Oral Presentation 33rd ASM of the Australian & New Zealand Bone & Mineral Society 2023

Co-localisation between genome-wide association and gene expression data identifies ATP6V1A as a potential regulator of bone mineral density that acts through osteoclasts (#3)

Benjamin H Mullin 1 2 , Monika Frysz 3 , Tianyuan Lu 4 , Haojie Lu 5 , Ryan C Chai 6 7 , Kun (Kathy) Zhu 1 8 , Michael J Rogers 9 , Peter I Croucher 6 7 , David Karasik 10 , J Brent Richards 4 11 , Claes Ohlsson 12 , Jonathan H Tobias 3 13 , Fernando Rivadeneira 5 , Douglas P Kiel 14 , John P Walsh 1 8 , Scott G Wilson 1 2 11 , Carolina Medina-Gomez 5 , John P Kemp 13 15 16
  1. Dept. of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
  2. School of Biomedical Sciences, University of Western Australia, Crawley, WA, Australia
  3. Musculoskeletal Research Unit, Bristol Medical School, University of Bristol, Bristol, UK
  4. Lady Davis Institute, Jewish General Hospital, Montreal, Canada
  5. Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
  6. Bone Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia
  7. St. Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia
  8. Medical School, University of Western Australia, Crawley, WA, Australia
  9. Skeletal Diseases Program, Garvan Institute of Medical Research, Sydney, NSW, Australia
  10. Hebrew SeniorLife, Marcus Institute for Aging Research, Roslindale, MA, USA
  11. Department of Twin Research & Genetic Epidemiology, King's College London, London, UK
  12. Sahlgrenska Osteoporosis Centre, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
  13. MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK
  14. Harvard Medical School, Boston, MA, USA
  15. Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia
  16. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia

Background: Whole-body bone mineral density (WB-BMD) is used to assess peak bone mass acquisition and bone health. It is highly heritable, with >50% of BMD variance accounted for by genetic factors. More than 80 genomic regions (loci) in the human genome have been associated with WB-BMD variation, and >500 with ultrasound-derived heel eBMD. However, underlying cell types and effector genes that regulate these loci remain largely unknown.

Aims: To conduct the largest genome-wide association study (GWAS) meta-analysis for WB-BMD and integrate the results with gene expression data from bone cells to identify genes and cellular mechanisms that regulate BMD.

Methods: GWAS meta-analysis included 11 cohorts and 107,000 individuals. WB-BMD associated loci were identified using GCTA-Cojo and deemed novel if located >1Mb from any known BMD-associated locus. Co-localisation analyses incorporating eQTL data from human osteoclast-like cells were used to screen WB-BMD loci and identify candidate effector genes. Effector genes were followed up in a single-cell RNA expression dataset encompassing 34 bone/marrow cell-types isolated from mice, as well the MGI mouse mutant database.

Results: 196 association signals for WB-BMD (P<5×10-8) were detected and 9 were novel. Co-localisation highlighted several potential effector genes acting through osteoclasts, including the V-ATPase proton pump subunit gene ATP6V1A (Fig.1A). The G-allele at the lead GWAS variant (rs2305545, MAF=0.35), was associated with increased WB-BMD and reduced ATP6V1A expression (Fig.1B). Differential gene expression analysis demonstrated up-regulation of ATP6V1A during differentiation of human osteoclast-like cells (P<0.0001, Fig.1C). Single-cell RNA-seq revealed that Atp6v1a is highly expressed in mouse osteoclasts relative to other cells (Fig.1D). Mice lacking Atp6v1a present with increased bone mineral content.

Conclusion: GWAS of WB-BMD identified 9 loci that have not been identified by much larger GWAS of ultrasound-derived heel eBMD. Co-localisation analysis implicated ATP6V1A as a potential effector gene that may act through osteoclasts to regulate BMD.

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