ArticleGenome biology2021
Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual.
Article in Genome biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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25 citing papers in PubMed, 147 citations in OpenAlex.
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- Leveraging the genetic correlation between traits improves the detection of epistasis in genome-wide association studies.G3 (Bethesda, Md.) · 2023Article
- Polygenic adaptation to overnutrition reveals a role for cholinergic signaling in longevity.bioRxiv : the preprint server for biology · 2023Article
- Variant-to-gene mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as a regulator of sleep.Science advances · 2023Article
- Precision genome editing in the eye.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
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Authors and funding
30 authors at 11 institutions in 2 countries.
Funding
Abstract
backgroundBone 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.
resultsWe 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.
conclusionsUsing 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.
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