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

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

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

5 Citations (Scopus)
29 Downloads (Pure)


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.

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.

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.
Original languageEnglish
Article number1
Number of pages32
JournalGenome Biology
Issue number1
Publication statusPublished - 4 Jan 2021


  • Genome-wide association study
  • Osteoblasts
  • Osteogenesis
  • Gene mapping
  • Chromatin
  • Longitudinal analysis
  • Skeletal development
  • Bone development


Dive into the research topics of 'Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual'. Together they form a unique fingerprint.

Cite this