Abstract: Objective
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 twosample
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.
Con clusions
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.
Fuente: BMJ. 2018 Aug 29;362:k3225
Editorial: BMJ Publishing Group
Fecha de publicación: 01/08/2018
Nº de páginas: 14
Tipo de publicación: Artículo de Revista
DOI: 10.1136/bmj.k3225
ISSN: 0959-8138,1756-1833
Proyecto español: SAF2014-56562-R
Url de la publicación: http://dx.doi.org/10.1136/bmj.k3225