中国人群室间隔缺损的全基因组关联及功能研究

先天性心脏病是一种最常见的先天性疾病。其中，室间隔缺损已超过先天性心脏病总数的20%。本课题组前期开展的中国人群全基因组关联研究（GWAS）发现了多个先心易感区域。然而，室间隔缺损特异的易感区域目前仍尚未可知，真正的致病变异及其生物学功能也有待鉴定。申请人前期已利用初筛芯片数据，对全基因组范围内遗传变异与室间隔缺损发生风险的关联性进行了单独分析，发现了5个显著相关的遗传变异。本研究将首先在人群中对上述5个遗传变异进行独立验证，发现显著相关的变异；继而在易感区域中开展连锁不平衡分析，挖掘潜在致病遗传变异，并通过生物信息学分析评价其潜在功能；进一步在细胞和动物模型中展开功能学研究，探讨致病变异在室间隔缺损发生过程中的生物学机制。本研究有助于阐明中国汉族人群室间隔缺损发生的分子遗传学机制。同时，研究结果可用于先心高危人群筛查，对于疾病早期诊断、预防和治疗具有重要意义。

Congenital heart disease (CHD) is currently the most common birth defect worldwide. More than 20% of all CHD consist of ventricular septal defect (VSD). Our previous genome-wide association study (GWAS) identified 2 susceptibility loci for CHD in Han Chinese. However, the specific susceptibility loci for VSD are still unknown. Moreover, causal variations and for VSD and their potential biological function need to be investigated. We have analysed the associations between single nucleotide polymorphisms (SNPs) and VSD risk by using our existing genome-wide scan data and found that 5SNPs showed significant associations with VSD risk . In the current study, we will first conduct a validation of the 5 SNPs in case-control study. For the susceptibility loci for VSD, we will perform linkage disequilibrium (LD) analysis and bioinformatics analysis to identify the potential causal variations and important genes for VSD. Furthermore, molecular biology assays will be implemented to investigate the potential functions of these potential causal variants and important genes. The study results in this project may provide insight into pathogenic mechanism of VSD and be used to screen high-risk populations, provide a new tool for early prevention, diagnosis and treatment strategy.