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BMJ. 2018 Aug 29;362:k3225. doi: 10.1136/bmj.k3225.

Assessment of the genetic and clinical determinants of fracture risk: genome wide association and mendelian randomisation study.

Collaborators (189)

Forgett V, Leong A, Ahmad OS, Laurin C, Mokry LE, Ross S, Elks CE, Bowden J, Warrington NM, Kleinman A, Willems SM, Wright D, Day FR, Murray A, Ruth KS, Tsilidis KK, Ackert-Bicknell CL, Bassett JHD, van der Eerden BCJ, Gautvik K, Reppe S, Williams GR, Medina-Gómez C, Estrada K, Amin N, Bis JC, Breda S, Chasman, Demissie S, Enneman AW, Hsu YH, Ingvarsson T, Kähönen M, Kammerer C, Lacroix AZ, Li G, Liu CT, Liu Y, Lorentzon M, Mägi R, Mihailov E, Mlani L, Moayyeri A, Nielson CM, Nerea A, Sham PC, Siggeirsdotir K, Sigurdsson G, Thorsteinsdottir U, Trompet S, Thorleifsson G, Vandenput L, van der Velde N, Viikari J, Xiao SM, Hua Zhao J, Akesson KE, Andersen M, Atanasovska B, Balcells S, Eriksson J, Formosa MM, Garcia-Ibarbia C, Gonzalez-Macias J, Garcia-Giralt N, Hallmans G, Karlsson M, Khusainova R, Kim, Lee SH, Leung PC, Mallmin H, Kwok TCY, Masi L, Melin BS, Mencej-Bedrac S, Nethander M, Olmos JM, Kollia P, Prezelj J, Van Schoor, Svensson O, Szulc P, Valero C, Woo J, Brandi M, Cheng S, Chapurlat R, Christiansen C, Cooper C, Dedoussis G, Eisman JA, Frost M, Giroux, Grinberg D, Goltzman D, Hocking LJ, Van Hul W, Koh JM, Rejnmark L, Jensen JB, Langdahl B, Lewis JR, Lorenc RS, Khusnutdinova E, Marc J, McGuigan FE, Mellström D, Michaelsson K, Nogues X, Nordström P, Obermayer-Pietsch B, Pettersson-Kymmer U, Prince RL, Reeve J, Reid DM, Riancho, Rousseau F, Tang NLS, Xuereb-Anastasi A, Leslie WD, Evans DS, Cummings SR, Cauley J, van Duijn CM, Brown M, Duncan EL, de Groot LC, Esko T, Gudnason V, Harris TB, Jackson RD, Jukema JW, Ikram MA, Karasik D, Kaptoge S, Khaw KT, Kung AW, Lehtimäki T, Lyytikäinen LP, Lips P, Luben R, Metspalu A, van Meurs JBJ, Minster RL, Orwoll E, Oei E, Psaty BM, Raitakari OT, Ralston SH, Ridker PM, Robbins JA, Smith AV, Spector TD, Styrkarsdottir U, Zmuda J, Tranah GJ, Stefansson K, Uitterlinden AG, Zillikens MC, Ntzani EE, Evangelou E, Ioannidis JPA, Perry JRB, Tung JY, Hinds DA, Scott R, Agee M, Alipanahi B, Auton A, Bell RK, Bryc K, Elson SL, Fontanillas P, Furlotte NA, Huber KE, Litterman NK, McIntyre MH, Mountain JL, Noblin ES, Northover CAM, Pitts SJ, Sathirapongsasuti JF, Sazonova OV, Shelton JF, Tian S, Tian C, Vacic V, Wilson. CH.

Author information

Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, Netherlands.
Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, Netherlands.
Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
Department of Human Genetics, McGill University, Montréal, Québec, Canada.
DaP Lab, School of Life Sciences, Westlake University and Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China.
Institute of Aging Research and the Affiliated Hospital, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China.
Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia.
Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, MA, USA.
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Centre for Bone and Arthritis Research, Department of Internal Medicine, Institute of Medicine, Sahlgrenska, Gothenburg, Sweden.
Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, Netherlands



To identify the genetic determinants of fracture risk and assess the role of 15 clinical risk factors on osteoporotic fracture risk.


Meta-analysis of genome wide association studies (GWAS) and a two-sample mendelian randomisation approach.


25 cohorts from Europe, United States, east Asia, and Australia with genome wide genotyping and fracture data.


A discovery set of 37 857 fracture cases and 227 116 controls; with replication in up to 147 200 fracture cases and 150 085 controls. Fracture cases were defined as individuals (>18 years old) who had fractures at any skeletal site confirmed by medical, radiological, or questionnaire reports. Instrumental variable analyses were performed to estimate effects of 15 selected clinical risk factors for fracture in a two-sample mendelian randomisation framework, using the largest previously published GWAS meta-analysis of each risk factor.


Of 15 fracture associated loci identified, all were also associated with bone mineral density and mapped to genes clustering in pathways known to be critical to bone biology (eg, SOST, WNT16, and ESR1) or novel pathways (FAM210A, GRB10, and ETS2). Mendelian randomisation analyses showed a clear effect of bone mineral density on fracture risk. One standard deviation decrease in genetically determined bone mineral density of the femoral neck was associated with a 55% increase in fracture risk (odds ratio 1.55 (95% confidence interval 1.48 to 1.63; P=1.5×10-68). Hand grip strength was inversely associated with fracture risk, but this result was not significant after multiple testing correction. The remaining clinical risk factors (including vitamin D levels) showed no evidence for an effect on fracture.


This large scale GWAS meta-analysis for fracture identified 15 genetic determinants of fracture, all of which also influenced bone mineral density. Among the clinical risk factors for fracture assessed, only bone mineral density showed a major causal effect on fracture. Genetic predisposition to lower levels of vitamin D and estimated calcium intake from dairy sources were not associated with fracture risk.

[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: support from the organisations listed in the funding statement for the submitted work; BMP serves on the data safety monitoring board of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson and Johnson; CEE is currently employed by AstraZeneca; SR has received grants from Eli Lilly, Amgen, UCB, and Ultragenyx, and has provided consultation for Novartis; KE is currently employed by Biogen; US, UT, GT, and KSt are employed by deCODE genetics/Amgen; and AK, JYT, and DAH are employed by 23andMe, and hold stock or stock options in 23andMe.

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