additional, Hovingh, Kees G, additional, Hveem, Kristian, additional, Illig, Thomas, additional, Jarvelin, Marjo-Riitta, additional, Jöckel, Karl-Heinz, additional, Keinanen-Kiukaanniemi, Sirkka M, additional, Kiemeney, Lambertus A, additional, Kuh, Diana, additional, Laakso, Markku, additional, Lehtimäki, Terho, additional, Levinson, Douglas F, additional, Martin, Nicholas G, additional, Metspalu, Andres, additional, Morris, Andrew D, additional, Nieminen, Markku S, additional, Njølstad, Inger, additional, Ohlsson, Claes, additional, Oldehinkel, Albertine J, additional, Ouwehand, Willem H, additional, Palmer, Lyle J, additional, Penninx, Brenda, additional, Power, Chris, additional, Province, Michael A, additional, Psaty, Bruce M, additional, Qi, Lu, additional, Rauramaa, Rainer, additional, Ridker, Paul M, additional, Ripatti, Samuli, additional, Salomaa, Veikko, additional, Samani, Nilesh J, additional, Snieder, Harold, additional, Sørensen, Thorkild I A, additional, Spector, Timothy D, additional, Stefansson, Kari, additional, Tönjes, Anke, additional, Tuomilehto, Jaakko, additional, Uitterlinden, André G, additional, Uusitupa, Matti, additional, van der Harst, Pim, additional, Vollenweider, Peter, additional, Wallaschofski, Henri, additional, Wareham, Nicholas J, additional, Watkins, Hugh, additional, Wichmann, H-Erich, additional, Wilson, James F, additional, Abecasis, Goncalo R, additional, Assimes, Themistocles L, additional, Barroso, Inês, additional, Boehnke, Michael, additional, Borecki, Ingrid B, additional, Deloukas, Panos, additional, Fox, Caroline S, additional, Frayling, Timothy, additional, Groop, Leif C, additional, Haritunian, Talin, additional, Heid, Iris M, additional, Hunter, David, additional, Kaplan, Robert C, additional, Karpe, Fredrik, additional, Moffatt, Miriam F, additional, Mohlke, Karen L, additional, O'Connell, Jeffrey R, additional, Pawitan, Yudi, additional, Schadt, Eric E, additional, Schlessinger, David, additional, Steinthorsdottir, Valgerdur, additional, Strachan, David P, additional, Thorsteinsdottir, Unnur, additional, van Duijn, Cornelia M, additional, Visscher, Peter M, additional, Di Blasio, Anna Maria, additional, Hirschhorn, Joel N, additional, Lindgren, Cecilia M, additional, Morris, Andrew P, additional, Meyre, David, additional, Scherag, André, additional, McCarthy, Mark I, additional, Speliotes, Elizabeth K, additional, North, Kari E, additional, Loos, Ruth J F, additional, and Ingelsson, Erik, additional

Published
2013
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16. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Author

