BACKGROUND: Osteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies. OBJECTIVE: To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes. DESIGN: Large-scale meta-analysis of genome-wide association data. SETTING: 5 international, multicenter, population-based studies. PARTICIPANTS: Data on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands. MEASUREMENTS: Systematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures. RESULTS: 150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST. LIMITATION: Only common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded. CONCLUSION: In this large-scale collaborative genome-wide meta-analysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD.
BACKGROUND:Osteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies. OBJECTIVE: To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes. DESIGN: Large-scale meta-analysis of genome-wide association data. SETTING: 5 international, multicenter, population-based studies. PARTICIPANTS: Data on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands. MEASUREMENTS: Systematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures. RESULTS: 150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST. LIMITATION: Only common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded. CONCLUSION: In this large-scale collaborative genome-wide meta-analysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD.
Authors: Mark I McCarthy; Gonçalo R Abecasis; Lon R Cardon; David B Goldstein; Julian Little; John P A Ioannidis; Joel N Hirschhorn Journal: Nat Rev Genet Date: 2008-05 Impact factor: 53.242
Authors: Ian P M Tomlinson; Emily Webb; Luis Carvajal-Carmona; Peter Broderick; Kimberley Howarth; Alan M Pittman; Sarah Spain; Steven Lubbe; Axel Walther; Kate Sullivan; Emma Jaeger; Sarah Fielding; Andrew Rowan; Jayaram Vijayakrishnan; Enric Domingo; Ian Chandler; Zoe Kemp; Mobshra Qureshi; Susan M Farrington; Albert Tenesa; James G D Prendergast; Rebecca A Barnetson; Steven Penegar; Ella Barclay; Wendy Wood; Lynn Martin; Maggie Gorman; Huw Thomas; Julian Peto; D Timothy Bishop; Richard Gray; Eamonn R Maher; Anneke Lucassen; David Kerr; D Gareth R Evans; Clemens Schafmayer; Stephan Buch; Henry Völzke; Jochen Hampe; Stefan Schreiber; Ulrich John; Thibaud Koessler; Paul Pharoah; Tom van Wezel; Hans Morreau; Juul T Wijnen; John L Hopper; Melissa C Southey; Graham G Giles; Gianluca Severi; Sergi Castellví-Bel; Clara Ruiz-Ponte; Angel Carracedo; Antoni Castells; Asta Försti; Kari Hemminki; Pavel Vodicka; Alessio Naccarati; Lara Lipton; Judy W C Ho; K K Cheng; Pak C Sham; J Luk; Jose A G Agúndez; Jose M Ladero; Miguel de la Hoya; Trinidad Caldés; Iina Niittymäki; Sari Tuupanen; Auli Karhu; Lauri Aaltonen; Jean-Baptiste Cazier; Harry Campbell; Malcolm G Dunlop; Richard S Houlston Journal: Nat Genet Date: 2008-03-30 Impact factor: 38.330
Authors: John B Harley; Marta E Alarcón-Riquelme; Lindsey A Criswell; Chaim O Jacob; Robert P Kimberly; Kathy L Moser; Betty P Tsao; Timothy J Vyse; Carl D Langefeld; Swapan K Nath; Joel M Guthridge; Beth L Cobb; Daniel B Mirel; Miranda C Marion; Adrienne H Williams; Jasmin Divers; Wei Wang; Summer G Frank; Bahram Namjou; Stacey B Gabriel; Annette T Lee; Peter K Gregersen; Timothy W Behrens; Kimberly E Taylor; Michelle Fernando; Raphael Zidovetzki; Patrick M Gaffney; Jeffrey C Edberg; John D Rioux; Joshua O Ojwang; Judith A James; Joan T Merrill; Gary S Gilkeson; Michael F Seldin; Hong Yin; Emily C Baechler; Quan-Zhen Li; Edward K Wakeland; Gail R Bruner; Kenneth M Kaufman; Jennifer A Kelly Journal: Nat Genet Date: 2008-01-20 Impact factor: 38.330
Authors: Bente L Langdahl; André G Uitterlinden; Stuart H Ralston; Thomas A Trikalinos; Susanne Balcells; Maria Luisa Brandi; Serena Scollen; Paul Lips; Roman Lorenc; Barbara Obermayer-Pietsch; David M Reid; Jácome Bruges Armas; Pascal P Arp; Amelia Bassiti; Mariona Bustamante; Lise Bjerre Husted; Alison H Carey; Ramon Pérez Cano; Harald Dobnig; Alison M Dunning; Astrid Fahrleitner-Pammer; Alberto Falchetti; Elzbieta Karczmarewicz; Marcin Kruk; Johannes P T M van Leeuwen; Laura Masi; Joyce B J van Meurs; Jon Mangion; Fiona E A McGuigan; Leonardo Mellibovsky; Leif Mosekilde; Xavier Nogués; Huibert A P Pols; Jonathan Reeve; Wilfried Renner; Fernando Rivadeneira; Natasja M van Schoor; John P A Ioannidis Journal: Bone Date: 2007-12-03 Impact factor: 4.398
Authors: Joyce B J van Meurs; Thomas A Trikalinos; Stuart H Ralston; Susana Balcells; Maria Luisa Brandi; Kim Brixen; Douglas P Kiel; Bente L Langdahl; Paul Lips; Osten Ljunggren; Roman Lorenc; Barbara Obermayer-Pietsch; Claes Ohlsson; Ulrika Pettersson; David M Reid; Francois Rousseau; Serena Scollen; Wim Van Hul; Lidia Agueda; Kristina Akesson; Lidia I Benevolenskaya; Serge L Ferrari; Göran Hallmans; Albert Hofman; Lise Bjerre Husted; Marcin Kruk; Stephen Kaptoge; David Karasik; Magnus K Karlsson; Mattias Lorentzon; Laura Masi; Fiona E A McGuigan; Dan Mellström; Leif Mosekilde; Xavier Nogues; Huibert A P Pols; Jonathan Reeve; Wilfried Renner; Fernando Rivadeneira; Natasja M van Schoor; Kurt Weber; John P A Ioannidis; André G Uitterlinden Journal: JAMA Date: 2008-03-19 Impact factor: 56.272
Authors: Kelly A Frazer; Dennis G Ballinger; David R Cox; David A Hinds; Laura L Stuve; Richard A Gibbs; John W Belmont; Andrew Boudreau; Paul Hardenbol; Suzanne M Leal; Shiran Pasternak; David A Wheeler; Thomas D Willis; Fuli Yu; Huanming Yang; Changqing Zeng; Yang Gao; Haoran Hu; Weitao Hu; Chaohua Li; Wei Lin; Siqi Liu; Hao Pan; Xiaoli Tang; Jian Wang; Wei Wang; Jun Yu; Bo Zhang; Qingrun Zhang; Hongbin Zhao; Hui Zhao; Jun Zhou; Stacey B Gabriel; Rachel Barry; Brendan Blumenstiel; Amy Camargo; Matthew Defelice; Maura Faggart; Mary Goyette; Supriya Gupta; Jamie Moore; Huy Nguyen; Robert C Onofrio; Melissa Parkin; Jessica Roy; Erich Stahl; Ellen Winchester; Liuda Ziaugra; David Altshuler; Yan Shen; Zhijian Yao; Wei Huang; Xun Chu; Yungang He; Li Jin; Yangfan Liu; Yayun Shen; Weiwei Sun; Haifeng Wang; Yi Wang; Ying Wang; Xiaoyan Xiong; Liang Xu; Mary M Y Waye; Stephen K W Tsui; Hong Xue; J Tze-Fei Wong; Luana M Galver; Jian-Bing Fan; Kevin Gunderson; Sarah S Murray; Arnold R Oliphant; Mark S Chee; Alexandre Montpetit; Fanny Chagnon; Vincent Ferretti; Martin Leboeuf; Jean-François Olivier; Michael S Phillips; Stéphanie Roumy; Clémentine Sallée; Andrei Verner; Thomas J Hudson; Pui-Yan Kwok; Dongmei Cai; Daniel C Koboldt; Raymond D Miller; Ludmila Pawlikowska; Patricia Taillon-Miller; Ming Xiao; Lap-Chee Tsui; William Mak; You Qiang Song; Paul K H Tam; Yusuke Nakamura; Takahisa Kawaguchi; Takuya Kitamoto; Takashi Morizono; Atsushi Nagashima; Yozo Ohnishi; Akihiro Sekine; Toshihiro Tanaka; Tatsuhiko Tsunoda; Panos Deloukas; Christine P Bird; Marcos Delgado; Emmanouil T Dermitzakis; Rhian Gwilliam; Sarah Hunt; Jonathan Morrison; Don Powell; Barbara E Stranger; Pamela Whittaker; David R Bentley; Mark J Daly; Paul I W de Bakker; Jeff Barrett; Yves R Chretien; Julian Maller; Steve McCarroll; Nick Patterson; Itsik Pe'er; Alkes Price; Shaun Purcell; Daniel J Richter; Pardis Sabeti; Richa Saxena; Stephen F Schaffner; Pak C Sham; Patrick Varilly; David Altshuler; Lincoln D Stein; Lalitha Krishnan; Albert Vernon Smith; Marcela K Tello-Ruiz; Gudmundur A Thorisson; Aravinda Chakravarti; Peter E Chen; David J Cutler; Carl S Kashuk; Shin Lin; Gonçalo R Abecasis; Weihua Guan; Yun Li; Heather M Munro; Zhaohui Steve Qin; Daryl J Thomas; Gilean McVean; Adam Auton; Leonardo Bottolo; Niall Cardin; Susana Eyheramendy; Colin Freeman; Jonathan Marchini; Simon Myers; Chris Spencer; Matthew Stephens; Peter Donnelly; Lon R Cardon; Geraldine Clarke; David M Evans; Andrew P Morris; Bruce S Weir; Tatsuhiko Tsunoda; James C Mullikin; Stephen T Sherry; Michael Feolo; Andrew Skol; Houcan Zhang; Changqing Zeng; Hui Zhao; Ichiro Matsuda; Yoshimitsu Fukushima; Darryl R Macer; Eiko Suda; Charles N Rotimi; Clement A Adebamowo; Ike Ajayi; Toyin Aniagwu; Patricia A Marshall; Chibuzor Nkwodimmah; Charmaine D M Royal; Mark F Leppert; Missy Dixon; Andy Peiffer; Renzong Qiu; Alastair Kent; Kazuto Kato; Norio Niikawa; Isaac F Adewole; Bartha M Knoppers; Morris W Foster; Ellen Wright Clayton; Jessica Watkin; Richard A Gibbs; John W Belmont; Donna Muzny; Lynne Nazareth; Erica Sodergren; George M Weinstock; David A Wheeler; Imtaz Yakub; Stacey B Gabriel; Robert C Onofrio; Daniel J Richter; Liuda Ziaugra; Bruce W Birren; Mark J Daly; David Altshuler; Richard K Wilson; Lucinda L Fulton; Jane Rogers; John Burton; Nigel P Carter; Christopher M Clee; Mark Griffiths; Matthew C Jones; Kirsten McLay; Robert W Plumb; Mark T Ross; Sarah K Sims; David L Willey; Zhu Chen; Hua Han; Le Kang; Martin Godbout; John C Wallenburg; Paul L'Archevêque; Guy Bellemare; Koji Saeki; Hongguang Wang; Daochang An; Hongbo Fu; Qing Li; Zhen Wang; Renwu Wang; Arthur L Holden; Lisa D Brooks; Jean E McEwen; Mark S Guyer; Vivian Ota Wang; Jane L Peterson; Michael Shi; Jack Spiegel; Lawrence M Sung; Lynn F Zacharia; Francis S Collins; Karen Kennedy; Ruth Jamieson; John Stewart Journal: Nature Date: 2007-10-18 Impact factor: 49.962
Authors: Albert Hofman; Monique M B Breteler; Cornelia M van Duijn; Gabriel P Krestin; Huibert A Pols; Bruno H Ch Stricker; Henning Tiemeier; André G Uitterlinden; Johannes R Vingerling; Jacqueline C M Witteman Journal: Eur J Epidemiol Date: 2007-10-23 Impact factor: 8.082
Authors: Michael N Weedon; Hana Lango; Cecilia M Lindgren; Chris Wallace; David M Evans; Massimo Mangino; Rachel M Freathy; John R B Perry; Suzanne Stevens; Alistair S Hall; Nilesh J Samani; Beverly Shields; Inga Prokopenko; Martin Farrall; Anna Dominiczak; Toby Johnson; Sven Bergmann; Jacques S Beckmann; Peter Vollenweider; Dawn M Waterworth; Vincent Mooser; Colin N A Palmer; Andrew D Morris; Willem H Ouwehand; Jing Hua Zhao; Shengxu Li; Ruth J F Loos; Inês Barroso; Panagiotis Deloukas; Manjinder S Sandhu; Eleanor Wheeler; Nicole Soranzo; Michael Inouye; Nicholas J Wareham; Mark Caulfield; Patricia B Munroe; Andrew T Hattersley; Mark I McCarthy; Timothy M Frayling Journal: Nat Genet Date: 2008-04-06 Impact factor: 38.330
Authors: I Peter; M D Crosier; M Yoshida; S L Booth; L A Cupples; B Dawson-Hughes; D Karasik; D P Kiel; J M Ordovas; T A Trikalinos Journal: Osteoporos Int Date: 2010-06-09 Impact factor: 4.507
Authors: Jane B Lian; Gary S Stein; Andre J van Wijnen; Janet L Stein; Mohammad Q Hassan; Tripti Gaur; Ying Zhang Journal: Nat Rev Endocrinol Date: 2012-01-31 Impact factor: 43.330
Authors: Nelson B Watts; John P Bilezikian; Pauline M Camacho; Susan L Greenspan; Steven T Harris; Stephen F Hodgson; Michael Kleerekoper; Marjorie M Luckey; Michael R McClung; Rachel Pessah Pollack; Steven M Petak Journal: Endocr Pract Date: 2010 Nov-Dec Impact factor: 3.443
Authors: Niklas R Jørgensen; Lise B Husted; Kristen K Skarratt; Leanne Stokes; Charlotte L Tofteng; Torben Kvist; Jens-Erik B Jensen; Pia Eiken; Kim Brixen; Stephen Fuller; Rory Clifton-Bligh; Alison Gartland; Peter Schwarz; Bente L Langdahl; James S Wiley Journal: Eur J Hum Genet Date: 2012-01-25 Impact factor: 4.246