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1. A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy

Author

Mingardo, Enrico, Beaman, Glenda, Grote, Philip, Nordenskjold, Agneta, Newman, William, Woolf, Adrian S., Eckstein, Markus, Hilger, Alina C., Dworschak, Gabriel C., Roesch, Wolfgang, Ebert, Anne-Karolin, Stein, Raimund, Brusco, Alfredo, Di Grazia, Massimo, Tamer, Ali, Torres, Federico M., Hernandez, Jose L., Erben, Philipp, Maj, Carlo, Olmos, Jose M., Riancho, Jose A., Valero, Carmen, Hostettler, Isabel C., Houlden, Henry, Werring, David J., Schumacher, Johannes, Gehlen, Jan, Giel, Ann-Sophie, Buerfent, Benedikt C., Arkani, Samara, Akesson, Elisabeth, Rotstein, Emilia, Ludwig, Michael, Holmdahl, Gundela, Giorgio, Elisa, Berettini, Alfredo, Keene, David, Cervellione, Raimondo M., Younsi, Nina, Ortlieb, Melissa, Oswald, Josef, Haid, Bernhard, Promm, Martin, Neissner, Claudia, Hirsch, Karin, Stehr, Maximilian, Schafer, Frank-Mattias, Schmiedeke, Eberhard, Boemers, Thomas M., van Rooij, Iris A. L. M., Feitz, Wouter F. J., Marcelis, Carlo L. M., Lacher, Martin, Nelson, Jana, Ure, Benno, Fortmann, Caroline, Gale, Daniel P., Chan, Melanie M. Y., Ludwig, Kerstin U., Noethen, Markus M., Heilmann, Stefanie, Zwink, Nadine, Jenetzky, Ekkehart, Odermatt, Benjamin, Knapp, Michael, Reutter, Heiko, Mingardo, Enrico, Beaman, Glenda, Grote, Philip, Nordenskjold, Agneta, Newman, William, Woolf, Adrian S., Eckstein, Markus, Hilger, Alina C., Dworschak, Gabriel C., Roesch, Wolfgang, Ebert, Anne-Karolin, Stein, Raimund, Brusco, Alfredo, Di Grazia, Massimo, Tamer, Ali, Torres, Federico M., Hernandez, Jose L., Erben, Philipp, Maj, Carlo, Olmos, Jose M., Riancho, Jose A., Valero, Carmen, Hostettler, Isabel C., Houlden, Henry, Werring, David J., Schumacher, Johannes, Gehlen, Jan, Giel, Ann-Sophie, Buerfent, Benedikt C., Arkani, Samara, Akesson, Elisabeth, Rotstein, Emilia, Ludwig, Michael, Holmdahl, Gundela, Giorgio, Elisa, Berettini, Alfredo, Keene, David, Cervellione, Raimondo M., Younsi, Nina, Ortlieb, Melissa, Oswald, Josef, Haid, Bernhard, Promm, Martin, Neissner, Claudia, Hirsch, Karin, Stehr, Maximilian, Schafer, Frank-Mattias, Schmiedeke, Eberhard, Boemers, Thomas M., van Rooij, Iris A. L. M., Feitz, Wouter F. J., Marcelis, Carlo L. M., Lacher, Martin, Nelson, Jana, Ure, Benno, Fortmann, Caroline, Gale, Daniel P., Chan, Melanie M. Y., Ludwig, Kerstin U., Noethen, Markus M., Heilmann, Stefanie, Zwink, Nadine, Jenetzky, Ekkehart, Odermatt, Benjamin, Knapp, Michael, and Reutter, Heiko

Abstract

Classic bladder exstrophy represents the most severe end of all human congenital anomalies of the kidney and urinary tract and is associated with bladder cancer susceptibility. Previous genetic studies identified one locus to be involved in classic bladder exstrophy, but were limited to a restrict number of cohort. Here we show the largest classic bladder exstrophy genome-wide association analysis to date where we identify eight genome-wide significant loci, seven of which are novel. In these regions reside ten coding and four non-coding genes. Among the coding genes is EFNA1, strongly expressed in mouse embryonic genital tubercle, urethra, and primitive bladder. Re-sequence of EFNA1 in the investigated classic bladder exstrophy cohort of our study displays an enrichment of rare protein altering variants. We show that all coding genes are expressed and/or significantly regulated in both mouse and human embryonic developmental bladder stages. Furthermore, nine of the coding genes residing in the regions of genome-wide significance are differentially expressed in bladder cancers. Our data suggest genetic drivers for classic bladder exstrophy, as well as a possible role for these drivers to relevant bladder cancer susceptibility. A genome-wide association study on classic bladder exstrophy reveals eight genome-wide significant loci, most of which contained genes expressed in embryonic developmental bladder stages.

Published
2022

2. Bone health: a reflection of the social mosaic

Author

Miszkiewicz, Justyna J., editor, Brennan-Olsen, Sharon L., editor, Riancho, Jose A., editor, Miszkiewicz, Justyna J., editor, Brennan-Olsen, Sharon L., editor, and Riancho, Jose A., editor

Published
2019

3. Bone health: a reflection of the social mosaic

Author

Miszkiewicz, Justyna J., editor, Brennan-Olsen, Sharon L., editor, Riancho, Jose A., editor, Miszkiewicz, Justyna J., editor, Brennan-Olsen, Sharon L., editor, and Riancho, Jose A., editor

Published
2019

4. Bone health: a reflection of the social mosaic

Author

Miszkiewicz, Justyna J., editor, Brennan-Olsen, Sharon L., editor, Riancho, Jose A., editor, Miszkiewicz, Justyna J., editor, Brennan-Olsen, Sharon L., editor, and Riancho, Jose A., editor

Published
2019

5. Bone health: a reflection of the social mosaic

Author

Miszkiewicz, Justyna J., editor, Brennan-Olsen, Sharon L., editor, Riancho, Jose A., editor, Miszkiewicz, Justyna J., editor, Brennan-Olsen, Sharon L., editor, and Riancho, Jose A., editor

Published
2019

6. The Social Context of Bone Health: Conclusions and Future Directions

Author

Miszkiewicz, J., Brennan-Olsen, S., Riancho, J., Brennan-Olsen, Sharon L., Riancho, Jose A., Miszkiewicz, Justyna, Miszkiewicz, J., Brennan-Olsen, S., Riancho, J., Brennan-Olsen, Sharon L., Riancho, Jose A., and Miszkiewicz, Justyna

Abstract

Just as observed in contemporary society, social status in the Middle Ages was a key determinant of nutrition, health, disease, and general lifestyle. Indeed, there are stark similarities between these two distinct time periods. Ease of access to a nutrient-rich diet and a privileged quality of life can be observed in individuals of upper socio-economic status (SES), whether they be a medieval royal or, for exam-ple, a chief executive officer (CEO) of a major corporation in current times. In contrast, individuals with less access to wealth, and thus fewer options for achieving the highest possible quality of life, are more likely to experience poor health, regard-less of when they lived. Data ascertained from medieval human skeletal samples deriving from a range of European archaeological sites indicate that, just as observed in contemporary society, a social gradient in bone quality is observed.

Published
2019

7. Bone health: a reflection of the social mosaic

Author

Miszkiewicz, Justyna J., editor, Brennan-Olsen, Sharon L., editor, Riancho, Jose A., editor, Miszkiewicz, Justyna J., editor, Brennan-Olsen, Sharon L., editor, and Riancho, Jose A., editor

Published
2019

10. Bone health: a reflection of the social mosaic

Author

Miszkiewicz, Justyna J., editor, Brennan-Olsen, Sharon L., editor, Riancho, Jose A., editor, Miszkiewicz, Justyna J., editor, Brennan-Olsen, Sharon L., editor, and Riancho, Jose A., editor

Published
2019

11. Genetic Variants Associated with Circulating Parathyroid Hormone.

Author

Robinson-Cohen, Cassianne, Robinson-Cohen, Cassianne, Lutsey, Pamela L, Kleber, Marcus E, Nielson, Carrie M, Mitchell, Braxton D, Bis, Joshua C, Eny, Karen M, Portas, Laura, Eriksson, Joel, Lorentzon, Mattias, Koller, Daniel L, Milaneschi, Yuri, Teumer, Alexander, Pilz, Stefan, Nethander, Maria, Selvin, Elizabeth, Tang, Weihong, Weng, Lu-Chen, Wong, Hoi Suen, Lai, Dongbing, Peacock, Munro, Hannemann, Anke, Völker, Uwe, Homuth, Georg, Nauk, Matthias, Murgia, Federico, Pattee, Jack W, Orwoll, Eric, Zmuda, Joseph M, Riancho, Jose Antonio, Wolf, Myles, Williams, Frances, Penninx, Brenda, Econs, Michael J, Ryan, Kathleen A, Ohlsson, Claes, Paterson, Andrew D, Psaty, Bruce M, Siscovick, David S, Rotter, Jerome I, Pirastu, Mario, Streeten, Elizabeth, März, Winfried, Fox, Caroline, Coresh, Josef, Wallaschofski, Henri, Pankow, James S, de Boer, Ian H, Kestenbaum, Bryan, Robinson-Cohen, Cassianne, Robinson-Cohen, Cassianne, Lutsey, Pamela L, Kleber, Marcus E, Nielson, Carrie M, Mitchell, Braxton D, Bis, Joshua C, Eny, Karen M, Portas, Laura, Eriksson, Joel, Lorentzon, Mattias, Koller, Daniel L, Milaneschi, Yuri, Teumer, Alexander, Pilz, Stefan, Nethander, Maria, Selvin, Elizabeth, Tang, Weihong, Weng, Lu-Chen, Wong, Hoi Suen, Lai, Dongbing, Peacock, Munro, Hannemann, Anke, Völker, Uwe, Homuth, Georg, Nauk, Matthias, Murgia, Federico, Pattee, Jack W, Orwoll, Eric, Zmuda, Joseph M, Riancho, Jose Antonio, Wolf, Myles, Williams, Frances, Penninx, Brenda, Econs, Michael J, Ryan, Kathleen A, Ohlsson, Claes, Paterson, Andrew D, Psaty, Bruce M, Siscovick, David S, Rotter, Jerome I, Pirastu, Mario, Streeten, Elizabeth, März, Winfried, Fox, Caroline, Coresh, Josef, Wallaschofski, Henri, Pankow, James S, de Boer, Ian H, and Kestenbaum, Bryan

Abstract

Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10-17), rs219779 adjacent to CLDN14 (P=3.5 × 10-16), rs4443100 near RTDR1 (P=8.7 × 10-9), and rs73186030 near CASR (P=4.8 × 10-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.

