Final Report Summary - GWAS FOR FRACTURES (Genome-Wide Search for Pleiotropic Genes Governing Vertebral Fractures)
SUMMARY. Vertebral fractures are the most common osteoporotic fractures, with a prevalence of 30%-50% in people over age 50; these fractures are accompanied by severe consequences in terms of morbidity and quality of life. A large amount of vertebral fractures are asymptomatic and as such are largely under-diagnosed, while it is known that having one vertebral fracture also significantly increases the risk of experiencing subsequent osteoporotic fractures, not only vertebral fracture. The socio-economic impact of vertebral fractures is therefore high, especially as the European population ages. Despite the enormous personal and public health impact of fractures, the underlying biologic mechanisms remain largely unknown, and treatment options are overwhelmingly bone-centric.
The aim of the project “GWAS for Fractures” is to address the problem of vertebral fracture etiology by utilizing the strength of recently-developed multivariate genome-wide association studies (GWAS) and advanced molecular technologies. An additional objective within the promise of advanced genomic research is the establishment of a laboratory to produce the functional follow-up necessary for confirming and validating results of the statistical genetic discovery.
The ultimate goal of genetic discovery is to define the molecular mechanisms that underlie the genotype-phenotype association, and to determine the potential for additional ways to treat disease (i.e. identify drug targets). This research leverages the synergy of genomics, bioinformatics, and experimentation to provide advances in the study of genetic contributions to vertebral fracture and its proxy phenotypes. Using techniques of the genetic epidemiology applied to other aging-related diseases, we discovered multiple chromosomal loci associated with osteoporotic fracture, as well as shared with bone density and bone geometry. This project provides a list of replicated potentially-pleiotropic loci with evidence of functional significance for bone, muscle, or both tissues. Our continuing studies will have the chance to bring genetics into practical use in medicine for osteoporotic fractures, by making possible new treatment options for both skeletal and muscle components of the vertebral fracture.
Scientist’s integration: This grant made a significant impact on the fellow’s prospects to receive full tenure and subsequently a position as Full Professor (application for promotion is imminent).
***
We estimated heritability of prevalent vertebral fracture in three generations of the Framingham Study (Liu et al. J Bone Mineral Res 2012) and estimated Genetic Correlations with Other Spine Traits, including CT-derived muscle size and density (Yau et al. J Bone Mineral Res 2016).
Several genome-wide association studies (GWAS) of vertebral fractures (VertFrx) and associated phenotypes were performed as proposed, some of them published: for vertebral fractures (Oei et al. 2014a); all-type osteoporotic Frx (Oei et al. 2014b); lean (muscle) mass (Kiel et al. 2013), and vertebral trabecular BMD (Nielson et al. 2016). Most of this research was performed in the framework of large European consortium (GEFOS).
Results of GWAS of the above phenotypes are uploaded to the consortium webpage (http://www.gefos.org/) and our user-friendly web repository and browser, which we have established for the scientific community’s use (named “GWAS Resource for Age-related Traits”, GREAT). The GREAT database is freely available at https://ifar-great.hsl.harvard.edu/.
We also followed one gene (METTL21C), potentially pleiotropic for osteoporosis and sarcopenia, as identified by multi-trait GWAS of bone and muscle traits (Huang et al. 2014), with experiments in bone and muscle primary cells and cell lines. In addition to in-vitro experiments (cell lines), we created a zebrafish (D. Rerio) mutation model of LRP5 knockout, and characterized its bone acquisition (Shochat et al. Bone Abstracts 2016). LRP5 is a well-established gene in the pathway to fracture; it might also contribute to mechanosensitivity of the bone.
Our findings regarding the long-term consequence of early life adversity (Raygorodskaya et al. Bone 2016) may shed light on the embryonic nature of age-related bone pathology. This in turn informed our interest in functional studies using zebrafish, a central model for vertebrate development and organogenesis.
The aim of the project “GWAS for Fractures” is to address the problem of vertebral fracture etiology by utilizing the strength of recently-developed multivariate genome-wide association studies (GWAS) and advanced molecular technologies. An additional objective within the promise of advanced genomic research is the establishment of a laboratory to produce the functional follow-up necessary for confirming and validating results of the statistical genetic discovery.
The ultimate goal of genetic discovery is to define the molecular mechanisms that underlie the genotype-phenotype association, and to determine the potential for additional ways to treat disease (i.e. identify drug targets). This research leverages the synergy of genomics, bioinformatics, and experimentation to provide advances in the study of genetic contributions to vertebral fracture and its proxy phenotypes. Using techniques of the genetic epidemiology applied to other aging-related diseases, we discovered multiple chromosomal loci associated with osteoporotic fracture, as well as shared with bone density and bone geometry. This project provides a list of replicated potentially-pleiotropic loci with evidence of functional significance for bone, muscle, or both tissues. Our continuing studies will have the chance to bring genetics into practical use in medicine for osteoporotic fractures, by making possible new treatment options for both skeletal and muscle components of the vertebral fracture.
Scientist’s integration: This grant made a significant impact on the fellow’s prospects to receive full tenure and subsequently a position as Full Professor (application for promotion is imminent).
***
We estimated heritability of prevalent vertebral fracture in three generations of the Framingham Study (Liu et al. J Bone Mineral Res 2012) and estimated Genetic Correlations with Other Spine Traits, including CT-derived muscle size and density (Yau et al. J Bone Mineral Res 2016).
Several genome-wide association studies (GWAS) of vertebral fractures (VertFrx) and associated phenotypes were performed as proposed, some of them published: for vertebral fractures (Oei et al. 2014a); all-type osteoporotic Frx (Oei et al. 2014b); lean (muscle) mass (Kiel et al. 2013), and vertebral trabecular BMD (Nielson et al. 2016). Most of this research was performed in the framework of large European consortium (GEFOS).
Results of GWAS of the above phenotypes are uploaded to the consortium webpage (http://www.gefos.org/) and our user-friendly web repository and browser, which we have established for the scientific community’s use (named “GWAS Resource for Age-related Traits”, GREAT). The GREAT database is freely available at https://ifar-great.hsl.harvard.edu/.
We also followed one gene (METTL21C), potentially pleiotropic for osteoporosis and sarcopenia, as identified by multi-trait GWAS of bone and muscle traits (Huang et al. 2014), with experiments in bone and muscle primary cells and cell lines. In addition to in-vitro experiments (cell lines), we created a zebrafish (D. Rerio) mutation model of LRP5 knockout, and characterized its bone acquisition (Shochat et al. Bone Abstracts 2016). LRP5 is a well-established gene in the pathway to fracture; it might also contribute to mechanosensitivity of the bone.
Our findings regarding the long-term consequence of early life adversity (Raygorodskaya et al. Bone 2016) may shed light on the embryonic nature of age-related bone pathology. This in turn informed our interest in functional studies using zebrafish, a central model for vertebrate development and organogenesis.