Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual.
Genome Biol
; 22(1): 1, 2021 01 04.
Article
em En
| MEDLINE
| ID: mdl-33397451
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Osso e Ossos
/
Desenvolvimento Ósseo
/
Doenças Ósseas
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Predisposição Genética para Doença
/
Estudo de Associação Genômica Ampla
Tipo de estudo:
Observational_studies
/
Prevalence_studies
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Prognostic_studies
/
Risk_factors_studies
Limite:
Adolescent
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Adult
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Child
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Child, preschool
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Female
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Humans
/
Male
Idioma:
En
Revista:
Genome Biol
Assunto da revista:
BIOLOGIA MOLECULAR
/
GENETICA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos