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

Katerina Trajanoska, John A. Morris, Ling Oei, Hou Feng Zheng, David M. Evans, Douglas P. Kiel, Claes Ohlsson, J.B. Richards, Fernando Rivadeneira, V. Forgett, A. Leong, O.S. Ahmad, C. Laurin, L.E. Mokry, S. Ross, C.E. Elks, J. Bowden, N.M. Warrington, A. Kleinman, S.M. Willems & 30 others D. Wright, F.R. Day, A. Murray, K.S. Ruth, K.K. Tsilidis, C.L. Ackert-Bicknell, J.H.D. Bassett, B.C.J. van der Eerden, K. Gautvik, S. Reppe, G.R. Williams, C. Medina-Gómez, K. Estrada, N. Amin, A.W. Enneman, G. Li, C.T. Liu, Y. Liu, S.M. Xiao, S.H. Lee, J.M. Koh, N.L.S. Tang, S.R. Cummings, M. Brown, L. de Groot, J.W. Jukema, P. Lips, J.B.J. van Meurs, A.V. Smith, S. Tian

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Abstract

Objectives To identify the genetic determinants of fracture risk and assess the role of 15 clinical risk factors on osteoporotic fracture risk. Design Meta-analysis of genome wide association studies (GWAS) and a two-sample mendelian randomisation approach. Setting 25 cohorts from Europe, United States, east Asia, and Australia with genome wide genotyping and fracture data. Participants 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. Results 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. Conclusions 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.

LanguageEnglish
Article numberk3225
JournalBMJ (Online)
Volume362
DOIs
Publication statusPublished - Aug 2018

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Random Allocation
Bone Density
Genome
Genome-Wide Association Study
Meta-Analysis
Hand Strength
Vitamin D
Mendelian Randomization Analysis
Odds Ratio
Osteoporotic Fractures
Far East
Femur Neck
Genetic Predisposition to Disease
Cluster Analysis
Confidence Intervals
Calcium
Bone and Bones
Genes

Cite this

Trajanoska, K., Morris, J. A., Oei, L., Zheng, H. F., Evans, D. M., Kiel, D. P., ... Tian, S. (2018). Assessment of the genetic and clinical determinants of fracture risk: Genome wide association and mendelian randomisation study. BMJ (Online), 362, [k3225]. https://doi.org/10.1136/bmj.k3225
Trajanoska, Katerina ; Morris, John A. ; Oei, Ling ; Zheng, Hou Feng ; Evans, David M. ; Kiel, Douglas P. ; Ohlsson, Claes ; Richards, J.B. ; Rivadeneira, Fernando ; Forgett, V. ; Leong, A. ; Ahmad, O.S. ; Laurin, C. ; Mokry, L.E. ; Ross, S. ; Elks, C.E. ; Bowden, J. ; Warrington, N.M. ; Kleinman, A. ; Willems, S.M. ; Wright, D. ; Day, F.R. ; Murray, A. ; Ruth, K.S. ; Tsilidis, K.K. ; Ackert-Bicknell, C.L. ; Bassett, J.H.D. ; van der Eerden, B.C.J. ; Gautvik, K. ; Reppe, S. ; Williams, G.R. ; Medina-Gómez, C. ; Estrada, K. ; Amin, N. ; Enneman, A.W. ; Li, G. ; Liu, C.T. ; Liu, Y. ; Xiao, S.M. ; Lee, S.H. ; Koh, J.M. ; Tang, N.L.S. ; Cummings, S.R. ; Brown, M. ; de Groot, L. ; Jukema, J.W. ; Lips, P. ; van Meurs, J.B.J. ; Smith, A.V. ; Tian, S. / Assessment of the genetic and clinical determinants of fracture risk : Genome wide association and mendelian randomisation study. In: BMJ (Online). 2018 ; Vol. 362.
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title = "Assessment of the genetic and clinical determinants of fracture risk: Genome wide association and mendelian randomisation study",
abstract = "Objectives To identify the genetic determinants of fracture risk and assess the role of 15 clinical risk factors on osteoporotic fracture risk. Design Meta-analysis of genome wide association studies (GWAS) and a two-sample mendelian randomisation approach. Setting 25 cohorts from Europe, United States, east Asia, and Australia with genome wide genotyping and fracture data. Participants 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. Results 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. Conclusions 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.",
author = "Katerina Trajanoska and Morris, {John A.} and Ling Oei and Zheng, {Hou Feng} and Evans, {David M.} and Kiel, {Douglas P.} and Claes Ohlsson and J.B. Richards and Fernando Rivadeneira and V. Forgett and A. Leong and O.S. Ahmad and C. Laurin and L.E. Mokry and S. Ross and C.E. Elks and J. Bowden and N.M. Warrington and A. Kleinman and S.M. Willems and D. Wright and F.R. Day and A. Murray and K.S. Ruth and K.K. Tsilidis and C.L. Ackert-Bicknell and J.H.D. Bassett and {van der Eerden}, B.C.J. and K. Gautvik and S. Reppe and G.R. Williams and C. Medina-G{\'o}mez and K. Estrada and N. Amin and A.W. Enneman and G. Li and C.T. Liu and Y. Liu and S.M. Xiao and S.H. Lee and J.M. Koh and N.L.S. Tang and S.R. Cummings and M. Brown and {de Groot}, L. and J.W. Jukema and P. Lips and {van Meurs}, J.B.J. and A.V. Smith and S. Tian",
year = "2018",
month = "8",
doi = "10.1136/bmj.k3225",
language = "English",
volume = "362",
journal = "BMJ: British Medical Journal",
issn = "0959-8138",
publisher = "British Medical Association",

