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Meta-Analysis
. 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

Katerina Trajanoska  1   2 , John A Morris  3   4 , Ling Oei  1   2 , Hou-Feng Zheng  5   6 , David M Evans  7   8 , Douglas P Kiel  9   10 , Claes Ohlsson  11 , J Brent Richards  12   4 , Fernando Rivadeneira  13   2 ; GEFOS/GENOMOS consortium and the 23andMe research team
Collaborators, Affiliations
Meta-Analysis

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

Katerina Trajanoska et al. BMJ. .

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.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf 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.

Figures

Fig 1
Fig 1
Mendelian randomisation study design
Fig 2
Fig 2
Manhattan plot of –log10 association P values for discovery meta-analysis, and quantile-quantile plot (QQ plot) of the distribution of observed −log10 association P values against the expected null distribution for discovery meta-analysis. Dashed horizontal red line=genome wide significant (GWS) threshold (P<5×10−8); blue dots=SNPs at GWS loci that are within 500kb of leading SNPs in previous genome wide association studies with different bone traits. Green lines and triangles=combined −log10 association P values after replication in the 23andMe cohort
Fig 3
Fig 3
Forest plot showing effect of 15 genetically determined risk factors on fracture risk. Power=statistical power to detect an odds ratio of 1.15 at α≤3.3×10−3; NA=not applicable; BMD=bone mineral density.
See this image and copyright information in PMC

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