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Your search keyword '"Trajanoska, Katerina"' showing total 16 results
Start Over Author "Trajanoska, Katerina" Publisher springer science and business media llc
16 results on '"Trajanoska, Katerina"'

1. A cost-effective sequencing method for genetic studies combining high-depth whole exome and low-depth whole genome

Author

Bhérer, Claude, primary, Eveleigh, Robert, additional, Trajanoska, Katerina, additional, St-Cyr, Janick, additional, Paccard, Antoine, additional, Nadukkalam Ravindran, Praveen, additional, Caron, Elizabeth, additional, Bader Asbah, Nimara, additional, McClelland, Peyton, additional, Wei, Clare, additional, Baumgartner, Iris, additional, Schindewolf, Marc, additional, Döring, Yvonne, additional, Perley, Danielle, additional, Lefebvre, François, additional, Lepage, Pierre, additional, Bourgey, Mathieu, additional, Bourque, Guillaume, additional, Ragoussis, Jiannis, additional, Mooser, Vincent, additional, and Taliun, Daniel, additional

Published
2024
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3. Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis

Author

Medina-Gomez, Carolina, primary, Mullin, Benjamin H., additional, Chesi, Alessandra, additional, Prijatelj, Vid, additional, Kemp, John P., additional, Shochat-Carvalho, Chen, additional, Trajanoska, Katerina, additional, Wang, Carol, additional, Joro, Raimo, additional, Evans, Tavia E., additional, Schraut, Katharina E., additional, Li-Gao, Ruifang, additional, Ahluwalia, Tarunveer S., additional, Zillikens, M. Carola, additional, Zhu, Kun, additional, Mook-Kanamori, Dennis O., additional, Evans, Daniel S., additional, Nethander, Maria, additional, Knol, Maria J., additional, Thorleifsson, Gudmar, additional, Prokic, Ivana, additional, Zemel, Babette, additional, Broer, Linda, additional, McGuigan, Fiona E., additional, van Schoor, Natasja M., additional, Reppe, Sjur, additional, Pawlak, Mikolaj A., additional, Ralston, Stuart H., additional, van der Velde, Nathalie, additional, Lorentzon, Mattias, additional, Stefansson, Kari, additional, Adams, Hieab H. H., additional, Wilson, Scott G., additional, Ikram, M. Arfan, additional, Walsh, John P., additional, Lakka, Timo A., additional, Gautvik, Kaare M., additional, Wilson, James F., additional, Orwoll, Eric S., additional, van Duijn, Cornelia M., additional, Bønnelykke, Klaus, additional, Uitterlinden, Andre G., additional, Styrkársdóttir, Unnur, additional, Akesson, Kristina E., additional, Spector, Timothy D., additional, Tobias, Jonathan H., additional, Ohlsson, Claes, additional, Felix, Janine F., additional, Bisgaard, Hans, additional, Grant, Struan F. A., additional, Richards, J. Brent, additional, Evans, David M., additional, van der Eerden, Bram, additional, van de Peppel, Jeroen, additional, Ackert-Bicknell, Cheryl, additional, Karasik, David, additional, Kague, Erika, additional, and Rivadeneira, Fernando, additional

Published
2023
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4. Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease