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Trajanoska, K, Morris, JA, Oei, L, Zheng, HF, Evans, DM, Kiel, DP, Ohlsson, C, Richards, JB, Rivadeneira, F, 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, Enneman, AW, Li, G, Liu, CT, Liu, Y, Xiao, SM, Lee, SH, Koh, JM, Tang, NLS, Cummings, SR, Brown, M, de Groot, L, Jukema, JW, Lips, P, van Meurs, JBJ, Smith, AV & Tian, S 2018, 'Assessment of the genetic and clinical determinants of fracture risk: Genome wide association and mendelian randomisation study', BMJ (Online), vol. 362, k3225. https://doi.org/10.1136/bmj.k3225

Assessment of the genetic and clinical determinants of fracture risk : Genome wide association and mendelian randomisation study. / Trajanoska, Katerina; Morris, John A.; Oei, Ling; Zheng, Hou Feng; Evans, David M.; Kiel, Douglas P.; Ohlsson, Claes; Richards, J.B.; Rivadeneira, Fernando; Forgett, V.; Leong, A.; Ahmad, O.S.; Laurin, C.; Mokry, L.E.; Ross, S.; Elks, C.E.; Bowden, J.; Warrington, N.M.; Kleinman, A.; Willems, S.M.; Wright, D.; Day, F.R.; Murray, A.; Ruth, K.S.; Tsilidis, K.K.; Ackert-Bicknell, C.L.; Bassett, J.H.D.; van der Eerden, B.C.J.; Gautvik, K.; Reppe, S.; Williams, G.R.; Medina-Gómez, C.; Estrada, K.; Amin, N.; Enneman, A.W.; Li, G.; Liu, C.T.; Liu, Y.; Xiao, S.M.; Lee, S.H.; Koh, J.M.; Tang, N.L.S.; Cummings, S.R.; Brown, M.; de Groot, L.; Jukema, J.W.; Lips, P.; van Meurs, J.B.J.; Smith, A.V.; Tian, S.

In: BMJ (Online), Vol. 362, k3225, 08.2018.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Assessment of the genetic and clinical determinants of fracture risk

T2 - BMJ: British Medical Journal

AU - Trajanoska, Katerina

AU - Morris, John A.

AU - Oei, Ling

AU - Zheng, Hou Feng

AU - Evans, David M.

AU - Kiel, Douglas P.

AU - Ohlsson, Claes

AU - Richards, J.B.

AU - Rivadeneira, Fernando

AU - Forgett, V.

AU - Leong, A.

AU - Ahmad, O.S.

AU - Laurin, C.

AU - Mokry, L.E.

AU - Ross, S.

AU - Elks, C.E.

AU - Bowden, J.

AU - Warrington, N.M.

AU - Kleinman, A.

AU - Willems, S.M.

AU - Wright, D.

AU - Day, F.R.

AU - Murray, A.

AU - Ruth, K.S.

AU - Tsilidis, K.K.

AU - Ackert-Bicknell, C.L.

AU - Bassett, J.H.D.

AU - van der Eerden, B.C.J.

AU - Gautvik, K.

AU - Reppe, S.

AU - Williams, G.R.

AU - Medina-Gómez, C.

AU - Estrada, K.

AU - Amin, N.

AU - Enneman, A.W.

AU - Li, G.

AU - Liu, C.T.

AU - Liu, Y.

AU - Xiao, S.M.

AU - Lee, S.H.

AU - Koh, J.M.

AU - Tang, N.L.S.

AU - Cummings, S.R.

AU - Brown, M.

AU - de Groot, L.

AU - Jukema, J.W.

AU - Lips, P.

AU - van Meurs, J.B.J.

AU - Smith, A.V.

AU - Tian, S.

PY - 2018/8

Y1 - 2018/8

N2 - Objectives To identify the genetic determinants of fracture risk and assess the role of 15 clinical risk factors on osteoporotic fracture risk. Design Meta-analysis of genome wide association studies (GWAS) and a two-sample mendelian randomisation approach. Setting 25 cohorts from Europe, United States, east Asia, and Australia with genome wide genotyping and fracture data. Participants 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. Results 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. Conclusions 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.

AB - Objectives To identify the genetic determinants of fracture risk and assess the role of 15 clinical risk factors on osteoporotic fracture risk. Design Meta-analysis of genome wide association studies (GWAS) and a two-sample mendelian randomisation approach. Setting 25 cohorts from Europe, United States, east Asia, and Australia with genome wide genotyping and fracture data. Participants 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. Results 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. Conclusions 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.

U2 - 10.1136/bmj.k3225

DO - 10.1136/bmj.k3225

M3 - Article

VL - 362

JO - BMJ: British Medical Journal

JF - BMJ: British Medical Journal

SN - 0959-8138

M1 - k3225

ER -