全基因组关联研究（GWAS）发现的疾病易感SNP位点90%以上位于非蛋白编码区，破解从非编码SNP到靶标基因到疾病的内在关系是当前研究的关键和难点。1p36.12是国际大规模GWAS报道的第一个白人骨质疏松易感区域，申请人在中国人中也验证到显著关联，然而，该区域的易感SNP多位于基因间隔区，功能机制至今未知。我们前期研究提示，该易感SNP区域可作为增强子远程调控长链非编码RNA（LINC00339）的表达。本项目拟在此基础上，通过整合各类表观调控、基因表达和三维基因组数据，对1p36.12上易感SNP进行系统生物信息学分析，并结合双荧光报告系统、3C、CRISPR/Cas9等各类功能学实验在细胞和小鼠上验证，同时研究LINC00339对其Cis调控的骨代谢重要基因CDC42的作用机制，旨在深入解析“非编码易感SNP—疾病”的远程调控模式。研究结果可为疾病精准医疗和药物开发提供潜在有效靶标。

Since more than 90% SNPs identified by genome-wide association studies (GWAS) are located in non-coding regions, it becomes difficult and important to discover the underlying mechanism of non-coding SNPs - target genes - diseases. 1p36.12 is a susceptibility locus firstly identified by large-scale GWAS on osteoporosis in white population. We have also validated the significant associations in Chinese population. However, most susceptibility SNPs in this locus are in intergenic region, the function of these SNPs remains unknown. Our preliminary study have shown that, SNPs in 1p36.12 could act as enhancer to regulate a long non-coding RNA (LINC00339) through long-range loop formation. Based on these work, we propose our plan: first, we will conduct a comprehensive bioinformatics analyses on susceptibility SNPs in 1p36.12 through integrating multiple epigenomic regulatory data, gene expression data, and three-dimension genomic data. Second, we will validate the results by conducting various functional experiments in cellular and mouse model, such as luciferase assay, chromosome conformation capture (3C), CRISPR/Cas9, and so on. Finally, we will investigate the relationship between LINC00339 and its target gene CDC42, which is an important gene involved in bone metabolism. Our aim is to identify the long-range regulation pattern of “non-coding susceptibility SNPs – disease”. The completion of this project will provide potential effective target for precision medicine and drug development.