Author

Young, William J., primary, Haessler, Jeffrey, additional, Benjamins, Jan-Walter, additional, Repetto, Linda, additional, Yao, Jie, additional, Isaacs, Aaron, additional, Harper, Andrew R., additional, Ramirez, Julia, additional, Garnier, Sophie, additional, van Duijvenboden, Stefan, additional, Baldassari, Antoine R., additional, Concas, Maria Pina, additional, Duong, ThuyVy, additional, Foco, Luisa, additional, Isaksen, Jonas L., additional, Mei, Hao, additional, Noordam, Raymond, additional, Nursyifa, Casia, additional, Richmond, Anne, additional, Santolalla, Meddly L., additional, Sitlani, Colleen M., additional, Soroush, Negin, additional, Thériault, Sébastien, additional, Trompet, Stella, additional, Aeschbacher, Stefanie, additional, Ahmadizar, Fariba, additional, Alonso, Alvaro, additional, Brody, Jennifer A., additional, Campbell, Archie, additional, Correa, Adolfo, additional, Darbar, Dawood, additional, De Luca, Antonio, additional, Deleuze, Jean-François, additional, Ellervik, Christina, additional, Fuchsberger, Christian, additional, Goel, Anuj, additional, Grace, Christopher, additional, Guo, Xiuqing, additional, Hansen, Torben, additional, Heckbert, Susan R., additional, Jackson, Rebecca D., additional, Kors, Jan A., additional, Lima-Costa, Maria Fernanda, additional, Linneberg, Allan, additional, Macfarlane, Peter W., additional, Morrison, Alanna C., additional, Navarro, Pau, additional, Porteous, David J., additional, Pramstaller, Peter P., additional, Reiner, Alexander P., additional, Risch, Lorenz, additional, Schotten, Ulrich, additional, Shen, Xia, additional, Sinagra, Gianfranco, additional, Soliman, Elsayed Z., additional, Stoll, Monika, additional, Tarazona-Santos, Eduardo, additional, Tinker, Andrew, additional, Trajanoska, Katerina, additional, Villard, Eric, additional, Warren, Helen R., additional, Whitsel, Eric A., additional, Wiggins, Kerri L., additional, Arking, Dan E., additional, Avery, Christy L., additional, Conen, David, additional, Girotto, Giorgia, additional, Grarup, Niels, additional, Hayward, Caroline, additional, Jukema, J.Wouter, additional, Mook-Kanamori, Dennis O., additional, Olesen, Morten Salling, additional, Padmanabhan, Sandosh, additional, Psaty, Bruce M., additional, Pattaro, Cristian, additional, Ribeiro, Antonio Luiz P., additional, Rotter, Jerome I., additional, Stricker, Bruno H., additional, van der Harst, Pim, additional, van Duijn, Cornelia M., additional, Verweij, Niek, additional, Wilson, James G., additional, Orini, Michele, additional, Charron, Philippe, additional, Watkins, Hugh, additional, Kooperberg, Charles, additional, Lin, Henry J., additional, Wilson, James F., additional, Kanters, Jørgen K., additional, Sotoodehnia, Nona, additional, Mifsud, Borbala, additional, Lambiase, Pier D., additional, Tereshchenko, Larisa G., additional, and Munroe, Patricia B., additional

Published
2023
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6. Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women

Author

Jones, Garan, primary, Trajanoska, Katerina, additional, Santanasto, Adam J., additional, Stringa, Najada, additional, Kuo, Chia-Ling, additional, Atkins, Janice L., additional, Lewis, Joshua R., additional, Duong, ThuyVy, additional, Hong, Shengjun, additional, Biggs, Mary L., additional, Luan, Jian’an, additional, Sarnowski, Chloe, additional, Lunetta, Kathryn L., additional, Tanaka, Toshiko, additional, Wojczynski, Mary K., additional, Cvejkus, Ryan, additional, Nethander, Maria, additional, Ghasemi, Sahar, additional, Yang, Jingyun, additional, Zillikens, M. Carola, additional, Walter, Stefan, additional, Sicinski, Kamil, additional, Kague, Erika, additional, Ackert-Bicknell, Cheryl L., additional, Arking, Dan E., additional, Windham, B. Gwen, additional, Boerwinkle, Eric, additional, Grove, Megan L., additional, Graff, Misa, additional, Spira, Dominik, additional, Demuth, Ilja, additional, van der Velde, Nathalie, additional, de Groot, Lisette C. P. G. M., additional, Psaty, Bruce M., additional, Odden, Michelle C., additional, Fohner, Alison E., additional, Langenberg, Claudia, additional, Wareham, Nicholas J., additional, Bandinelli, Stefania, additional, van Schoor, Natasja M., additional, Huisman, Martijn, additional, Tan, Qihua, additional, Zmuda, Joseph, additional, Mellström, Dan, additional, Karlsson, Magnus, additional, Bennett, David A., additional, Buchman, Aron S., additional, De Jager, Philip L., additional, Uitterlinden, Andre G., additional, Völker, Uwe, additional, Kocher, Thomas, additional, Teumer, Alexander, additional, Rodriguéz-Mañas, Leocadio, additional, García, Francisco J., additional, Carnicero, José A., additional, Herd, Pamela, additional, Bertram, Lars, additional, Ohlsson, Claes, additional, Murabito, Joanne M., additional, Melzer, David, additional, Kuchel, George A., additional, Ferrucci, Luigi, additional, Karasik, David, additional, Rivadeneira, Fernando, additional, Kiel, Douglas P., additional, and Pilling, Luke C., additional

