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BibTeX
Prioritization of Genes Relevant to Bone Fragility Through the Unbiased Integration of Aging Mouse Bone Transcriptomics and Human GWAS Analyses
Journal of bone and mineral research, 2022-04, Vol.37 (4), p.804-817
Kaya, Serra
Schurman, Charles A
Dole, Neha S
Evans, Daniel S
Alliston, Tamara
2022
Volltextzugriff (PDF)
Details
Autor(en) / Beteiligte
Kaya, Serra
Schurman, Charles A
Dole, Neha S
Evans, Daniel S
Alliston, Tamara
Titel
Prioritization of Genes Relevant to Bone Fragility Through the Unbiased Integration of Aging Mouse Bone Transcriptomics and Human GWAS Analyses
Ist Teil von
Journal of bone and mineral research, 2022-04, Vol.37 (4), p.804-817
Ort / Verlag
Hoboken, USA: John Wiley & Sons, Inc
Erscheinungsjahr
2022
Quelle
Wiley Online Library Journals Frontfile Complete
Beschreibungen/Notizen
ABSTRACT Identifying new genetic determinants of bone mineral density (BMD) and fracture promises to yield improved diagnostics and therapies for bone fragility. However, prioritizing candidate genes from genome‐wide screens can be challenging. To overcome this challenge, we prioritized mouse genes that are differentially expressed in aging mouse bone based on whether their human homolog is associated with human BMD and/or fracture. Unbiased RNA‐seq analysis of young and old male C57BL/6 mouse cortical bone identified 1499, 1685, and 5525 differentially expressed genes (DEGs) in 1, 2, and 2.5‐year‐old bone, relative to 2‐month‐old bone, respectively. Gene‐based scores for heel ultrasound bone mineral density (eBMD) and fracture were estimated using published genome‐wide association studies (GWAS) results of these traits in the UK Biobank. Enrichment analysis showed that mouse bone DEG sets for all three age groups, relative to young bone, are significantly enriched for eBMD, but only the oldest two DEG sets are enriched for fracture. Using gene‐based scores, this approach prioritizes among thousands of DEGs by a factor of 5‐ to 100‐fold, yielding 10 and 21 genes significantly associated with fracture in the two oldest groups of mouse DEGs. Though these genes were not the most differentially expressed, they included Sost, Lrp5, and others with well‐established functions in bone. Several others have, as yet, unknown roles in the skeleton. Therefore, this study accelerates identification of new genetic determinants of bone fragility by prioritizing a clinically relevant and experimentally tractable number of candidate genes for functional analysis. Finally, we provide a website (www.mouse2human.org) to enable other researchers to easily apply our strategy. © 2022 American Society for Bone and Mineral Research (ASBMR).
Sprache
Englisch
Identifikatoren
ISSN: 0884-0431
eISSN: 1523-4681
DOI: 10.1002/jbmr.4516
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9018503
Format
–
Schlagworte
AGING
,
Aging - genetics
,
Animals
,
Bone density
,
Bone Density - genetics
,
Bone mineral density
,
Cortical bone
,
DISEASES AND DISORDERS OF/RELATED TO BONE
,
EPIDEMIOLOGY
,
Fractures
,
Fractures, Bone - genetics
,
Genes
,
Genetic analysis
,
GENETIC RESEARCH
,
Genome-Wide Association Study
,
Genomes
,
Humans
,
LRP5 protein
,
Male
,
Mice
,
Mice, Inbred C57BL
,
OSTEOCYTES
,
Polymorphism, Single Nucleotide
,
Skeleton
,
SOST protein
,
Transcriptome - genetics
,
Transcriptomics
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