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DOI | 10.1038/s41467-017-00292-2 |
Functional testing of thousands of osteoarthritis-associated variants for regulatory activity | |
Klein, Jason C.1; Keith, Aidan1; Rice, Sarah J.2; Shepherd, Colin2; Agarwal, Vikram1; Loughlin, John2; Shendure, Jay1,3,4 | |
2019-06-04 | |
发表期刊 | NATURE COMMUNICATIONS |
ISSN | 2041-1723 |
出版年 | 2019 |
卷号 | 10 |
文章类型 | Article |
语种 | 英语 |
国家 | USA; England |
英文摘要 | To date, genome-wide association studies have implicated at least 35 loci in osteoarthritis but, due to linkage disequilibrium, the specific variants underlying these associations and the mechanisms by which they contribute to disease risk have yet to be pinpointed. Here, we functionally test 1,605 single nucleotide variants associated with osteoarthritis for regulatory activity using a massively parallel reporter assay. We identify six single nucleotide polymorphisms (SNPs) with differential regulatory activity between the major and minor alleles. We show that the most significant SNP, rs4730222, exhibits differential nuclear protein binding in electrophoretic mobility shift assays and drives increased expression of an alternative isoform of HBP1 in a heterozygote chondrosarcoma cell line, in a CRISPR-edited osteosarcoma cell line, and in chondrocytes derived from osteoarthritis patients. This study provides a framework for prioritization of GWAS variants and highlights a role of HBP1 and Wnt signaling in osteoarthritis pathogenesis. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000470082000001 |
WOS关键词 | GENOME-WIDE ASSOCIATION ; SUSCEPTIBILITY LOCUS ; GENETIC-VARIATION ; TRANSCRIPTIONAL REPRESSOR ; STUDIES IDENTIFY ; WNT ; HIP ; POLYMORPHISM ; DISSECTION ; EXPRESSION |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/203415 |
专题 | 资源环境科学 |
作者单位 | 1.Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA; 2.Newcastle Univ, Int Ctr Life, Inst Genet Med, Skeletal Res Grp, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England; 3.Brotman Baty Inst Precis Med, Seattle, WA 98195 USA; 4.Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA |
推荐引用方式 GB/T 7714 | Klein, Jason C.,Keith, Aidan,Rice, Sarah J.,et al. Functional testing of thousands of osteoarthritis-associated variants for regulatory activity[J]. NATURE COMMUNICATIONS,2019,10. |
APA | Klein, Jason C..,Keith, Aidan.,Rice, Sarah J..,Shepherd, Colin.,Agarwal, Vikram.,...&Shendure, Jay.(2019).Functional testing of thousands of osteoarthritis-associated variants for regulatory activity.NATURE COMMUNICATIONS,10. |
MLA | Klein, Jason C.,et al."Functional testing of thousands of osteoarthritis-associated variants for regulatory activity".NATURE COMMUNICATIONS 10(2019). |
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