Risk of wrist fracture in women is heritable and is influenced by genes that are largely independent of those influencing BMD

Abstract

Using a classical twin design study, we estimated the genetic contribution to liability of wrist fracture in women to be statistically and clinically significant. BMD is highly heritable, but statistical models showed very little overlap of shared genes between the two traits.

Introduction: Studies have observed contradictory evidence for genetic effects influencing the outcome of osteoporotic fracture, in part because of the methodological problems involved in analyzing age-related "censored" outcomes. Although a shared genetic etiology is often assumed between fracture and low BMD, this has not been shown to be the case.

Materials and methods: In a study of 6570 white healthy female volunteer twins between 18 and 80 years of age, we identified and validated 220 nontraumatic wrist fracture cases. From this we estimated the population prevalence, case-wise twin concordance, heritability in liability to wrist fracture (WF), and the genetic contribution to WFs controlling for age by analyzing the survival outcome using generalized linear mixed models implemented in Winbugs software. We included forearm BMD as a co-variate in some of the models to test whether there is a shared genetic etiology between WFs and BMD.

Results: The prevalence of WFs in women was estimated to be 3.3% with a case-wise concordance in monozygotic twins of 0.28 and 0.11 in dizygotic twins. The additive polygenic heritability in liability was approximately 54%, and a significant genetic etiology was confirmed by analyzing WFs as a survival outcome. The magnitude of the genetic influence on risk of WFs reduced very little when BMD was included as a co-variate in the survival analysis model.

Conclusions: There is an important genetic contribution to the risk of WFs, but for the most part, these genes are unlikely to play a direct etiological role in the development of low BMD. If these results are confirmed for other sites, fracture and low BMD will have their own specific genetic risk factors that are unlikely to be shared between the two traits. This has important clinical and research implications.