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Cousminer DL, Wagley Y, Pippin JA, et al. Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual. Genome Biol. 2021;22(1):1doi: 10.1186/s13059-020-02207-9.
Cousminer, D. L., Wagley, Y., Pippin, J. A., Elhakeem, A., Way, G. P., Pahl, M. C., McCormack, S. E., Chesi, A., Mitchell, J. A., Kindler, J. M., Baird, D., Hartley, A., Howe, L., Kalkwarf, H. J., Lappe, J. M., Lu, S., Leonard, M. E., Johnson, M. E., Hakonarson, H., Gilsanz, V., Shepherd, J. A., Oberfield, S. E., Greene, C. S., Kelly, A., Lawlor, D. A., Voight, B. F., Wells, A. D., Zemel, B. S., Hankenson, K. D., & Grant, S. F. A. (2021). Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual. Genome biology, 22(1), 1. https://doi.org/10.1186/s13059-020-02207-9
Cousminer, Diana L, et al. "Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual." Genome biology vol. 22,1 (2021): 1. doi: https://doi.org/10.1186/s13059-020-02207-9
Cousminer DL, Wagley Y, Pippin JA, Elhakeem A, Way GP, Pahl MC, McCormack SE, Chesi A, Mitchell JA, Kindler JM, Baird D, Hartley A, Howe L, Kalkwarf HJ, Lappe JM, Lu S, Leonard ME, Johnson ME, Hakonarson H, Gilsanz V, Shepherd JA, Oberfield SE, Greene CS, Kelly A, Lawlor DA, Voight BF, Wells AD, Zemel BS, Hankenson KD, Grant SFA. Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual. Genome Biol. 2021 Jan 04;22(1):1. doi: 10.1186/s13059-020-02207-9. PMID: 33397451; PMCID: PMC7780623.
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Genome Biol. 2021 Jan 04;22(1):1. doi: 10.1186/s13059-020-02207-9.

Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual.

Genome biology

Diana L Cousminer, Yadav Wagley, James A Pippin, Ahmed Elhakeem, Gregory P Way, Matthew C Pahl, Shana E McCormack, Alessandra Chesi, Jonathan A Mitchell, Joseph M Kindler, Denis Baird, April Hartley, Laura Howe, Heidi J Kalkwarf, Joan M Lappe, Sumei Lu, Michelle E Leonard, Matthew E Johnson, Hakon Hakonarson, Vicente Gilsanz, John A Shepherd, Sharon E Oberfield, Casey S Greene, Andrea Kelly, Deborah A Lawlor, Benjamin F Voight, Andrew D Wells, Babette S Zemel, Kurt D Hankenson, Struan F A Grant

Affiliations

  1. Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. [email protected].
  2. Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
  3. Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. [email protected].
  4. Department of Orthopedic Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
  5. Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  6. MRC Integrative Epidemiology Unit, Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK.
  7. Genomics and Computational Biology Graduate Group, University of Pennsylvania, Philadelphia, PA, USA.
  8. Imaging Platform, Broad Institute of MIT and Harvard, Cambridge, MA, 02140, USA.
  9. Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  10. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  11. Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  12. Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  13. Department of Pediatrics, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH, USA.
  14. Department of Medicine and College of Nursing, Creighton University School of Medicine, Omaha, NB, USA.
  15. Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  16. Division of Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  17. Center for Endocrinology, Diabetes & Metabolism, Children's Hospital Los Angeles, Los Angeles, CA, USA.
  18. Department of Epidemiology and Population Science, University of Hawaii Cancer Center, Honolulu, HI, USA.
  19. Division of Pediatric Endocrinology, Columbia University Medical Center, New York, NY, USA.
  20. Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.
  21. Childhood Cancer Data Lab, Alex's Lemonade Stand Foundation, Philadelphia, PA, USA.
  22. Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
  23. Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  24. Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  25. Department of Orthopedic Surgery, University of Michigan Medical School, Ann Arbor, MI, USA. [email protected].
  26. Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. [email protected].
  27. Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
  28. Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. [email protected].
  29. Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA. [email protected].
  30. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].

PMID: 33397451 PMCID: PMC7780623 DOI: 10.1186/s13059-020-02207-9

Abstract

BACKGROUND: Bone accrual impacts lifelong skeletal health, but genetic discovery has been primarily limited to cross-sectional study designs and hampered by uncertainty about target effector genes. Here, we capture this dynamic phenotype by modeling longitudinal bone accrual across 11,000 bone scans in a cohort of healthy children and adolescents, followed by genome-wide association studies (GWAS) and variant-to-gene mapping with functional follow-up.

RESULTS: We identify 40 loci, 35 not previously reported, with various degrees of supportive evidence, half residing in topological associated domains harboring known bone genes. Of several loci potentially associated with later-life fracture risk, a candidate SNP lookup provides the most compelling evidence for rs11195210 (SMC3). Variant-to-gene mapping combining ATAC-seq to assay open chromatin with high-resolution promoter-focused Capture C identifies contacts between GWAS loci and nearby gene promoters. siRNA knockdown of gene expression supports the putative effector gene at three specific loci in two osteoblast cell models. Finally, using CRISPR-Cas9 genome editing, we confirm that the immediate genomic region harboring the putative causal SNP influences PRPF38A expression, a location which is predicted to coincide with a set of binding sites for relevant transcription factors.

CONCLUSIONS: Using a new longitudinal approach, we expand the number of genetic loci putatively associated with pediatric bone gain. Functional follow-up in appropriate cell models finds novel candidate genes impacting bone accrual. Our data also raise the possibility that the cell fate decision between osteogenic and adipogenic lineages is important in normal bone accrual.

Keywords: Bone development; CRISPR; Chromatin; Gene mapping; Genome-wide association study; Longitudinal analysis; Osteoblasts; Osteogenesis; Skeletal development

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