Meng Li 1 , Shi Yao 2 , Yuan-Yuan Duan 2 , Yu-Jie Zhang 2 , Yan Guo 2 , Hui-Min Niu 2 , Shan-Shan Dong 2 , Yu-Sheng Qiu 1 , Tie-Lin Yang 2 Show Affiliations »
Abstract
PURPOSE: Genome-wide association studies (GWASs) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with osteoporosis. Most of these SNPs are noncoding variants and could be mapped to enhancers. Transcription factors (TFs) play important roles in gene regulation via enhancers harboring these SNPs; thus, we aimed to identify common regulatory TFs binding to enhancers associated with osteoporosis. METHODS: We first annotated all the osteoporosis-related SNPs identified by GWASs to enhancers and conducted TF enrichment analyses to identify common TFs binding to osteoporosis-associated enhancers. We further conducted genetic association analyses between the identified TFs and bone mineral density (BMD) in a Han Chinese population. RESULTS: After functional annotation, a total of 5081 osteoporosis-related SNPs were mapped to enhancers. TF enrichment analyses identified 2 significant TFs after multiple testing adjustments, which are EZH2 (Padj = .028) and NRSF (Padj = .038). We also found 1 SNP, rs111851041, in EZH2 was significantly associated with BMD both at the hip and spine after multiple testing adjustments (hip BMD: P = 4.32 × 10-4; spine BMD: P = 2.72 × 10-3). The expression of EZH2 decreased significantly from 12 to 48 hours of osteogenic differentiation. And functional validation showed that EZH2 was associated with osteoporosis-related phenotypes in knockout mice. CONCLUSIONS: By conducting TF enrichment analyses, we identified EZH2 as a common TF binding to osteoporosis-associated enhancers, and EZH2 was also associated with BMD in a Chinese population. EZH2 is functionally related to bone phenotypes. The identified gene could provide new insight into osteoporosis pathophysiology and highlight opportunities for future clinical and pharmacological research on osteoporosis. © Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
PURPOSE: Genome-wide association studies (GWASs) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with osteoporosis . Most of these SNPs are noncoding variants and could be mapped to enhancers. Transcription factors (TFs) play important roles in gene regulation via enhancers harboring these SNPs; thus, we aimed to identify common regulatory TFs binding to enhancers associated with osteoporosis . METHODS: We first annotated all the osteoporosis -related SNPs identified by GWASs to enhancers and conducted TF enrichment analyses to identify common TFs binding to osteoporosis -associated enhancers. We further conducted genetic association analyses between the identified TFs and bone mineral density (BMD) in a Han Chinese population. RESULTS: After functional annotation, a total of 5081 osteoporosis -related SNPs were mapped to enhancers. TF enrichment analyses identified 2 significant TFs after multiple testing adjustments, which are EZH2 (Padj = .028) and NRSF (Padj = .038). We also found 1 SNP, rs111851041 , in EZH2 was significantly associated with BMD both at the hip and spine after multiple testing adjustments (hip BMD: P = 4.32 × 10-4; spine BMD: P = 2.72 × 10-3). The expression of EZH2 decreased significantly from 12 to 48 hours of osteogenic differentiation. And functional validation showed that EZH2 was associated with osteoporosis -related phenotypes in knockout mice . CONCLUSIONS: By conducting TF enrichment analyses, we identified EZH2 as a common TF binding to osteoporosis -associated enhancers, and EZH2 was also associated with BMD in a Chinese population. EZH2 is functionally related to bone phenotypes. The identified gene could provide new insight into osteoporosis pathophysiology and highlight opportunities for future clinical and pharmacological research on osteoporosis . © Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Entities: Disease
Gene
Mutation
Species
Keywords:
EZH2; SNP; enhancer; osteoporosis; transcription factor
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Substances： See more »
Year: 2020
PMID： 31833556 DOI： 10.1210/clinem/dgz270
Source DB: PubMed Journal: J Clin Endocrinol Metab ISSN： 0021-972X Impact factor: 5.958