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

GEFOS/GENOMOS consortium and the 23andMe research team

doi:10.1136/bmj.k3225

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

GEFOS/GENOMOS consortium and the 23andMe research team

Research output: Contribution to journal › Article › peer-review

176 Scopus citations

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.

Original language	English (US)
Article number	k3225
Journal	The BMJ
Volume	362
DOIs	https://doi.org/10.1136/bmj.k3225
State	Published - 2018

ASJC Scopus subject areas

General Medicine

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10.1136/bmj.k3225

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@article{c1b276950ae74e61a192bb39ddfe7c04,

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 = "{GEFOS/GENOMOS consortium and the 23andMe research team} and 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 Richards, {J. Brent} and Fernando Rivadeneira and V. Forgett and A. Leong and Ahmad, {O. S.} and C. Laurin and Mokry, {L. E.} and S. Ross and Elks, {C. E.} and J. Bowden and Warrington, {N. M.} and A. Kleinman and Willems, {S. M.} and D. Wright and Day, {F. R.} and A. Murray and Ruth, {K. S.} and Tsilidis, {K. K.} and Ackert-Bicknell, {C. L.} and Bassett, {J. H.D.} and {van der Eerden}, {B. C.J.} and K. Gautvik and S. Reppe and Williams, {G. R.} and C. Medina-G{\'o}mez and K. Estrada and N. Amin and Bis, {J. C.} and S. Breda and Chasman and S. Demissie and Enneman, {A. W.} and Hsu, {Y. H.} and T. Ingvarsson and M. K{\"a}h{\"o}nen and C. Kammerer and Lacroix, {A. Z.} and G. Li and Liu, {C. T.} and Y. Liu and M. Lorentzon and Nielson, {C. M.} and E. Orwoll",

note = "Publisher Copyright: {\textcopyright} Published by the BMJ Publishing Group Limited.",

year = "2018",

doi = "10.1136/bmj.k3225",

language = "English (US)",

volume = "362",

journal = "The BMJ",

issn = "0959-8146",

publisher = "BMJ Publishing Group",

}

TY - JOUR

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

T2 - Genome wide association and mendelian randomisation study

AU - GEFOS/GENOMOS consortium and the 23andMe research team

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. Brent

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 - Bis, J. C.

AU - Breda, S.

AU - Chasman,

AU - Demissie, S.

AU - Enneman, A. W.

AU - Hsu, Y. H.

AU - Ingvarsson, T.

AU - Kähönen, M.

AU - Kammerer, C.

AU - Lacroix, A. Z.

AU - Li, G.

AU - Liu, C. T.

AU - Liu, Y.

AU - Lorentzon, M.

AU - Nielson, C. M.

AU - Orwoll, E.

PY - 2018

Y1 - 2018

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.

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U2 - 10.1136/bmj.k3225

DO - 10.1136/bmj.k3225

M3 - Article

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AN - SCOPUS:85052645025

SN - 0959-8146

VL - 362

JO - The BMJ

JF - The BMJ

M1 - k3225

ER -

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

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