Published
2017

12. Genetic Variants Associated with Circulating Parathyroid Hormone.

Author

Robinson-Cohen, Cassianne, Robinson-Cohen, Cassianne, Lutsey, Pamela L, Kleber, Marcus E, Nielson, Carrie M, Mitchell, Braxton D, Bis, Joshua C, Eny, Karen M, Portas, Laura, Eriksson, Joel, Lorentzon, Mattias, Koller, Daniel L, Milaneschi, Yuri, Teumer, Alexander, Pilz, Stefan, Nethander, Maria, Selvin, Elizabeth, Tang, Weihong, Weng, Lu-Chen, Wong, Hoi Suen, Lai, Dongbing, Peacock, Munro, Hannemann, Anke, Völker, Uwe, Homuth, Georg, Nauk, Matthias, Murgia, Federico, Pattee, Jack W, Orwoll, Eric, Zmuda, Joseph M, Riancho, Jose Antonio, Wolf, Myles, Williams, Frances, Penninx, Brenda, Econs, Michael J, Ryan, Kathleen A, Ohlsson, Claes, Paterson, Andrew D, Psaty, Bruce M, Siscovick, David S, Rotter, Jerome I, Pirastu, Mario, Streeten, Elizabeth, März, Winfried, Fox, Caroline, Coresh, Josef, Wallaschofski, Henri, Pankow, James S, de Boer, Ian H, Kestenbaum, Bryan, Robinson-Cohen, Cassianne, Robinson-Cohen, Cassianne, Lutsey, Pamela L, Kleber, Marcus E, Nielson, Carrie M, Mitchell, Braxton D, Bis, Joshua C, Eny, Karen M, Portas, Laura, Eriksson, Joel, Lorentzon, Mattias, Koller, Daniel L, Milaneschi, Yuri, Teumer, Alexander, Pilz, Stefan, Nethander, Maria, Selvin, Elizabeth, Tang, Weihong, Weng, Lu-Chen, Wong, Hoi Suen, Lai, Dongbing, Peacock, Munro, Hannemann, Anke, Völker, Uwe, Homuth, Georg, Nauk, Matthias, Murgia, Federico, Pattee, Jack W, Orwoll, Eric, Zmuda, Joseph M, Riancho, Jose Antonio, Wolf, Myles, Williams, Frances, Penninx, Brenda, Econs, Michael J, Ryan, Kathleen A, Ohlsson, Claes, Paterson, Andrew D, Psaty, Bruce M, Siscovick, David S, Rotter, Jerome I, Pirastu, Mario, Streeten, Elizabeth, März, Winfried, Fox, Caroline, Coresh, Josef, Wallaschofski, Henri, Pankow, James S, de Boer, Ian H, and Kestenbaum, Bryan

Abstract

Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10-17), rs219779 adjacent to CLDN14 (P=3.5 × 10-16), rs4443100 near RTDR1 (P=8.7 × 10-9), and rs73186030 near CASR (P=4.8 × 10-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.

Published
2017

13. 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-Gomez, 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 C. P. G. M., 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, Josee, 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, Mellstrom, Dan, Vandenput, Liesbeth, Amin, Najaf, van Duijn, Cornelia M., Karlsson, Magnus K., Ljunggren, Osten, Svensson, Olle, Hallmans, Göran, Rousseau, Francois, Giroux, Sylvie, Bussiere, 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, Akesson, 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, Smith, Albert V., Siggeirsdottir, Kristin, Harris, Tamara B., Zillikens, M. Carola, van Meurs, Joyce B. J., Thorsteinsdottir, Unnur, Maurano, Matthew T., Timpson, Nicholas J., Soranzo, Nicole, Durbin, Richard, Wilson, ScottG., Ntzani, Evangelia E., Brown, Matthew A., Stefansson, Kari, Hinds, David A., Spector, Tim, Cupples, L. Adrienne, Ohlsson, Claes, Greenwood, Celia M. T., 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, 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-Gomez, 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 C. P. G. M., 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, Josee, 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, Mellstrom, Dan, Vandenput, Liesbeth, Amin, Najaf, van Duijn, Cornelia M., Karlsson, Magnus K., Ljunggren, Osten, Svensson, Olle, Hallmans, Göran, Rousseau, Francois, Giroux, Sylvie, Bussiere, 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, Akesson, 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, Smith, Albert V., Siggeirsdottir, Kristin, Harris, Tamara B., Zillikens, M. Carola, van Meurs, Joyce B. J., Thorsteinsdottir, Unnur, Maurano, Matthew T., Timpson, Nicholas J., Soranzo, Nicole, Durbin, Richard, Wilson, ScottG., Ntzani, Evangelia E., Brown, Matthew A., Stefansson, Kari, Hinds, David A., Spector, Tim, Cupples, L. Adrienne, Ohlsson, Claes, Greenwood, Celia M. T., 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, and Richards, J. Brent

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(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 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 BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/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 +10.41 s.d., P-meta = 1 x 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 imput

Published
2015
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14. 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-Gomez, 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 C. P. G. M., 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, Josee, 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, Mellstrom, Dan, Vandenput, Liesbeth, Amin, Najaf, van Duijn, Cornelia M., Karlsson, Magnus K., Ljunggren, Östen, Svensson, Olle, Hallmans, Goran, Rousseau, Francois, Giroux, Sylvie, Bussiere, 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, Akesson, 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, Smith, Albert V., Siggeirsdottir, Kristin, Harris, Tamara B., Zillikens, M. Carola, van Meurs, Joyce B. J., Thorsteinsdottir, Unnur, Maurano, Matthew T., Timpson, Nicholas J., Soranzo, Nicole, Durbin, Richard, Wilson, ScottG., Ntzani, Evangelia E., Brown, Matthew A., Stefansson, Kari, Hinds, David A., Spector, Tim, Cupples, L. Adrienne, Ohlsson, Claes, Greenwood, Celia M. T., 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, 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-Gomez, 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 C. P. G. M., 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, Josee, 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, Mellstrom, Dan, Vandenput, Liesbeth, Amin, Najaf, van Duijn, Cornelia M., Karlsson, Magnus K., Ljunggren, Östen, Svensson, Olle, Hallmans, Goran, Rousseau, Francois, Giroux, Sylvie, Bussiere, 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, Akesson, 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, Smith, Albert V., Siggeirsdottir, Kristin, Harris, Tamara B., Zillikens, M. Carola, van Meurs, Joyce B. J., Thorsteinsdottir, Unnur, Maurano, Matthew T., Timpson, Nicholas J., Soranzo, Nicole, Durbin, Richard, Wilson, ScottG., Ntzani, Evangelia E., Brown, Matthew A., Stefansson, Kari, Hinds, David A., Spector, Tim, Cupples, L. Adrienne, Ohlsson, Claes, Greenwood, Celia M. T., 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, and Richards, J. Brent

