Prioritization of genes relevant to bone fragility through the unbiased integration of aging mouse bone transcriptomics and human GWAS analyses

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Kaya, Serra¹; Schurman, Charles A.^1,2; Dole, Neha S.¹; Evans, Daniel S.³; Alliston, Tamara^1,2

Prioritization of genes relevant to bone fragility through the unbiased integration of aging mouse bone transcriptomics and human GWAS analyses

J Bone Miner Res. April 2022;37(4):804-817

©2022 American Society for Bone and Mineral Research (ASBMR)

Affiliations

¹Department of Orthopaedic Surgery, University of California, San Francisco, CA, USA

²UC Berkeley-UCSF Graduate Program in Bioengineering, San Francisco, CA, USA

³California Pacific Medical Center Research Institute, San Francisco, CA, USA
Abstract and keywords

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.

Keywords: AGING; GENETIC RESEARCH; EPIDEMIOLOGY; DISEASES AND DISORDERS OF/RELATED TO BONE; OSTEOCYTES
Links

DOI: 10.1002/jbmr.4516

PubMed: 35094432

WoS: 000761963300001
History

Received: 2021-02-06

Revised: 2021-12-20

Accepted: 2022-01-17

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Cited By (1)

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2023	Bergen DJM, Maurizi A, Formosa MM, McDonald GLK, El-Gazzar A, Hassan N, Brandi M-L, Riancho JA, Rivadeneira F, Ntzani E, Duncan EL, Gregson CL, Kiel DP, Zillikens MC, Sangiorgi L, Högler W, Duran I, Mäkitie O, Van Hul W, Hendrickx G. High bone mass disorders: new insights from connecting the clinic and the bench. J Bone Miner Res. February 2023;38(2):229-247.