Estrada, Karol, primary, Styrkarsdottir, Unnur, additional, Evangelou, Evangelos, additional, Hsu, Yi-Hsiang, additional, Duncan, Emma L, additional, Ntzani, Evangelia E, additional, Oei, Ling, additional, Albagha, Omar M E, additional, Amin, Najaf, additional, Kemp, John P, additional, Koller, Daniel L, additional, Li, Guo, additional, Liu, Ching-Ti, additional, Minster, Ryan L, additional, Moayyeri, Alireza, additional, Vandenput, Liesbeth, additional, Willner, Dana, additional, Xiao, Su-Mei, additional, Yerges-Armstrong, Laura M, additional, Zheng, Hou-Feng, additional, Alonso, Nerea, additional, Eriksson, Joel, additional, Kammerer, Candace M, additional, Kaptoge, Stephen K, additional, Leo, Paul J, additional, Thorleifsson, Gudmar, additional, Wilson, Scott G, additional, Wilson, James F, additional, Aalto, Ville, additional, Alen, Markku, additional, Aragaki, Aaron K, additional, Aspelund, Thor, additional, Center, Jacqueline R, additional, Dailiana, Zoe, additional, Duggan, David J, additional, Garcia, Melissa, additional, Garcia-Giralt, Natàlia, additional, Giroux, Sylvie, additional, Hallmans, Göran, additional, Hocking, Lynne J, additional, Husted, Lise Bjerre, additional, Jameson, Karen A, additional, Khusainova, Rita, additional, Kim, Ghi Su, additional, Kooperberg, Charles, additional, Koromila, Theodora, additional, Kruk, Marcin, additional, Laaksonen, Marika, additional, Lacroix, Andrea Z, additional, Lee, Seung Hun, additional, Leung, Ping C, additional, Lewis, Joshua R, additional, Masi, Laura, additional, Mencej-Bedrac, Simona, additional, Nguyen, Tuan V, additional, Nogues, Xavier, additional, Patel, Millan S, additional, Prezelj, Janez, additional, Rose, Lynda M, additional, Scollen, Serena, additional, Siggeirsdottir, Kristin, additional, Smith, Albert V, additional, Svensson, Olle, additional, Trompet, Stella, additional, Trummer, Olivia, additional, van Schoor, Natasja M, additional, Woo, Jean, additional, Zhu, Kun, additional, Balcells, Susana, additional, Brandi, Maria Luisa, additional, Buckley, Brendan M, additional, Cheng, Sulin, additional, Christiansen, Claus, additional, Cooper, Cyrus, additional, Dedoussis, George, additional, Ford, Ian, additional, Frost, Morten, additional, Goltzman, David, additional, González-Macías, Jesús, additional, Kähönen, Mika, additional, Karlsson, Magnus, additional, Khusnutdinova, Elza, additional, Koh, Jung-Min, additional, Kollia, Panagoula, additional, Langdahl, Bente Lomholt, additional, Leslie, William D, additional, Lips, Paul, additional, Ljunggren, Östen, additional, Lorenc, Roman S, additional, Marc, Janja, additional, Mellström, Dan, additional, Obermayer-Pietsch, Barbara, additional, Olmos, José M, additional, Pettersson-Kymmer, Ulrika, additional, Reid, David M, additional, Riancho, José A, additional, Ridker, Paul M, additional, Rousseau, François, additional, lagboom, P Eline S, additional, Tang, Nelson L S, additional, Urreizti, Roser, additional, Van Hul, Wim, additional, Viikari, Jorma, additional, Zarrabeitia, María T, additional, Aulchenko, Yurii S, additional, Castano-Betancourt, Martha, additional, Grundberg, Elin, additional, Herrera, Lizbeth, additional, Ingvarsson, Thorvaldur, additional, Johannsdottir, Hrefna, additional, Kwan, Tony, additional, Li, Rui, additional, Luben, Robert, additional, Medina-Gómez, Carolina, additional, Th Palsson, Stefan, additional, Reppe, Sjur, additional, Rotter, Jerome I, additional, Sigurdsson, Gunnar, additional, van Meurs, Joyce B J, additional, Verlaan, Dominique, additional, Williams, Frances M K, additional, Wood, Andrew R, additional, Zhou, Yanhua, additional, Gautvik, Kaare M, additional, Pastinen, Tomi, additional, Raychaudhuri, Soumya, additional, Cauley, Jane A, additional, Chasman, Daniel I, additional, Clark, Graeme R, additional, Cummings, Steven R, additional, Danoy, Patrick, additional, Dennison, Elaine M, additional, Eastell, Richard, additional, Eisman, John A, additional, Gudnason, Vilmundur, additional, Hofman, Albert, additional, Jackson, Rebecca D, additional, Jones, Graeme, additional, Jukema, J Wouter, additional, Khaw, Kay-Tee, additional, Lehtimäki, Terho, additional, Liu, Yongmei, additional, Lorentzon, Mattias, additional, McCloskey, Eugene, additional, Mitchell, Braxton D, additional, Nandakumar, Kannabiran, additional, Nicholson, Geoffrey C, additional, Oostra, Ben A, additional, Peacock, Munro, additional, Pols, Huibert A P, additional, Prince, Richard L, additional, Raitakari, Olli, additional, Reid, Ian R, additional, Robbins, John, additional, Sambrook, Philip N, additional, Sham, Pak Chung, additional, Shuldiner, Alan R, additional, Tylavsky, Frances A, additional, van Duijn, Cornelia M, additional, Wareham, Nick J, additional, Cupples, L Adrienne, additional, Econs, Michael J, additional, Evans, David M, additional, Harris, Tamara B, additional, Kung, Annie Wai Chee, additional, Psaty, Bruce M, additional, Reeve, Jonathan, additional, Spector, Timothy D, additional, Streeten, Elizabeth A, additional, Zillikens, M Carola, additional, Thorsteinsdottir, Unnur, additional, Ohlsson, Claes, additional, Karasik, David, additional, Richards, J Brent, additional, Brown, Matthew A, additional, Stefansson, Kari, additional, Uitterlinden, André G, additional, Ralston, Stuart H, additional, Ioannidis, John P A, additional, Kiel, Douglas P, additional, and Rivadeneira, Fernando, additional

Published
2012
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17. Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets

Author

Wain, Louise V, Shrine, Nick, Artigas, María Soler, Erzurumluoglu, A Mesut, Noyvert, Boris, Bossini-Castillo, Lara, Obeidat, Ma'en, Henry, Amanda P, Portelli, Michael A, Hall, Robert J, Billington, Charlotte K, Rimington, Tracy L, Fenech, Anthony G, John, Catherine, Blake, Tineka, Jackson, Victoria E, Allen, Richard J, Prins, Bram P, Campbell, Archie, Porteous, David J, Jarvelin, Marjo-Riitta, Wielscher, Matthias, James, Alan L, Hui, Jennie, Wareham, Nicholas J, Zhao, Jing Hua, Wilson, James F, Joshi, Peter K, Stubbe, Beate, Rawal, Rajesh, Schulz, Holger, Imboden, Medea, Probst-Hensch, Nicole M, Karrasch, Stefan, Gieger, Christian, Deary, Ian J, Harris, Sarah E, Marten, Jonathan, Rudan, Igor, Enroth, Stefan, Gyllensten, Ulf, Kerr, Shona M, Polasek, Ozren, Kähönen, Mika, Surakka, Ida, Vitart, Veronique, Hayward, Caroline, Lehtimäki, Terho, Raitakari, Olli T, Evans, David M, Henderson, A John, Pennell, Craig E, Wang, Carol A, Sly, Peter D, Wan, Emily S, Busch, Robert, Hobbs, Brian D, Litonjua, Augusto A, Sparrow, David W, Gulsvik, Amund, Bakke, Per S, Crapo, James D, Beaty, Terri H, Hansel, Nadia N, Mathias, Rasika A, Ruczinski, Ingo, Barnes, Kathleen C, Bossé, Yohan, Joubert, Philippe, van den Berge, Maarten, Brandsma, Corry-Anke, Paré, Peter D, Sin, Don D, Nickle, David C, Hao, Ke, Gottesman, Omri, Dewey, Frederick E, Bruse, Shannon E, Carey, David J, Kirchner, H Lester, Jonsson, Stefan, Thorleifsson, Gudmar, Jonsdottir, Ingileif, Gislason, Thorarinn, Stefansson, Kari, Schurmann, Claudia, Nadkarni, Girish, Bottinger, Erwin P, Loos, Ruth J F, Walters, Robin G, Chen, Zhengming, Millwood, Iona Y, Vaucher, Julien, Kurmi, Om P, Li, Liming, Hansell, Anna L, Brightling, Chris, Zeggini, Eleftheria, Cho, Michael H, Silverman, Edwin K, Sayers, Ian, Trynka, Gosia, Morris, Andrew P, Strachan, David P, Hall, Ian P, and Tobin, Martin D

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20–1.27), P = 5.05 × 10−49), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.