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(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 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 BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/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 +10.41 s.d., P-meta = 1 x 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 imput

Published
2015
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15. Genetic determinants of heel bone properties : genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

Author

Moayyeri, Alireza, Hsu, Yi-Hsiang, Karasik, David, Estrada, Karol, Xiao, Su-Mei, Nielson, Carrie, Srikanth, Priya, Giroux, Sylvie, Wilson, Scott G., Zheng, Hou-Feng, Smith, Albert V., Pye, Stephen R., Leo, Paul J., Teumer, Alexander, Hwang, Joo-Yeon, Ohlsson, Claes, McGuigan, Fiona, Minster, Ryan L., Hayward, Caroline, Olmos, Jose M., Lyytikaeinen, Leo-Pekka, Lewis, Joshua R., Swart, Karin M. A., Masi, Laura, Oldmeadow, Chris, Holliday, Elizabeth G., Cheng, Sulin, van Schoor, Natasja M., Harvey, Nicholas C., Kruk, Marcin, Fabiola Del Greco, M., Igl, Wilmar, Trummer, Olivia, Grigoriou, Efi, Luben, Robert, Liu, Ching-Ti, Zhou, Yanhua, Oei, Ling, Medina-Gomez, Carolina, Zmuda, Joseph, Tranah, Greg, Brown, Suzanne J., Williams, Frances M., Soranzo, Nicole, Jakobsdottir, Johanna, Siggeirsdottir, Kristin, Holliday, Kate L., Hannemann, Anke, Go, Min Jin, Garcia, Melissa, Polasek, Ozren, Laaksonen, Marika, Zhu, Kun, Enneman, Anke W., McEvoy, Mark, Peel, Roseanne, Sham, Pak Chung, Jaworski, Maciej, Johansson, Asa, Hicks, Andrew A., Pludowski, Pawel, Scott, Rodney, Dhonukshe-Rutten, Rosalie A. M., van der Velde, Nathalie, Kaehoenen, Mika, Viikari, Jorma S., Sievaenen, Harri, Raitakari, Olli T., Gonzalez-Macias, Jesus, Hernandez, Jose L., Mellstroem, Dan, Ljunggren, Östen, Cho, Yoon Shin, Voelker, Uwe, Nauck, Matthias, Homuth, Georg, Voelzke, Henry, Haring, Robin, Brown, Matthew A., McCloskey, Eugene, Nicholson, Geoffrey C., Eastell, Richard, Eisman, John A., Jones, Graeme, Reid, Ian R., Dennison, Elaine M., Wark, John, Boonen, Steven, Vanderschueren, Dirk, Wu, Frederick C. W., Aspelund, Thor, Richards, J. Brent, Bauer, Doug, Hofman, Albert, Khaw, Kay-Tee, Dedoussis, George, Obermayer-Pietsch, Barbara, Gyllensten, Ulf, Pramstaller, Peter P., Lorenc, Roman S., Cooper, Cyrus, Kung, Annie Wai Chee, Lips, Paul, Alen, Markku, Attia, John, Luisa Brandi, Maria, de Groot, Lisette C. P. G. M., Lehtimaeki, Terho, Riancho, Jose A., Campbell, Harry, Liu, Yongmei, Harris, Tamara B., Akesson, Kristina, Karlsson, Magnus, Lee, Jong-Young, Wallaschofski, Henri, Duncan, Emma L., O'Neill, Terence W., Gudnason, Vilmundur, Spector, Timothy D., Rousseau, Francois, Orwoll, Eric, Cummings, Steven R., Wareham, Nick J., Rivadeneira, Fernando, Uitterlinden, Andre G., Prince, Richard L., Kiel, Douglas P., Reeve, Jonathan, Kaptoge, Stephen K., Moayyeri, Alireza, Hsu, Yi-Hsiang, Karasik, David, Estrada, Karol, Xiao, Su-Mei, Nielson, Carrie, Srikanth, Priya, Giroux, Sylvie, Wilson, Scott G., Zheng, Hou-Feng, Smith, Albert V., Pye, Stephen R., Leo, Paul J., Teumer, Alexander, Hwang, Joo-Yeon, Ohlsson, Claes, McGuigan, Fiona, Minster, Ryan L., Hayward, Caroline, Olmos, Jose M., Lyytikaeinen, Leo-Pekka, Lewis, Joshua R., Swart, Karin M. A., Masi, Laura, Oldmeadow, Chris, Holliday, Elizabeth G., Cheng, Sulin, van Schoor, Natasja M., Harvey, Nicholas C., Kruk, Marcin, Fabiola Del Greco, M., Igl, Wilmar, Trummer, Olivia, Grigoriou, Efi, Luben, Robert, Liu, Ching-Ti, Zhou, Yanhua, Oei, Ling, Medina-Gomez, Carolina, Zmuda, Joseph, Tranah, Greg, Brown, Suzanne J., Williams, Frances M., Soranzo, Nicole, Jakobsdottir, Johanna, Siggeirsdottir, Kristin, Holliday, Kate L., Hannemann, Anke, Go, Min Jin, Garcia, Melissa, Polasek, Ozren, Laaksonen, Marika, Zhu, Kun, Enneman, Anke W., McEvoy, Mark, Peel, Roseanne, Sham, Pak Chung, Jaworski, Maciej, Johansson, Asa, Hicks, Andrew A., Pludowski, Pawel, Scott, Rodney, Dhonukshe-Rutten, Rosalie A. M., van der Velde, Nathalie, Kaehoenen, Mika, Viikari, Jorma S., Sievaenen, Harri, Raitakari, Olli T., Gonzalez-Macias, Jesus, Hernandez, Jose L., Mellstroem, Dan, Ljunggren, Östen, Cho, Yoon Shin, Voelker, Uwe, Nauck, Matthias, Homuth, Georg, Voelzke, Henry, Haring, Robin, Brown, Matthew A., McCloskey, Eugene, Nicholson, Geoffrey C., Eastell, Richard, Eisman, John A., Jones, Graeme, Reid, Ian R., Dennison, Elaine M., Wark, John, Boonen, Steven, Vanderschueren, Dirk, Wu, Frederick C. W., Aspelund, Thor, Richards, J. Brent, Bauer, Doug, Hofman, Albert, Khaw, Kay-Tee, Dedoussis, George, Obermayer-Pietsch, Barbara, Gyllensten, Ulf, Pramstaller, Peter P., Lorenc, Roman S., Cooper, Cyrus, Kung, Annie Wai Chee, Lips, Paul, Alen, Markku, Attia, John, Luisa Brandi, Maria, de Groot, Lisette C. P. G. M., Lehtimaeki, Terho, Riancho, Jose A., Campbell, Harry, Liu, Yongmei, Harris, Tamara B., Akesson, Kristina, Karlsson, Magnus, Lee, Jong-Young, Wallaschofski, Henri, Duncan, Emma L., O'Neill, Terence W., Gudnason, Vilmundur, Spector, Timothy D., Rousseau, Francois, Orwoll, Eric, Cummings, Steven R., Wareham, Nick J., Rivadeneira, Fernando, Uitterlinden, Andre G., Prince, Richard L., Kiel, Douglas P., Reeve, Jonathan, and Kaptoge, Stephen K.

