Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual.
Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual.
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DOI：
10.1186/s13059-020-02207-9
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发表时间：
2021-01-04
期刊：
影响因子：
12.3
通讯作者：
Grant SFA
中科院分区：
文献类型：
--
作者：
Cousminer DL;Wagley Y;Pippin JA;Elhakeem A;Way GP;Pahl MC;McCormack SE;Chesi A;Mitchell JA;Kindler JM;Baird D;Hartley A;Howe L;Kalkwarf HJ;Lappe JM;Lu S;Leonard ME;Johnson ME;Hakonarson H;Gilsanz V;Shepherd JA;Oberfield SE;Greene CS;Kelly A;Lawlor DA;Voight BF;Wells AD;Zemel BS;Hankenson KD;Grant SFA
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.
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影响因子：
7.7
作者：
Cole TJ;Donaldson MD;Ben-Shlomo Y
通讯作者：
Ben-Shlomo Y
影响因子：
12.4
作者：
Chen Q;Shou P;Zheng C;Jiang M;Cao G;Yang Q;Cao J;Xie N;Velletri T;Zhang X;Xu C;Zhang L;Yang H;Hou J;Wang Y;Shi Y
通讯作者：
Shi Y
影响因子：
5
作者：
HAHN, FJ;CHU, WK;CHEUNG, JY
通讯作者：
CHEUNG, JY
影响因子：
11.8
作者：
Bialek, P;Kern, B;Karsenty, G
通讯作者：
Karsenty, G
影响因子：
9.8
作者：
Deardorff, Matthew A.;Kaur, Maninder;Krantz, Ian D.
通讯作者：
Krantz, Ian D.