Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual through variant-to-gene mapping

Bone accrual impacts lifelong skeletal health, but genetic discovery has been hampered by cross-sectional study designs and uncertainty about target effector genes. Here, we captured this dynamic phenotype by modeling longitudinal bone accrual across 11,000 bone scans followed by genome-wide association studies (GWAS). We revealed 40 loci (35 novel), half residing in topological associated domains harboring known bone genes. Several of these loci also associated with fracture risk later in life. Variant-to-gene mapping identified contacts between GWAS loci and nearby gene promoters, and siRNA knockdown of gene expression clarified the putative effector gene at three specific loci in two osteoblast cell models. The resulting target genes highlight the cell fate decision between osteogenic and adipogenic lineages as important in normal bone accrual.