Abstract

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

Published
2014
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16. Genome-wide association study for radiographic vertebral fractures : A potential role for the 16q24 BMD locus

Author

Oei, Ling, Estrada, Karol, Duncan, Emma L., Christiansen, Claus, Liu, Ching-Ti, Langdahl, Bente L., Obermayer-Pietsch, Barbara, Riancho, Jose A., Prince, Richard L., van Schoor, Natasja M., McCloskey, Eugene, Hsu, Yi-Hsiang, Evangelou, Evangelos, Ntzani, Evangelia, Evans, David M., Alonso, Nerea, Husted, Lise B., Valero, Carmen, Hernandez, Jose L., Lewis, Joshua R., Kaptoge, Stephen K., Zhu, Kun, Cupples, L. Adrienne, Medina-Gomez, Carolina, Vandenput, Liesbeth, Kim, Ghi Su, Lee, Seung Hun, Castano-Betancourt, Martha C., Oei, Edwin H. G., Martinez, Josefina, Daroszewska, Anna, van der Klift, Marjolein, Mellstrom, Dan, Herrera, Lizbeth, Karlsson, Magnus K., Hofman, Albert, Ljunggren, Östen, Pols, Huibert A. P., Stolk, Lisette, van Meurs, Joyce B. J., Ioannidis, John P. A., Zillikens, M. Carola, Lips, Paul, Karasik, David, Uitterlinden, Andre G., Styrkarsdottir, Unnur, Brown, Matthew A., Koh, Jung-Min, Richards, J. Brent, Reeve, Jonathan, Ohlsson, Claes, Ralston, Stuart H., Kiel, Douglas P., Rivadeneira, Fernando, Oei, Ling, Estrada, Karol, Duncan, Emma L., Christiansen, Claus, Liu, Ching-Ti, Langdahl, Bente L., Obermayer-Pietsch, Barbara, Riancho, Jose A., Prince, Richard L., van Schoor, Natasja M., McCloskey, Eugene, Hsu, Yi-Hsiang, Evangelou, Evangelos, Ntzani, Evangelia, Evans, David M., Alonso, Nerea, Husted, Lise B., Valero, Carmen, Hernandez, Jose L., Lewis, Joshua R., Kaptoge, Stephen K., Zhu, Kun, Cupples, L. Adrienne, Medina-Gomez, Carolina, Vandenput, Liesbeth, Kim, Ghi Su, Lee, Seung Hun, Castano-Betancourt, Martha C., Oei, Edwin H. G., Martinez, Josefina, Daroszewska, Anna, van der Klift, Marjolein, Mellstrom, Dan, Herrera, Lizbeth, Karlsson, Magnus K., Hofman, Albert, Ljunggren, Östen, Pols, Huibert A. P., Stolk, Lisette, van Meurs, Joyce B. J., Ioannidis, John P. A., Zillikens, M. Carola, Lips, Paul, Karasik, David, Uitterlinden, Andre G., Styrkarsdottir, Unnur, Brown, Matthew A., Koh, Jung-Min, Richards, J. Brent, Reeve, Jonathan, Ohlsson, Claes, Ralston, Stuart H., Kiel, Douglas P., and Rivadeneira, Fernando

Abstract

Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fracture applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5 x 10(-8). In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 x 10(-8). However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% Cl: 0.98-1.14; p = 0.17), displaying high degree of heterogeneity (I-2= 57%; Q(het)p = 0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is

Published
2014
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17. A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip.

