Oral Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

GWAS meta-analysis of bone stiffness indices in 544,864 individuals identifies new candidate genes that may control the structural integrity of bone and susceptibility to fracture. (#136)

Kaitlyn A Flynn 1 , Yu-Ting Yan 2 , Dorothy Hsai 2 , Ryan C Chai 3 , Yuandan Zhang 1 , Shih-Jen Tsai 4 , Fernando Rivadeneira 5 , Carolina Medina-Gomez 5 , Robert D Blank 3 , Graham Williams 6 , Duncan Bassett 6 , Cheryl Ackert-Bicknell 7 , David Evans 8 , Jonathan H Tobias 9 , Peter Croucher 3 , Douglas P Kiel 10 , Loic Yengo 8 , Nicole Warrington 8 , Po-Hsiu Kuo 2 , John Kemp 1
  1. Mater Research, University of Queensland, Brisbane, QLD , Australia
  2. Insititute of Epidemiology and Preventative Medicine, National Taiwan University, Taipei, Taiwan
  3. Bone Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia
  4. Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
  5. Department of Internal Medicine, Erasmus MC, Rotterdam, Netherlands
  6. Molecular Endocrinology Laboratory, Imperial College London, London, England, United Kingdom
  7. Department of Orthopedics, University of Colorado, Aurora, Colorado
  8. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
  9. Muscuoskeletal Research Unit, University of Bristol, Bristol, United Kingdom
  10. Hebrew SeniorLife Marcus Institute for Aging Research, Harvard Medical School, Boston, United States of America

66875e38c0269-Figure+1.F.png

Background

Quantitative ultrasound (QUS) evaluates bone structural integrity by measuring changes in speed and attenuation of sound waves.  These parameters are combined to form indices that predict bone fractures independent of BMD and FRAX. Indices include a “stiffness index’’ (SI) for Lunar devices, and a “quantitative ultrasound index” (QUI) for Hologic systems. SI and QUI are heritable, yet the underlying genetic determinants remain uncharacterised.

Purpose

To quantify the genetic similarity of SI and QUI, identify shared genetic determinants, and evaluate their relationship with fractures.

Methods

Genome-wide association studies (GWAS) were conducted on standardised measures of QUI in the UK-Biobank (N=447,873) and SI in the Taiwan Biobank (N=96,991). Pairwise genetic correlations correcting for genetic ancestry were estimated. QUI and SI GWAS were meta-analysed using a random effects method and clumped with ancestry-matched data. Associated variants were followed-up in GWAS of hip and forearm fractures. The closest protein coding gene to each associated variant was followed up in a single-cell transcriptomics dataset of murine bone and marrow cells, and the MGI mutant mouse database.

Results

QUI and SI were highly genetically correlated rg=0.83(CI95:0.73–0.92). 1,637 associated variants were identified (pmeta<5×10-8). 31 were robustly associated with forearm fractures (p<5×10-8), but not with hip fractures (p>0.05, Figure.1). 58 were located >1mb away from known DXA/QUS GWAS loci and deemed novel. Four novel variants were associated with forearm fractures [RYBP, CACNB2, IGF1 and HMGA1 (p<0.05)], and 2 with hip fractures (DRG1 and HMGA1). Genes closest to novel variants were differentially expressed in osteoblasts (e.g., CDH11), osteoclasts (S100A10), endothelial (FKBP1C) and vascular cells (CRIM1). CRIM1 resulted in abnormal skeletal phenotypes when mutated in mice.

Conclusions

Genetic determinants of QUI and SI are largely shared and highlight that such phenotypes enable the discovery of genes that may control bone structural integrity and fracture susceptibility.