Published
2017
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18. Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population

Author

Robinson, Elise B, St Pourcain, Beate, Anttila, Verneri, Kosmicki, Jack A, Bulik-Sullivan, Brendan, Grove, Jakob, Maller, Julian, Samocha, Kaitlin E, Sanders, Stephan J, Ripke, Stephan, Martin, Joanna, Hollegaard, Mads V, Werge, Thomas, Hougaard, David M, Neale, Benjamin M, Evans, David M, Skuse, David, Mortensen, Preben Bo, Børglum, Anders D, Ronald, Angelica, Smith, George Davey, and Daly, Mark J

Abstract

Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology.

Published
2016
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19. Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.

Author

den Hoed, Marcel, Eijgelsheim, Mark, Esko, Tõnu, Brundel, Bianca J J M, Peal, David S, Evans, David M, Nolte, Ilja M, Segrè, Ayellet V, Holm, Hilma, Handsaker, Robert E, Westra, Harm-Jan, Johnson, Toby, Isaacs, Aaron, Yang, Jian, Lundby, Alicia, Zhao, Jing Hua, Kim, Young Jin, Go, Min Jin, Almgren, Peter, and Bochud, Murielle

Subjects
HEART beat, CARDIOVASCULAR diseases, DANIO, DROSOPHILA melanogaster
Abstract

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets. [ABSTRACT FROM AUTHOR]

Published
2013
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20. New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Author

Horikoshi, Momoko, Yaghootkar, Hanieh, Mook-Kanamori, Dennis O, Sovio, Ulla, Taal, H Rob, Hennig, Branwen J, Bradfield, Jonathan P, St Pourcain, Beate, Evans, David M, Charoen, Pimphen, Kaakinen, Marika, Cousminer, Diana L, Lehtimäki, Terho, Kreiner-Møller, Eskil, Warrington, Nicole M, Bustamante, Mariona, Feenstra, Bjarke, Berry, Diane J, Thiering, Elisabeth, and Pfab, Thiemo

Subjects
FETAL development, BIRTH weight, LOCUS (Genetics), META-analysis, TYPE 2 diabetes, WOMEN'S tobacco use, PREGNANT women, PHENOTYPES
Abstract

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism. [ABSTRACT FROM AUTHOR]

Published
2013
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21. Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.

Author

Artigas, María Soler, Loth, Daan W, Wain, Louise V, Gharib, Sina A, Obeidat, Ma'en, Tang, Wenbo, Zhai, Guangju, Zhao, Jing Hua, Smith, Albert Vernon, Huffman, Jennifer E, Albrecht, Eva, Jackson, Catherine M, Evans, David M, Cadby, Gemma, Fornage, Myriam, Manichaikul, Ani, Lopez, Lorna M, Johnson, Toby, Aldrich, Melinda C, and Aspelund, Thor

Subjects
LUNGS, GENOMES, PULMONARY function tests, RESPIRATORY organs, GENOMICS
Abstract

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10?8) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function. [ABSTRACT FROM AUTHOR]

Published
2011
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22. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility.

Author

Evans, David M., Spencer, Chris C. A., Pointon, Jennifer J., Zhan Su, Harvey, David, Kochan, Grazyna, Opperman, Udo, Dilthey, Alexander, Pirinen, Matti, Stone, Millicent A., Appleton, Louise, Moutsianis, Loukas, Leslie, Stephen, Wordsworth, Tom, Kenna, Tony J., Karaderi, Tugce, Thomas, Gethin P., AWard, Michael M., Weisman, Michael H., and Farrar, Claire

Subjects
*ANKYLOSING spondylitis, *PEPTIDES, *DISEASE susceptibility, *ARTHRITIS, *ENDOPLASMIC reticulum, *AMINOPEPTIDASES, *GENES
Abstract

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10?8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10?6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides. [ABSTRACT FROM AUTHOR]

Published
2011
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23. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci.

Author

Reveille, John D., Sims, Anne-Marie, Danoy, Patrick, Evans, David M., Leo, Paul, Pointon, Jennifer J., Rui Jin, Xiaodong Zhou, Bradbury, Linda A., Appleton, Louise H., Davis, John C., Diekman, Laura, Doan, Tracey, Dowling, Alison, Duan, Ran, Duncan, Emma L., Farrar, Claire, Hadler, Johanna, Harvey, David, and Karaderi, Tugce

Subjects
ANKYLOSING spondylitis, INTERLEUKIN-1, CYTOKINES, GENOMICS, GENOTYPE-environment interaction, TUMOR necrosis factors
Abstract

To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10−800), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 × 10−19) and 21q22 (rs2242944; P = 8.3 × 10−20), as well as in the genes ANTXR2 (rs4333130; P = 9.3 × 10−8) and IL1R2 (rs2310173; P = 4.8 × 10−7). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 × 10−14) and ERAP1 (rs27434; P = 5.3 × 10−12). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility. [ABSTRACT FROM AUTHOR]

Published
2010
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24. Genome-wide association analysis identifies 20 loci that influence adult height.

Author

Weedon, Michael N., Lango, Hana, Lindgren, Cecilia M., Wallace, Chris, Evans, David M., Mangino, Massimo, Freathy, Rachel M., Perry, John R. B., Stevens, Suzanne, Hall, Alistair S., Samani, Nilesh J., Shields, Beverly, Prokopenko, Inga, Farrall, Martin, Dominiczak, Anna, Johnson, Toby, Bergmann, Sven, Beckmann, Jacques S., Vollenweider, Peter, and Waterworth, Dawn M.

Subjects
GENETIC research, HUMAN genetic variation, EXTRACELLULAR matrix, STATURE, HUMAN growth, ADULTS
Abstract

Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 × 10−7, with 10 reaching P < 1 × 10−10). Combined, the 20 SNPs explain ∼3% of height variation, with a ∼5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait. [ABSTRACT FROM AUTHOR]

Published
2008
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25. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.