Author

Evangelou, Evangelos, Evangelou, Evangelos, Kerkhof, Hanneke J, Styrkarsdottir, Unnur, Ntzani, Evangelia E, Bos, Steffan D, Esko, Tonu, Evans, Daniel S, Metrustry, Sarah, Panoutsopoulou, Kalliope, Ramos, Yolande FM, Thorleifsson, Gudmar, Tsilidis, Konstantinos K, arcOGEN Consortium, Arden, Nigel, Aslam, Nadim, Bellamy, Nicholas, Birrell, Fraser, Blanco, Francisco J, Carr, Andrew, Chapman, Kay, Day-Williams, Aaron G, Deloukas, Panos, Doherty, Michael, Engström, Gunnar, Helgadottir, Hafdis T, Hofman, Albert, Ingvarsson, Thorvaldur, Jonsson, Helgi, Keis, Aime, Keurentjes, J Christiaan, Kloppenburg, Margreet, Lind, Penelope A, McCaskie, Andrew, Martin, Nicholas G, Milani, Lili, Montgomery, Grant W, Nelissen, Rob GHH, Nevitt, Michael C, Nilsson, Peter M, Ollier, William Er, Parimi, Neeta, Rai, Ashok, Ralston, Stuart H, Reed, Mike R, Riancho, Jose A, Rivadeneira, Fernando, Rodriguez-Fontenla, Cristina, Southam, Lorraine, Thorsteinsdottir, Unnur, Tsezou, Aspasia, Wallis, Gillian A, Wilkinson, J Mark, Gonzalez, Antonio, Lane, Nancy E, Lohmander, L Stefan, Loughlin, John, Metspalu, Andres, Uitterlinden, Andre G, Jonsdottir, Ingileif, Stefansson, Kari, Slagboom, P Eline, Zeggini, Eleftheria, Meulenbelt, Ingrid, Ioannidis, John Pa, Spector, Tim D, van Meurs, Joyce BJ, Valdes, Ana M, Evangelou, Evangelos, Evangelou, Evangelos, Kerkhof, Hanneke J, Styrkarsdottir, Unnur, Ntzani, Evangelia E, Bos, Steffan D, Esko, Tonu, Evans, Daniel S, Metrustry, Sarah, Panoutsopoulou, Kalliope, Ramos, Yolande FM, Thorleifsson, Gudmar, Tsilidis, Konstantinos K, arcOGEN Consortium, Arden, Nigel, Aslam, Nadim, Bellamy, Nicholas, Birrell, Fraser, Blanco, Francisco J, Carr, Andrew, Chapman, Kay, Day-Williams, Aaron G, Deloukas, Panos, Doherty, Michael, Engström, Gunnar, Helgadottir, Hafdis T, Hofman, Albert, Ingvarsson, Thorvaldur, Jonsson, Helgi, Keis, Aime, Keurentjes, J Christiaan, Kloppenburg, Margreet, Lind, Penelope A, McCaskie, Andrew, Martin, Nicholas G, Milani, Lili, Montgomery, Grant W, Nelissen, Rob GHH, Nevitt, Michael C, Nilsson, Peter M, Ollier, William Er, Parimi, Neeta, Rai, Ashok, Ralston, Stuart H, Reed, Mike R, Riancho, Jose A, Rivadeneira, Fernando, Rodriguez-Fontenla, Cristina, Southam, Lorraine, Thorsteinsdottir, Unnur, Tsezou, Aspasia, Wallis, Gillian A, Wilkinson, J Mark, Gonzalez, Antonio, Lane, Nancy E, Lohmander, L Stefan, Loughlin, John, Metspalu, Andres, Uitterlinden, Andre G, Jonsdottir, Ingileif, Stefansson, Kari, Slagboom, P Eline, Zeggini, Eleftheria, Meulenbelt, Ingrid, Ioannidis, John Pa, Spector, Tim D, van Meurs, Joyce BJ, and Valdes, Ana M

Abstract

ObjectivesOsteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects.MethodsWe performed a two-stage meta-analysis on more than 78,000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used.ResultsWe accumulated 11,277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis).ConclusionsNovel genetic loci for hip OA were found in this meta-analysis of GWAS.

Published
2014

18. Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus

Author

Oei, Ling, Estrada, Karol, Duncan, Emma, Christiansen, Claus, Liu, Ching-Ti, Langdahl, Bente, Obermayer-Pietsch, Barbara, Riancho, Jose, Prince, Richard, Brown, Matthew, other, and, Oei, Ling, Estrada, Karol, Duncan, Emma, Christiansen, Claus, Liu, Ching-Ti, Langdahl, Bente, Obermayer-Pietsch, Barbara, Riancho, Jose, Prince, Richard, Brown, Matthew, and other, and

Abstract

Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5×10-8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p=4.6×10-8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98-1.14; p=0.17), displaying high degree of heterogeneity (I2=57%; Qhet p=0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p=0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject th

