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

Abstract

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.

Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant complex traits

“…Recently, we combined a suite of techniques to systematically evaluate GWAS signals located in distal elements [19][20][21][22] . Together, our integrated "variant-to-gene mapping" approach aims to physically fine-map significant GWAS loci by identifying open proxy SNPs in LD with each given sentinel signal that directly contact a gene promoter.…”

Opportunities and Challenges in Functional Genomics Research in Osteoporosis: Report From a Workshop Held by the Causes Working Group of the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society on October 5th 2020

“…That said, only relatively small GWAS datasets are available relating to endophenotypes obtained using methods such as HR-pQCT, which are helpful in determining the mechanisms by which genetic pathways influence overall bone strength as reflected by BMD/eBMD. In addition, genetic studies in osteoporosis have largely been confined to cross sectional analyses, with only limited studies examining associations with longitudinal changes, exemplified by a previous look up of adult GWAS hits in BMD acquisition in adolescents ( 83 ), and a recent GWAS of pediatric bone accrual ( 84 ).…”

The Polygenic and Monogenic Basis of Paediatric Fractures

“…In 2009, a BMD GWAS combined samples of children and adults to identify SP7, encoding Osterix, an osteoblast transcription factor [24]. Since then, several studies have provided evidence that genetic factors account for a substantial proportion of the variance in paediatric BMD [17,[25][26][27][28][29][30][31][32]. To date, the largest GWAS meta-analysis of paediatric BMD com-prised~11800 children aged 3-15 years and identified 8 different loci associated with TB BMD (i.e.…”