Author

Burton, Paul R, Clayton, David G, Cardon, Lon R, Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P, McCarthy, Mark I, Ouwehand, Willem H, Samani, Nilesh J, Todd, John A, Donnelly (Chair), Peter, Barrett, Jeffrey C, Davison, Dan, Donnelly, Peter, Easton, Doug, Evans, David M, Leung, Hin-Tak, Marchini, Jonathan L, and Morris, Andrew P

Subjects
MAJOR histocompatibility complex, IMMUNOGENETICS, ANKYLOSING spondylitis, AUTOIMMUNE thyroiditis, MULTIPLE sclerosis, BREAST cancer
Abstract

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases. [ABSTRACT FROM AUTHOR]

Published
2007
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26. Author Correction: An atlas of genetic influences on osteoporosis in humans and mice

Author

Morris, John A., Kemp, John P., Youlten, Scott E., Laurent, Laetitia, Logan, John G., Chai, Ryan C., Vulpescu, Nicholas A., Forgetta, Vincenzo, Kleinman, Aaron, Mohanty, Sindhu T., Sergio, C. Marcelo, Quinn, Julian, Nguyen-Yamamoto, Loan, Luco, Aimee-Lee, Vijay, Jinchu, Simon, Marie-Michelle, Pramatarova, Albena, Medina-Gomez, Carolina, Trajanoska, Katerina, Ghirardello, Elena J., Butterfield, Natalie C., Curry, Katharine F., Leitch, Victoria D., Sparkes, Penny C., Adoum, Anne-Tounsia, Mannan, Naila S., Komla-Ebri, Davide S. K., Pollard, Andrea S., Dewhurst, Hannah F., Hassall, Thomas A. D., Beltejar, Michael-John G., Adams, Douglas J., Vaillancourt, Suzanne M., Kaptoge, Stephen, Baldock, Paul, Cooper, Cyrus, Reeve, Jonathan, Ntzani, Evangelia E., Evangelou, Evangelos, Ohlsson, Claes, Karasik, David, Rivadeneira, Fernando, Kiel, Douglas P., Tobias, Jonathan H., Gregson, Celia L., Harvey, Nicholas C., Grundberg, Elin, Goltzman, David, Adams, David J., Lelliott, Christopher J., Hinds, David A., Ackert-Bicknell, Cheryl L., Hsu, Yi-Hsiang, Maurano, Matthew T., Croucher, Peter I., Williams, Graham R., Bassett, J. H. Duncan, Evans, David M., and Richards, J. Brent

Abstract

In the version of this article initially published, in Fig. 5a, the data in the right column of ‘DAAM2 gRNA1’ were incorrectly plotted as circles indicating ‘untreated’ rather than as squares indicating ‘treated’. The error has been corrected in the HTML and PDF versions of the article.

Published
2019
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27. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.

Author

Paternoster L, Standl M, Waage J, Baurecht H, Hotze M, Strachan DP, Curtin JA, Bønnelykke K, Tian C, Takahashi A, Esparza-Gordillo J, Alves AC, Thyssen JP, den Dekker HT, Ferreira MA, Altmaier E, Sleiman PM, Xiao FL, Gonzalez JR, Marenholz I, Kalb B, Yanes MP, Xu CJ, Carstensen L, Groen-Blokhuis MM, Venturini C, Pennell CE, Barton SJ, Levin AM, Curjuric I, Bustamante M, Kreiner-Møller E, Lockett GA, Bacelis J, Bunyavanich S, Myers RA, Matanovic A, Kumar A, Tung JY, Hirota T, Kubo M, McArdle WL, Henderson AJ, Kemp JP, Zheng J, Smith GD, Rüschendorf F, Bauerfeind A, Lee-Kirsch MA, Arnold A, Homuth G, Schmidt CO, Mangold E, Cichon S, Keil T, Rodríguez E, Peters A, Franke A, Lieb W, Novak N, Fölster-Holst R, Horikoshi M, Pekkanen J, Sebert S, Husemoen LL, Grarup N, de Jongste JC, Rivadeneira F, Hofman A, Jaddoe VW, Pasmans SG, Elbert NJ, Uitterlinden AG, Marks GB, Thompson PJ, Matheson MC, Robertson CF, Ried JS, Li J, Zuo XB, Zheng XD, Yin XY, Sun LD, McAleer MA, O'Regan GM, Fahy CM, Campbell LE, Macek M, Kurek M, Hu D, Eng C, Postma DS, Feenstra B, Geller F, Hottenga JJ, Middeldorp CM, Hysi P, Bataille V, Spector T, Tiesler CM, Thiering E, Pahukasahasram B, Yang JJ, Imboden M, Huntsman S, Vilor-Tejedor N, Relton CL, Myhre R, Nystad W, Custovic A, Weiss ST, Meyers DA, Söderhäll C, Melén E, Ober C, Raby BA, Simpson A, Jacobsson B, Holloway JW, Bisgaard H, Sunyer J, Hensch NMP, Williams LK, Godfrey KM, Wang CA, Boomsma DI, Melbye M, Koppelman GH, Jarvis D, McLean WI, Irvine AD, Zhang XJ, Hakonarson H, Gieger C, Burchard EG, Martin NG, Duijts L, Linneberg A, Jarvelin MR, Noethen MM, Lau S, Hübner N, Lee YA, Tamari M, Hinds DA, Glass D, Brown SJ, Heinrich J, Evans DM, and Weidinger S

Subjects
Case-Control Studies, Dermatitis, Atopic pathology, Humans, Immunity, Innate genetics, Risk Factors, T-Lymphocytes cytology, T-Lymphocytes immunology, T-Lymphocytes metabolism, Dermatitis, Atopic ethnology, Dermatitis, Atopic genetics, Ethnicity genetics, Genetic Loci, Genetic Markers genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Polymorphism, Single Nucleotide genetics
Abstract

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.