Published
2021
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7. Genetic basis of falling risk susceptibility in the UK Biobank Study

Author

Trajanoska, Katerina, primary, Seppala, Lotta J., additional, Medina-Gomez, Carolina, additional, Hsu, Yi-Hsiang, additional, Zhou, Sirui, additional, van Schoor, Natasja M., additional, de Groot, Lisette C. P. G. M., additional, Karasik, David, additional, Richards, J. Brent, additional, Kiel, Douglas P., additional, Uitterlinden, Andre G., additional, Perry, John R. B., additional, van der Velde, Nathalie, additional, Day, Felix R., additional, and Rivadeneira, Fernando, additional

Published
2020
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8. Identifying potential causal effects of age at menarche: a Mendelian randomization phenome-wide association study

Author

Magnus, Maria C., primary, Guyatt, Anna L., additional, Lawn, Rebecca B., additional, Wyss, Annah B., additional, Trajanoska, Katerina, additional, Küpers, Leanne K., additional, Rivadeneira, Fernando, additional, Tobin, Martin D., additional, London, Stephanie J., additional, Lawlor, Debbie A., additional, Millard, Louise A. C., additional, and Fraser, Abigail, additional

Published
2020
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9. 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 SK, Pollard, Andrea S, Dewhurst, Hannah F, Hassall, Thomas AD, Beltejar, Michael-John G, 23andMe Research Team, 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, JH Duncan, Evans, David M, Richards, J Brent, Morris, John A [0000-0003-2769-8202], Kemp, John P [0000-0002-9105-2249], Youlten, Scott E [0000-0001-9314-2945], Vulpescu, Nicholas A [0000-0003-1310-0257], Sergio, C Marcelo [0000-0002-5426-0583], Medina-Gomez, Carolina [0000-0001-7999-5538], Reeve, Jonathan [0000-0002-4364-2682], Ntzani, Evangelia E [0000-0003-3712-4181], Rivadeneira, Fernando [0000-0001-9435-9441], Kiel, Douglas P [0000-0001-8474-0310], Gregson, Celia L [0000-0001-6414-0529], Harvey, Nicholas C [0000-0002-8194-2512], Lelliott, Christopher J [0000-0001-8087-4530], Hinds, David A [0000-0002-4911-803X], Williams, Graham R [0000-0002-8555-8219], Bassett, JH Duncan [0000-0003-0817-0082], Evans, David M [0000-0003-0663-4621], Richards, J Brent [0000-0002-3746-9086], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Mice, Knockout, Middle Aged, Polymorphism, Single Nucleotide, Fractures, Bone, Mice, Phenotype, Bone Density, Animals, Humans, Osteoporosis, Female, Genetic Predisposition to Disease, Aged, Genome-Wide Association Study
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

10. Do Vitamin D Level and Dietary Calcium Intake Modify the Association Between Loop Diuretics and Bone Health?

Author

Oliai Araghi, Sadaf, primary, Kiefte-de Jong, Jessica C., additional, Trajanoska, Katerina, additional, Koromani, Fjorda, additional, Rivadeneira, Fernando, additional, Zillikens, M. Carola, additional, van Schoor, Natasja M., additional, de Groot, Lisette C. P. G. M., additional, Ikram, M. Arfan, additional, Uitterlinden, André G., additional, Stricker, Bruno H., additional, and van der Velde, Nathalie, additional

Published
2019
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11. Publisher Correction: GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures

Author

Styrkarsdottir, Unnur, primary, Stefansson, Olafur A., additional, Gunnarsdottir, Kristbjorg, additional, Thorleifsson, Gudmar, additional, Lund, Sigrun H., additional, Stefansdottir, Lilja, additional, Juliusson, Kristinn, additional, Agustsdottir, Arna B., additional, Zink, Florian, additional, Halldorsson, Gisli H., additional, Ivarsdottir, Erna V., additional, Benonisdottir, Stefania, additional, Jonsson, Hakon, additional, Gylfason, Arnaldur, additional, Norland, Kristjan, additional, Trajanoska, Katerina, additional, Boer, Cindy G., additional, Southam, Lorraine, additional, Leung, Jason C. S., additional, Tang, Nelson L. S., additional, Kwok, Timothy C. Y., additional, Lee, Jenny S. W., additional, Ho, Suzanne C., additional, Byrjalsen, Inger, additional, Center, Jacqueline R., additional, Lee, Seung Hun, additional, Koh, Jung-Min, additional, Lohmander, L. Stefan, additional, Ho-Pham, Lan T., additional, Nguyen, Tuan V., additional, Eisman, John A., additional, Woo, Jean, additional, Leung, Ping-C., additional, Loughlin, John, additional, Zeggini, Eleftheria, additional, Christiansen, Claus, additional, Rivadeneira, Fernando, additional, van Meurs, Joyce, additional, Uitterlinden, Andre G., additional, Mogensen, Brynjolfur, additional, Jonsson, Helgi, additional, Ingvarsson, Thorvaldur, additional, Sigurdsson, Gunnar, additional, Benediktsson, Rafn, additional, Sulem, Patrick, additional, Jonsdottir, Ingileif, additional, Masson, Gisli, additional, Holm, Hilma, additional, Norddahl, Gudmundur L., additional, Thorsteinsdottir, Unnur, additional, Gudbjartsson, Daniel F., additional, and Stefansson, Kari, additional

Published
2019
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12. GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures

Author

Styrkarsdottir, Unnur, primary, Stefansson, Olafur A., additional, Gunnarsdottir, Kristbjorg, additional, Thorleifsson, Gudmar, additional, Lund, Sigrun H., additional, Stefansdottir, Lilja, additional, Juliusson, Kristinn, additional, Agustsdottir, Arna B., additional, Zink, Florian, additional, Halldorsson, Gisli H., additional, Ivarsdottir, Erna V., additional, Benonisdottir, Stefania, additional, Jonsson, Hakon, additional, Gylfason, Arnaldur, additional, Norland, Kristjan, additional, Trajanoska, Katerina, additional, Boer, Cindy G., additional, Southam, Lorraine, additional, Leung, Jason C. S., additional, Tang, Nelson L. S., additional, Kwok, Timothy C. Y., additional, Lee, Jenny S. W., additional, Ho, Suzanne C., additional, Byrjalsen, Inger, additional, Center, Jacqueline R., additional, Lee, Seung Hun, additional, Koh, Jung-Min, additional, Lohmander, L. Stefan, additional, Ho-Pham, Lan T., additional, Nguyen, Tuan V., additional, Eisman, John A., additional, Woo, Jean, additional, Leung, Ping-C., additional, Loughlin, John, additional, Zeggini, Eleftheria, additional, Christiansen, Claus, additional, Rivadeneira, Fernando, additional, van Meurs, Joyce, additional, Uitterlinden, Andre G., additional, Mogensen, Brynjolfur, additional, Jonsson, Helgi, additional, Ingvarsson, Thorvaldur, additional, Sigurdsson, Gunnar, additional, Benediktsson, Rafn, additional, Sulem, Patrick, additional, Jonsdottir, Ingileif, additional, Masson, Gisli, additional, Holm, Hilma, additional, Norddahl, Gudmundur L., additional, Thorsteinsdottir, Unnur, additional, Gudbjartsson, Daniel F., additional, and Stefansson, Kari, additional

Published
2019
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15. Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis

Author

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

Published
2017
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16. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

