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Review ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Endocrinol. | doi: 10.3389/fendo.2019.00807

Use of Mendelian Randomization to examine causal inference in osteoporosis

  • 1Population Health Sciences, MRC Integrative Epidemiology Unit, University of Bristol, United Kingdom
  • 2Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, University of Bristol, United Kingdom
  • 3Diamantina Institute, University of Queensland, Australia
  • 4MRC Integrative Epidemiology Unit, University of Bristol, United Kingdom
  • 5Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, University of Bristol, United Kingdom

Epidemiological studies have identified many risk factors for osteoporosis, however it is unclear whether these observational associations reflect true causal effects, or the effects of latent confounding or reverse causality. Mendelian randomization (MR) enables causal relationships to be evaluated, by examining the relationship between genetic susceptibility to the risk factor in question, and the disease outcome of interest. This has been facilitated by the development of two-sample MR analysis, where the exposure and outcome are measured in different studies, and by exploiting summary result statistics from large well-powered genome-wide association studies that are available for thousands of traits. Though MR has several inherent limitations, the field is rapidly evolving and at least 14 methodological extensions have been developed to overcome these. The present paper aims to discuss some of the limitations in the MR analytical framework, and how this method has been applied to the osteoporosis field, helping to reinforce conclusions about causality, and discovering potential new regulatory pathways, exemplified by our recent MR study of sclerostin.

Keywords: Bone Mineral Density (BMD), Fractures - Bone, pleiotropy, Sclerostin, GWAS - genome-wide association study

Received: 26 Jul 2019; Accepted: 04 Nov 2019.

Copyright: © 2019 ZHENG, Frysz, Kemp, Evans, Davey Smith and Tobias. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Jonathan H. Tobias, University of Bristol, Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, Bristol, BS10 5NB, United Kingdom, jon.tobias@bristol.ac.uk