Published
2014

19. A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip.

Author

Evangelou, Evangelos, Evangelou, Evangelos, Kerkhof, Hanneke J, Styrkarsdottir, Unnur, Ntzani, Evangelia E, Bos, Steffan D, Esko, Tonu, Evans, Daniel S, Metrustry, Sarah, Panoutsopoulou, Kalliope, Ramos, Yolande FM, Thorleifsson, Gudmar, Tsilidis, Konstantinos K, arcOGEN Consortium, Arden, Nigel, Aslam, Nadim, Bellamy, Nicholas, Birrell, Fraser, Blanco, Francisco J, Carr, Andrew, Chapman, Kay, Day-Williams, Aaron G, Deloukas, Panos, Doherty, Michael, Engström, Gunnar, Helgadottir, Hafdis T, Hofman, Albert, Ingvarsson, Thorvaldur, Jonsson, Helgi, Keis, Aime, Keurentjes, J Christiaan, Kloppenburg, Margreet, Lind, Penelope A, McCaskie, Andrew, Martin, Nicholas G, Milani, Lili, Montgomery, Grant W, Nelissen, Rob GHH, Nevitt, Michael C, Nilsson, Peter M, Ollier, William Er, Parimi, Neeta, Rai, Ashok, Ralston, Stuart H, Reed, Mike R, Riancho, Jose A, Rivadeneira, Fernando, Rodriguez-Fontenla, Cristina, Southam, Lorraine, Thorsteinsdottir, Unnur, Tsezou, Aspasia, Wallis, Gillian A, Wilkinson, J Mark, Gonzalez, Antonio, Lane, Nancy E, Lohmander, L Stefan, Loughlin, John, Metspalu, Andres, Uitterlinden, Andre G, Jonsdottir, Ingileif, Stefansson, Kari, Slagboom, P Eline, Zeggini, Eleftheria, Meulenbelt, Ingrid, Ioannidis, John Pa, Spector, Tim D, van Meurs, Joyce BJ, Valdes, Ana M, Evangelou, Evangelos, Evangelou, Evangelos, Kerkhof, Hanneke J, Styrkarsdottir, Unnur, Ntzani, Evangelia E, Bos, Steffan D, Esko, Tonu, Evans, Daniel S, Metrustry, Sarah, Panoutsopoulou, Kalliope, Ramos, Yolande FM, Thorleifsson, Gudmar, Tsilidis, Konstantinos K, arcOGEN Consortium, Arden, Nigel, Aslam, Nadim, Bellamy, Nicholas, Birrell, Fraser, Blanco, Francisco J, Carr, Andrew, Chapman, Kay, Day-Williams, Aaron G, Deloukas, Panos, Doherty, Michael, Engström, Gunnar, Helgadottir, Hafdis T, Hofman, Albert, Ingvarsson, Thorvaldur, Jonsson, Helgi, Keis, Aime, Keurentjes, J Christiaan, Kloppenburg, Margreet, Lind, Penelope A, McCaskie, Andrew, Martin, Nicholas G, Milani, Lili, Montgomery, Grant W, Nelissen, Rob GHH, Nevitt, Michael C, Nilsson, Peter M, Ollier, William Er, Parimi, Neeta, Rai, Ashok, Ralston, Stuart H, Reed, Mike R, Riancho, Jose A, Rivadeneira, Fernando, Rodriguez-Fontenla, Cristina, Southam, Lorraine, Thorsteinsdottir, Unnur, Tsezou, Aspasia, Wallis, Gillian A, Wilkinson, J Mark, Gonzalez, Antonio, Lane, Nancy E, Lohmander, L Stefan, Loughlin, John, Metspalu, Andres, Uitterlinden, Andre G, Jonsdottir, Ingileif, Stefansson, Kari, Slagboom, P Eline, Zeggini, Eleftheria, Meulenbelt, Ingrid, Ioannidis, John Pa, Spector, Tim D, van Meurs, Joyce BJ, and Valdes, Ana M

Abstract

ObjectivesOsteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects.MethodsWe performed a two-stage meta-analysis on more than 78,000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used.ResultsWe accumulated 11,277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis).ConclusionsNovel genetic loci for hip OA were found in this meta-analysis of GWAS.

Published
2014

20. A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip

Author

Evangelou, Evangelos, Kerkhof, Hanneke J., Styrkarsdottir, Unnur, Ntzani, Evangelia E., Bos, Steffan D., Esko, Tonu, Evans, Daniel S., Metrustry, Sarah, Panoutsopoulou, Kalliope, Ramos, Yolande F. M., Thorleifsson, Gudmar, Tsilidis, Konstantinos K., Arden, Nigel, Aslam, Nadim, Bellamy, Nicholas, Birrell, Fraser, Blanco, Francisco J., Carr, Andrew, Chapman, Kay, Day-Williams, Aaron G., Deloukas, Panos, Doherty, Michael, Engström, Gunnar, Helgadottir, Hafdis T., Hofman, Albert, Ingvarsson, Thorvaldur, Jonsson, Helgi, Keis, Aime, Keurentjes, J. Christiaan, Kloppenburg, Margreet, Lind, Penelope A., McCaskie, Andrew, Martin, Nicholas G., Milani, Lili, Montgomery, Grant W., Nelissen, Rob G. H. H., Nevitt, Michael C., Nilsson, Peter, Ollier, William E. R., Parimi, Neeta, Rai, Ashok, Ralston, Stuart H., Reed, Mike R., Riancho, Jose A., Rivadeneira, Fernando, Rodriguez-Fontenla, Cristina, Southam, Lorraine, Thorsteinsdottir, Unnur, Tsezou, Aspasia, AWallis, Gillian, Wilkinson, J. Mark, Gonzalez, Antonio, Lane, Nancy E., Lohmander, Stefan, Loughlin, John, Metspalu, Andres, Uitterlinden, Andre G., Jonsdottir, Ingileif, Stefansson, Kari, Slagboom, P. Eline, Zeggini, Eleftheria, Meulenbelt, Ingrid, Ioannidis, John P. A., Spector, Tim D., van Meurs, Joyce B. J., Valdes, Ana M., Evangelou, Evangelos, Kerkhof, Hanneke J., Styrkarsdottir, Unnur, Ntzani, Evangelia E., Bos, Steffan D., Esko, Tonu, Evans, Daniel S., Metrustry, Sarah, Panoutsopoulou, Kalliope, Ramos, Yolande F. M., Thorleifsson, Gudmar, Tsilidis, Konstantinos K., Arden, Nigel, Aslam, Nadim, Bellamy, Nicholas, Birrell, Fraser, Blanco, Francisco J., Carr, Andrew, Chapman, Kay, Day-Williams, Aaron G., Deloukas, Panos, Doherty, Michael, Engström, Gunnar, Helgadottir, Hafdis T., Hofman, Albert, Ingvarsson, Thorvaldur, Jonsson, Helgi, Keis, Aime, Keurentjes, J. Christiaan, Kloppenburg, Margreet, Lind, Penelope A., McCaskie, Andrew, Martin, Nicholas G., Milani, Lili, Montgomery, Grant W., Nelissen, Rob G. H. H., Nevitt, Michael C., Nilsson, Peter, Ollier, William E. R., Parimi, Neeta, Rai, Ashok, Ralston, Stuart H., Reed, Mike R., Riancho, Jose A., Rivadeneira, Fernando, Rodriguez-Fontenla, Cristina, Southam, Lorraine, Thorsteinsdottir, Unnur, Tsezou, Aspasia, AWallis, Gillian, Wilkinson, J. Mark, Gonzalez, Antonio, Lane, Nancy E., Lohmander, Stefan, Loughlin, John, Metspalu, Andres, Uitterlinden, Andre G., Jonsdottir, Ingileif, Stefansson, Kari, Slagboom, P. Eline, Zeggini, Eleftheria, Meulenbelt, Ingrid, Ioannidis, John P. A., Spector, Tim D., van Meurs, Joyce B. J., and Valdes, Ana M.