Author

Zheng, Hou-Feng, Forgetta, Vincenzo, Hsu, Yi-Hsiang, Estrada, Karol, Rosello-Diez, Alberto, Leo, Paul J, Dahia, Chitra L, Park-Min, Kyung Hyun, Tobias, Jonathan H, Kooperberg, Charles, Kleinman, Aaron, Styrkarsdottir, Unnur, Liu, Ching-Ti, Uggla, Charlotta, Evans, Daniel S, Nielson, Carrie M, Walter, Klaudia, Pettersson-Kymmer, Ulrika, McCarthy, Shane, Eriksson, Joel, Kwan, Tony, Jhamai, Mila, Trajanoska, Katerina, Memari, Yasin, Min, Josine, Huang, Jie, Danecek, Petr, Wilmot, Beth, Li, Rui, Chou, Wen-Chi, Mokry, Lauren E, Moayyeri, Alireza, Claussnitzer, Melina, Cheng, Chia-Ho, Cheung, Warren, Medina-Gómez, Carolina, Ge, Bing, Chen, Shu-Huang, Choi, Kwangbom, Oei, Ling, Fraser, James, Kraaij, Robert, Hibbs, Matthew A, Gregson, Celia L, Paquette, Denis, Hofman, Albert, Wibom, Carl, Tranah, Gregory J, Marshall, Mhairi, Gardiner, Brooke B, Cremin, Katie, Auer, Paul, Hsu, Li, Ring, Sue, Tung, Joyce Y, Thorleifsson, Gudmar, Enneman, Anke W, Van Schoor, Natasja M, De Groot, Lisette CPGM, Van Der Velde, Nathalie, Melin, Beatrice, Kemp, John P, Christiansen, Claus, Sayers, Adrian, Zhou, Yanhua, Calderari, Sophie, Van Rooij, Jeroen, Carlson, Chris, Peters, Ulrike, Berlivet, Soizik, Dostie, Josée, Uitterlinden, Andre G, Williams, Stephen R, Farber, Charles, Grinberg, Daniel, LaCroix, Andrea Z, Haessler, Jeff, Chasman, Daniel I, Giulianini, Franco, Rose, Lynda M, Ridker, Paul M, Eisman, John A, Nguyen, Tuan V, Center, Jacqueline R, Nogues, Xavier, Garcia-Giralt, Natalia, Launer, Lenore L, Gudnason, Vilmunder, Mellström, Dan, Vandenput, Liesbeth, Amin, Najaf, Van Duijn, Cornelia M, Karlsson, Magnus K, Ljunggren, Östen, Svensson, Olle, Hallmans, Göran, Rousseau, François, Giroux, Sylvie, Bussière, Johanne, Arp, Pascal P, Koromani, Fjorda, Prince, Richard L, Lewis, Joshua R, Langdahl, Bente L, Hermann, A Pernille, Jensen, Jens-Erik B, Kaptoge, Stephen, Khaw, Kay-Tee, Reeve, Jonathan, Formosa, Melissa M, Xuereb-Anastasi, Angela, Åkesson, Kristina, McGuigan, Fiona E, Garg, Gaurav, Olmos, Jose M, Zarrabeitia, Maria T, Riancho, Jose A, Ralston, Stuart H, Alonso, Nerea, Jiang, Xi, Goltzman, David, Pastinen, Tomi, Grundberg, Elin, Gauguier, Dominique, Orwoll, Eric S, Karasik, David, Davey-Smith, George, AOGC Consortium, Smith, Albert V, Siggeirsdottir, Kristin, Harris, Tamara B, Zillikens, M Carola, Van Meurs, Joyce BJ, Thorsteinsdottir, Unnur, Maurano, Matthew T, Timpson, Nicholas J, Soranzo, Nicole, Durbin, Richard, Wilson, Scott G, Ntzani, Evangelia E, Brown, Matthew A, Stefansson, Kari, Hinds, David A, Spector, Tim, Cupples, L Adrienne, Ohlsson, Claes, Greenwood, Celia MT, UK10K Consortium, Jackson, Rebecca D, Rowe, David W, Loomis, Cynthia A, Evans, David M, Ackert-Bicknell, Cheryl L, Joyner, Alexandra L, Duncan, Emma L, Kiel, Douglas P, Rivadeneira, Fernando, Richards, J Brent, Rosello-Diez, Alberto [0000-0002-5550-9846], Kaptoge, Stephen [0000-0002-1155-4872], Khaw, Kay-Tee [0000-0002-8802-2903], Soranzo, Nicole [0000-0003-1095-3852], and Apollo - University of Cambridge Repository

Subjects
Homeodomain Proteins, Genotype, Genome, Human, Genetic Variation, Genomics, Sequence Analysis, DNA, Bone and Bones, White People, Europe, Wnt Proteins, Disease Models, Animal, Fractures, Bone, Mice, Gene Frequency, Bone Density, Animals, Humans, Exome, Female, Genetic Predisposition to Disease
Abstract

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

Published
2015

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