Published
2015
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28. Genome-wide meta-analysis identifies new susceptibility loci for migraine.

Author

Anttila V, Winsvold BS, Gormley P, Kurth T, Bettella F, McMahon G, Kallela M, Malik R, de Vries B, Terwindt G, Medland SE, Todt U, McArdle WL, Quaye L, Koiranen M, Ikram MA, Lehtimäki T, Stam AH, Ligthart L, Wedenoja J, Dunham I, Neale BM, Palta P, Hamalainen E, Schürks M, Rose LM, Buring JE, Ridker PM, Steinberg S, Stefansson H, Jakobsson F, Lawlor DA, Evans DM, Ring SM, Färkkilä M, Artto V, Kaunisto MA, Freilinger T, Schoenen J, Frants RR, Pelzer N, Weller CM, Zielman R, Heath AC, Madden PAF, Montgomery GW, Martin NG, Borck G, Göbel H, Heinze A, Heinze-Kuhn K, Williams FMK, Hartikainen AL, Pouta A, van den Ende J, Uitterlinden AG, Hofman A, Amin N, Hottenga JJ, Vink JM, Heikkilä K, Alexander M, Muller-Myhsok B, Schreiber S, Meitinger T, Wichmann HE, Aromaa A, Eriksson JG, Traynor B, Trabzuni D, Rossin E, Lage K, Jacobs SBR, Gibbs JR, Birney E, Kaprio J, Penninx BW, Boomsma DI, van Duijn C, Raitakari O, Jarvelin MR, Zwart JA, Cherkas L, Strachan DP, Kubisch C, Ferrari MD, van den Maagdenberg AMJM, Dichgans M, Wessman M, Smith GD, Stefansson K, Daly MJ, Nyholt DR, Chasman D, and Palotie A

Subjects
Cerebellum metabolism, Computational Biology, Frontal Lobe metabolism, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Migraine Disorders genetics
Abstract

Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P<5×10(-8)). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B.

Published
2013
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29. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci.

Author

Cortes A, Hadler J, Pointon JP, Robinson PC, Karaderi T, Leo P, Cremin K, Pryce K, Harris J, Lee S, Joo KB, Shim SC, Weisman M, Ward M, Zhou X, Garchon HJ, Chiocchia G, Nossent J, Lie BA, Førre Ø, Tuomilehto J, Laiho K, Jiang L, Liu Y, Wu X, Bradbury LA, Elewaut D, Burgos-Vargas R, Stebbings S, Appleton L, Farrah C, Lau J, Kenna TJ, Haroon N, Ferreira MA, Yang J, Mulero J, Fernandez-Sueiro JL, Gonzalez-Gay MA, Lopez-Larrea C, Deloukas P, Donnelly P, Bowness P, Gafney K, Gaston H, Gladman DD, Rahman P, Maksymowych WP, Xu H, Crusius JB, van der Horst-Bruinsma IE, Chou CT, Valle-Oñate R, Romero-Sánchez C, Hansen IM, Pimentel-Santos FM, Inman RD, Videm V, Martin J, Breban M, Reveille JD, Evans DM, Kim TH, Wordsworth BP, and Brown MA

Subjects
Alleles, Case-Control Studies, DNA Mutational Analysis methods, Genetic Predisposition to Disease ethnology, Genome-Wide Association Study methods, Genotype, Genotyping Techniques methods, HLA-B27 Antigen genetics, High-Throughput Nucleotide Sequencing, Humans, Risk Factors, Spondylitis, Ankylosing ethnology, Spondylitis, Ankylosing immunology, Genetic Loci immunology, Genetic Predisposition to Disease genetics, Immune System Phenomena genetics, Polymorphism, Single Nucleotide, Spondylitis, Ankylosing genetics
Abstract

Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis-associated haplotypes at 11 loci. Two ankylosing spondylitis-associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.

Published
2013
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30. Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia.

Author

Verhoeven VJ, Hysi PG, Wojciechowski R, Fan Q, Guggenheim JA, Höhn R, MacGregor S, Hewitt AW, Nag A, Cheng CY, Yonova-Doing E, Zhou X, Ikram MK, Buitendijk GH, McMahon G, Kemp JP, Pourcain BS, Simpson CL, Mäkelä KM, Lehtimäki T, Kähönen M, Paterson AD, Hosseini SM, Wong HS, Xu L, Jonas JB, Pärssinen O, Wedenoja J, Yip SP, Ho DW, Pang CP, Chen LJ, Burdon KP, Craig JE, Klein BE, Klein R, Haller T, Metspalu A, Khor CC, Tai ES, Aung T, Vithana E, Tay WT, Barathi VA, Chen P, Li R, Liao J, Zheng Y, Ong RT, Döring A, Evans DM, Timpson NJ, Verkerk AJ, Meitinger T, Raitakari O, Hawthorne F, Spector TD, Karssen LC, Pirastu M, Murgia F, Ang W, Mishra A, Montgomery GW, Pennell CE, Cumberland PM, Cotlarciuc I, Mitchell P, Wang JJ, Schache M, Janmahasatian S, Igo RP Jr, Lass JH, Chew E, Iyengar SK, Gorgels TG, Rudan I, Hayward C, Wright AF, Polasek O, Vatavuk Z, Wilson JF, Fleck B, Zeller T, Mirshahi A, Müller C, Uitterlinden AG, Rivadeneira F, Vingerling JR, Hofman A, Oostra BA, Amin N, Bergen AA, Teo YY, Rahi JS, Vitart V, Williams C, Baird PN, Wong TY, Oexle K, Pfeiffer N, Mackey DA, Young TL, van Duijn CM, Saw SM, Bailey-Wilson JE, Stambolian D, Klaver CC, and Hammond CJ

Subjects
Alcohol Oxidoreductases genetics, Asian People genetics, Bone Morphogenetic Protein 2 genetics, Genetic Predisposition to Disease, Homeodomain Proteins genetics, Humans, KCNQ Potassium Channels genetics, Laminin genetics, Receptors, AMPA genetics, Risk Factors, Serine Proteases genetics, Trans-Activators genetics, White People genetics, Genome-Wide Association Study, Myopia genetics, Refractive Errors genetics
Abstract

Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.