Abstract

Objectives Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. Methods We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. Results We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9x10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p= 5.6x10(-8)) and follow-up studies (p=7.3x10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9x10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2x10(-6), OR=1.27 in male specific analysis). Conclusions Novel genetic loci for hip OA were found in this meta-analysis of GWAS.

Published
2014

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

Author

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

Abstract

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 x 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 x 10(-4), Bonferroni corrected), of which six reached P < 5 x 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

Published
2012
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22. Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density

Author

Alonso, Nerea, Estrada, Karol, Albagha, Omar M. E., Herrera, Lizbeth, Reppe, Sjur, Olstad, Ole K., Gautvik, Kaare M., Ryan, Niamh M., Evans, Kathryn L., Nielson, Carrie M., Hsu, Yi-Hsiang, Kiel, Douglas P., Markozannes, George, Ntzani, Evangelia E., Evangelou, Evangelos, Feenstra, Bjarke, Liu, Xueping, Melbye, Mads, Masi, Laura, Brandi, Maria Luisa, Riches, Philip, Daroszewska, Anna, Olmos, Jose manuel, Valero, Carmen, Castillo, Jesus, Riancho, Jose A., Husted, Lise B., Langdahl, Bente L., Brown, Matthew A., Duncan, Emma L., Kaptoge, Stephen, Khaw, Kay-Tee, Usategui-Martin, Ricardo, Del Pino-Montes, Javier, Gonzalez-Sarmiento, Rogelio, Lewis, Joshua R., Prince, Richard L., D'Amelio, Patrizia, Garcia-Giralt, Natalia, Nogues, Xavier, Mencej-Bedrac, Simona, Marc, Janja, Wolstein, Orit, Eisman, John A., Oei, Ling, Medina-Gomez, Carolina, Schraut, Katharina E., Navarro, Pau, Wilson, James F., Davies, Gail, Starr, John, Deary, Ian, Tanaka, Toshiko, Ferrucci, Luigi, Gianfrancesco, Fernando, Gennari, Luigi, Lucas, Gavin, Elosua, Roberto, Uitterlinden, Andre G., Rivadeneira, Fernando, Ralston, Stuart H., Alonso, Nerea, Estrada, Karol, Albagha, Omar M. E., Herrera, Lizbeth, Reppe, Sjur, Olstad, Ole K., Gautvik, Kaare M., Ryan, Niamh M., Evans, Kathryn L., Nielson, Carrie M., Hsu, Yi-Hsiang, Kiel, Douglas P., Markozannes, George, Ntzani, Evangelia E., Evangelou, Evangelos, Feenstra, Bjarke, Liu, Xueping, Melbye, Mads, Masi, Laura, Brandi, Maria Luisa, Riches, Philip, Daroszewska, Anna, Olmos, Jose manuel, Valero, Carmen, Castillo, Jesus, Riancho, Jose A., Husted, Lise B., Langdahl, Bente L., Brown, Matthew A., Duncan, Emma L., Kaptoge, Stephen, Khaw, Kay-Tee, Usategui-Martin, Ricardo, Del Pino-Montes, Javier, Gonzalez-Sarmiento, Rogelio, Lewis, Joshua R., Prince, Richard L., D'Amelio, Patrizia, Garcia-Giralt, Natalia, Nogues, Xavier, Mencej-Bedrac, Simona, Marc, Janja, Wolstein, Orit, Eisman, John A., Oei, Ling, Medina-Gomez, Carolina, Schraut, Katharina E., Navarro, Pau, Wilson, James F., Davies, Gail, Starr, John, Deary, Ian, Tanaka, Toshiko, Ferrucci, Luigi, Gianfrancesco, Fernando, Gennari, Luigi, Lucas, Gavin, Elosua, Roberto, Uitterlinden, Andre G., Rivadeneira, Fernando, and Ralston, Stuart H.

Abstract

Alonso, N., Estrada, K., Albagha, O. M., Herrera, L., Reppe, S., Olstad, O. K., ... & Hsu, Y. H. (2017). Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density. Annals of the Rheumatic Diseases, 77(3), 378-385. doi:10.1136/annrheumdis-2017-212469 Available here.

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