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Principal Investigator: Charles R Farber
Organization: UNIVERSITY OF VIRGINIA
Fiscal Year: 2024
Award: $773,856
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Project Summary:
Reduced bone strength is a hallmark of many bone disorders, including osteoporosis, a debilitating disease
affecting millions of Americans. The strength of bone is influenced by multiple characteristics of bone including
microarchitecture, biomechanical properties (e.g., stiffness), and bone mineral density (BMD). Genome-wide
association studies (GWASs) have successfully identified over 1100 independent associations for BMD.
However, BMD is the only bone strength trait investigated using large-scale GWASs. This is largely due to the
inability to directly measure bone strength in vivo and quantify other strength-related traits in humans at scale.
The sole focus on BMD has limited the development of a comprehensive understanding of the genetics of
bone strength. Here, we propose to use Diversity Outbred (DO) mice to address this limitation. We will perform
GWAS in ~5792 mice (an ~9-fold increase in our current sample size) to significantly increase our power for
association detection. The following three specific aims will identify novel genes influencing bone strength. In
Aim 1, we will perform GWAS for bone strength and multiple strength-related traits in 5792 DO mice and utilize
an extensive set of transcriptomics data on bone to identify causal genes. In Aim 2, we will use DO bone
strength mapping data to inform human bone mineral density GWAS. In Aim 3, we will validate the role of
multiple candidate genes using in vitro and in vivo approaches. We will begin by investigating the role of eyes
absent homolog 4 (Eya4) in the regulation of bone strength. In this project we will significantly expand a proven
resource to discover new genes impacting bone strength – the most clinically relevant feature of bone, but one
that cannot be studied directly in humans. Our approach will significantly expand gene discovery efforts and
has the potential to identify dozens of new bone strength loci. These efforts will not only increase our
understanding of the biological mechanisms underlying bone strength, but point to new therapeutic targets for
the prevention and treatment of low bone strength and skeletal fragility.
Terms: <Address><Affect><American><Biological><Biology><Biomechanics><Body Tissues><Bone Density><Bone Diseases><Bone Mineral Density><Candidate Disease Gene><Candidate Gene><Cell Line><CellLine><Characteristics><Chromosome 1><Chromosome 10><Chromosome 6><Data><Detection><Development><Disease><Disorder><Eye><Eyeball><FAD-dependent sulfhydryl oxidase><Female><GWA study><GWAS><GeneHomolog><Genes><Genetic><Genetic analyses><Homolog><Homologous Gene><Homologue><Human><In Vitro><KO mice><Knock-out Mice><Knockout Mice><Maps><Measures><Mice><Mice Mammals><Minerals><Modern Man><Molecular><Murine><Mus><Null Mouse><Osteoblasts><Osteoclasts><Osteocytes><Osteoporosis><Persons><Phenotype><Population><Prevention><Property><Public Health><QTL><Quantitative Trait Loci><Regulation><Research Resources><Resources><Role><SOx enzyme><Sample Size><Strains Cell Lines><Surface><Testing><Tissues><Work><biologic><biomechanical><bone><bone cell><bone disorder><bone mass><bone strength><candidate identification><causal allele><causal gene><causal mutation><causal variant><causative mutation><causative variant><clinical relevance><clinically relevant><cohort><cultured cell line><data diversity><density><developmental><discover genes><diverse data><entire genome><full genome><gene discovery><genetic analysis><genetic approach><genetic strategy><genome scale><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genome-wide><genomewide><genomewide association scan><genomewide association studies><genomewide association study><genomic data><genomic data-set><genomic dataset><in vivo><innovate><innovation><innovative><mouse genetics><mouse model><murine model><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><skeletal><social role><sulfhydryl oxidase><sulphydryloxidase><trait><transcriptomics><whole genome><whole genome association analysis><whole genome association studies><whole genome association study>