Published
2013
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31. Common variants at 12q15 and 12q24 are associated with infant head circumference.

Author

Taal HR, Pourcain BS, Thiering E, Das S, Mook-Kanamori DO, Warrington NM, Kaakinen M, Kreiner-Møller E, Bradfield JP, Freathy RM, Geller F, Guxens M, Cousminer DL, Kerkhof M, Timpson NJ, Ikram MA, Beilin LJ, Bønnelykke K, Buxton JL, Charoen P, Chawes BLK, Eriksson J, Evans DM, Hofman A, Kemp JP, Kim CE, Klopp N, Lahti J, Lye SJ, McMahon G, Mentch FD, Müller M, O'Reilly PF, Prokopenko I, Rivadeneira F, Steegers EAP, Sunyer J, Tiesler C, Yaghootkar H, Breteler MMB, Debette S, Fornage M, Gudnason V, Launer LJ, van der Lugt A, Mosley TH, Seshadri S, Smith AV, Vernooij MW, Blakemore AI, Chiavacci RM, Feenstra B, Fernandez-Benet J, Grant SFA, Hartikainen AL, van der Heijden AJ, Iñiguez C, Lathrop M, McArdle WL, Mølgaard A, Newnham JP, Palmer LJ, Palotie A, Pouta A, Ring SM, Sovio U, Standl M, Uitterlinden AG, Wichmann HE, Vissing NH, DeCarli C, van Duijn CM, McCarthy MI, Koppelman GH, Estivill X, Hattersley AT, Melbye M, Bisgaard H, Pennell CE, Widen E, Hakonarson H, Smith GD, Heinrich J, Jarvelin MR, and Jaddoe VWV

Subjects
Female, Humans, Infant, Male, Pregnancy, Genetic Loci, Genetic Markers, Genome-Wide Association Study, Chromosomes, Human, Pair 12 genetics, Head growth & development, Head pathology, Polymorphism, Single Nucleotide genetics, Pregnancy Complications etiology, Pregnancy Complications pathology, White People genetics
Abstract

To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 × 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10(-7) for rs7980687 and P = 1.3 × 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.

Published
2012
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32. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis.

Author

Paternoster L, Standl M, Chen CM, Ramasamy A, Bønnelykke K, Duijts L, Ferreira MA, Alves AC, Thyssen JP, Albrecht E, Baurecht H, Feenstra B, Sleiman PM, Hysi P, Warrington NM, Curjuric I, Myhre R, Curtin JA, Groen-Blokhuis MM, Kerkhof M, Sääf A, Franke A, Ellinghaus D, Fölster-Holst R, Dermitzakis E, Montgomery SB, Prokisch H, Heim K, Hartikainen AL, Pouta A, Pekkanen J, Blakemore AI, Buxton JL, Kaakinen M, Duffy DL, Madden PA, Heath AC, Montgomery GW, Thompson PJ, Matheson MC, Le Souëf P, St Pourcain B, Smith GD, Henderson J, Kemp JP, Timpson NJ, Deloukas P, Ring SM, Wichmann HE, Müller-Nurasyid M, Novak N, Klopp N, Rodríguez E, McArdle W, Linneberg A, Menné T, Nohr EA, Hofman A, Uitterlinden AG, van Duijn CM, Rivadeneira F, de Jongste JC, van der Valk RJ, Wjst M, Jogi R, Geller F, Boyd HA, Murray JC, Kim C, Mentch F, March M, Mangino M, Spector TD, Bataille V, Pennell CE, Holt PG, Sly P, Tiesler CM, Thiering E, Illig T, Imboden M, Nystad W, Simpson A, Hottenga JJ, Postma D, Koppelman GH, Smit HA, Söderhäll C, Chawes B, Kreiner-Møller E, Bisgaard H, Melén E, Boomsma DI, Custovic A, Jacobsson B, Probst-Hensch NM, Palmer LJ, Glass D, Hakonarson H, Melbye M, Jarvis DL, Jaddoe VW, Gieger C, Strachan DP, Martin NG, Jarvelin MR, Heinrich J, Evans DM, and Weidinger S

Subjects
Cell Differentiation genetics, Chromosomes, Human, Pair 11 genetics, Chromosomes, Human, Pair 20 genetics, Chromosomes, Human, Pair 5, Cytokines genetics, DNA-Binding Proteins genetics, Dermatitis, Atopic immunology, Epidermis immunology, Female, Filaggrin Proteins, Genetic Predisposition to Disease, Humans, Intermediate Filament Proteins genetics, Kinesins genetics, Male, Polymorphism, Single Nucleotide, Risk, Transcription Factors genetics, Dermatitis, Atopic genetics, Genetic Loci, Genome-Wide Association Study
Abstract

Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.

Published
2011
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33. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.

Author

Strange A, Capon F, Spencer CC, Knight J, Weale ME, Allen MH, Barton A, Band G, Bellenguez C, Bergboer JG, Blackwell JM, Bramon E, Bumpstead SJ, Casas JP, Cork MJ, Corvin A, Deloukas P, Dilthey A, Duncanson A, Edkins S, Estivill X, Fitzgerald O, Freeman C, Giardina E, Gray E, Hofer A, Hüffmeier U, Hunt SE, Irvine AD, Jankowski J, Kirby B, Langford C, Lascorz J, Leman J, Leslie S, Mallbris L, Markus HS, Mathew CG, McLean WH, McManus R, Mössner R, Moutsianas L, Naluai AT, Nestle FO, Novelli G, Onoufriadis A, Palmer CN, Perricone C, Pirinen M, Plomin R, Potter SC, Pujol RM, Rautanen A, Riveira-Munoz E, Ryan AW, Salmhofer W, Samuelsson L, Sawcer SJ, Schalkwijk J, Smith CH, Ståhle M, Su Z, Tazi-Ahnini R, Traupe H, Viswanathan AC, Warren RB, Weger W, Wolk K, Wood N, Worthington J, Young HS, Zeeuwen PL, Hayday A, Burden AD, Griffiths CE, Kere J, Reis A, McVean G, Evans DM, Brown MA, Barker JN, Peltonen L, Donnelly P, and Trembath RC

