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

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...

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Autores principales: Trajanoska, Katerina, Morris, John A, Oei, Ling, Zheng, Hou-Feng, Evans, David M, Kiel, Douglas P, Ohlsson, Claes, Richards, J Brent, Rivadeneira, Fernando
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group Ltd. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113773/
https://www.ncbi.nlm.nih.gov/pubmed/30158200
http://dx.doi.org/10.1136/bmj.k3225
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author Trajanoska, Katerina
Morris, John A
Oei, Ling
Zheng, Hou-Feng
Evans, David M
Kiel, Douglas P
Ohlsson, Claes
Richards, J Brent
Rivadeneira, Fernando
author_facet Trajanoska, Katerina
Morris, John A
Oei, Ling
Zheng, Hou-Feng
Evans, David M
Kiel, Douglas P
Ohlsson, Claes
Richards, J Brent
Rivadeneira, Fernando
author_sort Trajanoska, Katerina
collection PubMed
description 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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spelling pubmed-61137732018-08-30 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 Brent Rivadeneira, Fernando BMJ Research 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. BMJ Publishing Group Ltd. 2018-08-29 /pmc/articles/PMC6113773/ /pubmed/30158200 http://dx.doi.org/10.1136/bmj.k3225 Text en Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research
Trajanoska, Katerina
Morris, John A
Oei, Ling
Zheng, Hou-Feng
Evans, David M
Kiel, Douglas P
Ohlsson, Claes
Richards, J Brent
Rivadeneira, Fernando
Assessment of the genetic and clinical determinants of fracture risk: genome wide association and mendelian randomisation study
title Assessment of the genetic and clinical determinants of fracture risk: genome wide association and mendelian randomisation study
title_full Assessment of the genetic and clinical determinants of fracture risk: genome wide association and mendelian randomisation study
title_fullStr Assessment of the genetic and clinical determinants of fracture risk: genome wide association and mendelian randomisation study
title_full_unstemmed Assessment of the genetic and clinical determinants of fracture risk: genome wide association and mendelian randomisation study
title_short Assessment of the genetic and clinical determinants of fracture risk: genome wide association and mendelian randomisation study
title_sort assessment of the genetic and clinical determinants of fracture risk: genome wide association and mendelian randomisation study
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113773/
https://www.ncbi.nlm.nih.gov/pubmed/30158200
http://dx.doi.org/10.1136/bmj.k3225
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