Subjects
Chromosome Mapping, Chromosomes, Human genetics, Chromosomes, Human, X genetics, Europe, Genetic Variation, Humans, Major Histocompatibility Complex genetics, Minor Histocompatibility Antigens, Polymorphism, Single Nucleotide, Reference Values, Risk Assessment, Aminopeptidases genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA-C Antigens genetics, Psoriasis genetics
Abstract

To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10⁻⁸ and two loci with a combined P < 5 × 10⁻⁷). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10⁻⁶). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.

Published
2010
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34. Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight.

Author

Freathy RM, Mook-Kanamori DO, Sovio U, Prokopenko I, Timpson NJ, Berry DJ, Warrington NM, Widen E, Hottenga JJ, Kaakinen M, Lange LA, Bradfield JP, Kerkhof M, Marsh JA, Mägi R, Chen CM, Lyon HN, Kirin M, Adair LS, Aulchenko YS, Bennett AJ, Borja JB, Bouatia-Naji N, Charoen P, Coin LJ, Cousminer DL, de Geus EJ, Deloukas P, Elliott P, Evans DM, Froguel P, Glaser B, Groves CJ, Hartikainen AL, Hassanali N, Hirschhorn JN, Hofman A, Holly JM, Hyppönen E, Kanoni S, Knight BA, Laitinen J, Lindgren CM, McArdle WL, O'Reilly PF, Pennell CE, Postma DS, Pouta A, Ramasamy A, Rayner NW, Ring SM, Rivadeneira F, Shields BM, Strachan DP, Surakka I, Taanila A, Tiesler C, Uitterlinden AG, van Duijn CM, Wijga AH, Willemsen G, Zhang H, Zhao J, Wilson JF, Steegers EA, Hattersley AT, Eriksson JG, Peltonen L, Mohlke KL, Grant SF, Hakonarson H, Koppelman GH, Dedoussis GV, Heinrich J, Gillman MW, Palmer LJ, Frayling TM, Boomsma DI, Davey Smith G, Power C, Jaddoe VW, Jarvelin MR, and McCarthy MI

Subjects
Alleles, Birth Weight, Cohort Studies, Diabetes Mellitus, Type 2 genetics, Ethnicity, Female, Genetic Predisposition to Disease, Genotype, Glucose metabolism, Humans, Male, Models, Genetic, Pregnancy, Adenylyl Cyclases genetics, Cyclins genetics, Isoenzymes genetics
Abstract

To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 x 10(-35)) and rs9883204 in ADCY5 (P = 7 x 10(-15)) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113 g (95% CI 89-137 g) lighter at birth than the 24% with zero or one alleles (P(trend) = 7 x 10(-30)). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.

Published
2010
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35. Genome-wide association study identifies five loci associated with lung function.

Author

Repapi E, Sayers I, Wain LV, Burton PR, Johnson T, Obeidat M, Zhao JH, Ramasamy A, Zhai G, Vitart V, Huffman JE, Igl W, Albrecht E, Deloukas P, Henderson J, Granell R, McArdle WL, Rudnicka AR, Barroso I, Loos RJ, Wareham NJ, Mustelin L, Rantanen T, Surakka I, Imboden M, Wichmann HE, Grkovic I, Jankovic S, Zgaga L, Hartikainen AL, Peltonen L, Gyllensten U, Johansson A, Zaboli G, Campbell H, Wild SH, Wilson JF, Gläser S, Homuth G, Völzke H, Mangino M, Soranzo N, Spector TD, Polasek O, Rudan I, Wright AF, Heliövaara M, Ripatti S, Pouta A, Naluai AT, Olin AC, Torén K, Cooper MN, James AL, Palmer LJ, Hingorani AD, Wannamethee SG, Whincup PH, Smith GD, Ebrahim S, McKeever TM, Pavord ID, MacLeod AK, Morris AD, Porteous DJ, Cooper C, Dennison E, Shaheen S, Karrasch S, Schnabel E, Schulz H, Grallert H, Bouatia-Naji N, Delplanque J, Froguel P, Blakey JD, Britton JR, Morris RW, Holloway JW, Lawlor DA, Hui J, Nyberg F, Jarvelin MR, Jackson C, Kähönen M, Kaprio J, Probst-Hensch NM, Koch B, Hayward C, Evans DM, Elliott P, Strachan DP, Hall IP, and Tobin MD

Subjects
Female, Forced Expiratory Volume, Glutathione Transferase genetics, Humans, Lung metabolism, Lung physiopathology, Male, Meta-Analysis as Topic, Microfilament Proteins genetics, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive genetics, Pulmonary Disease, Chronic Obstructive physiopathology, RNA, Messenger genetics, RNA, Messenger metabolism, Receptor for Advanced Glycation End Products, Receptors, Immunologic genetics, Receptors, Serotonin, 5-HT4 genetics, Respiratory Function Tests, Spirometry, Tensins, Thrombospondins genetics, Vital Capacity, Gene Expression Profiling, Genome, Human genetics, Genome-Wide Association Study methods, Lung physiology
Abstract

Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n < or = 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n < or = 883). We confirmed the reported locus at 4q31 and identified associations with FEV(1) or FEV(1)/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 x 10(-12)), 4q24 in GSTCD (2.18 x 10(-23)), 5q33 in HTR4 (P = 4.29 x 10(-9)), 6p21 in AGER (P = 3.07 x 10(-15)) and 15q23 in THSD4 (P = 7.24 x 10(-15)). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.

Published
2010
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36. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.

Author

Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, Heid IM, Berndt SI, Elliott AL, Jackson AU, Lamina C, Lettre G, Lim N, Lyon HN, McCarroll SA, Papadakis K, Qi L, Randall JC, Roccasecca RM, Sanna S, Scheet P, Weedon MN, Wheeler E, Zhao JH, Jacobs LC, Prokopenko I, Soranzo N, Tanaka T, Timpson NJ, Almgren P, Bennett A, Bergman RN, Bingham SA, Bonnycastle LL, Brown M, Burtt NP, Chines P, Coin L, Collins FS, Connell JM, Cooper C, Smith GD, Dennison EM, Deodhar P, Elliott P, Erdos MR, Estrada K, Evans DM, Gianniny L, Gieger C, Gillson CJ, Guiducci C, Hackett R, Hadley D, Hall AS, Havulinna AS, Hebebrand J, Hofman A, Isomaa B, Jacobs KB, Johnson T, Jousilahti P, Jovanovic Z, Khaw KT, Kraft P, Kuokkanen M, Kuusisto J, Laitinen J, Lakatta EG, Luan J, Luben RN, Mangino M, McArdle WL, Meitinger T, Mulas A, Munroe PB, Narisu N, Ness AR, Northstone K, O'Rahilly S, Purmann C, Rees MG, Ridderstråle M, Ring SM, Rivadeneira F, Ruokonen A, Sandhu MS, Saramies J, Scott LJ, Scuteri A, Silander K, Sims MA, Song K, Stephens J, Stevens S, Stringham HM, Tung YC, Valle TT, Van Duijn CM, Vimaleswaran KS, Vollenweider P, Waeber G, Wallace C, Watanabe RM, Waterworth DM, Watkins N, Witteman JC, Zeggini E, Zhai G, Zillikens MC, Altshuler D, Caulfield MJ, Chanock SJ, Farooqi IS, Ferrucci L, Guralnik JM, Hattersley AT, Hu FB, Jarvelin MR, Laakso M, Mooser V, Ong KK, Ouwehand WH, Salomaa V, Samani NJ, Spector TD, Tuomi T, Tuomilehto J, Uda M, Uitterlinden AG, Wareham NJ, Deloukas P, Frayling TM, Groop LC, Hayes RB, Hunter DJ, Mohlke KL, Peltonen L, Schlessinger D, Strachan DP, Wichmann HE, McCarthy MI, Boehnke M, Barroso I, Abecasis GR, and Hirschhorn JN

Subjects
Alleles, Anthropometry, Cohort Studies, Gene Dosage, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Meta-Analysis as Topic, Obesity complications, Obesity genetics, Polymorphism, Single Nucleotide genetics, Quantitative Trait, Heritable, Body Mass Index, Body Weight genetics, Central Nervous System physiology, Quantitative Trait Loci genetics
Abstract

Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.

Published
2009
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37. Common variants near MC4R are associated with fat mass, weight and risk of obesity.

Author

Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, Inouye M, Freathy RM, Attwood AP, Beckmann JS, Berndt SI, Jacobs KB, Chanock SJ, Hayes RB, Bergmann S, Bennett AJ, Bingham SA, Bochud M, Brown M, Cauchi S, Connell JM, Cooper C, Smith GD, Day I, Dina C, De S, Dermitzakis ET, Doney AS, Elliott KS, Elliott P, Evans DM, Sadaf Farooqi I, Froguel P, Ghori J, Groves CJ, Gwilliam R, Hadley D, Hall AS, Hattersley AT, Hebebrand J, Heid IM, Lamina C, Gieger C, Illig T, Meitinger T, Wichmann HE, Herrera B, Hinney A, Hunt SE, Jarvelin MR, Johnson T, Jolley JD, Karpe F, Keniry A, Khaw KT, Luben RN, Mangino M, Marchini J, McArdle WL, McGinnis R, Meyre D, Munroe PB, Morris AD, Ness AR, Neville MJ, Nica AC, Ong KK, O'Rahilly S, Owen KR, Palmer CN, Papadakis K, Potter S, Pouta A, Qi L, Randall JC, Rayner NW, Ring SM, Sandhu MS, Scherag A, Sims MA, Song K, Soranzo N, Speliotes EK, Syddall HE, Teichmann SA, Timpson NJ, Tobias JH, Uda M, Vogel CI, Wallace C, Waterworth DM, Weedon MN, Willer CJ, Wraight, Yuan X, Zeggini E, Hirschhorn JN, Strachan DP, Ouwehand WH, Caulfield MJ, Samani NJ, Frayling TM, Vollenweider P, Waeber G, Mooser V, Deloukas P, McCarthy MI, Wareham NJ, Barroso I, Jacobs KB, Chanock SJ, Hayes RB, Lamina C, Gieger C, Illig T, Meitinger T, Wichmann HE, Kraft P, Hankinson SE, Hunter DJ, Hu FB, Lyon HN, Voight BF, Ridderstrale M, Groop L, Scheet P, Sanna S, Abecasis GR, Albai G, Nagaraja R, Schlessinger D, Jackson AU, Tuomilehto J, Collins FS, Boehnke M, and Mohlke KL

Subjects
Adolescent, Adult, Aged, Alleles, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Body Mass Index, Case-Control Studies, Child, Chromosomes, Human, Pair 18 genetics, Cohort Studies, Cross-Sectional Studies, Female, Genome, Human, Humans, Linkage Disequilibrium, Male, Meta-Analysis as Topic, Middle Aged, Obesity epidemiology, Obesity pathology, Polymorphism, Single Nucleotide, Proteins, Quantitative Trait Loci, Randomized Controlled Trials as Topic, Adiposity genetics, Body Weight genetics, Genetic Predisposition to Disease, Genetic Variation, Obesity genetics, Receptor, Melanocortin, Type 4 genetics
Abstract

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.

Published
2008
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