先天性心脏病是新生儿死亡的首要病因。其中，先天性心脏间隔缺损是先天性心脏病中最常见的类型。本课题组前期开展的中国人群全基因组关联研究（GWAS）发现了多个先天性心脏病易感区域。然而其真正的致病变异目前仍尚未可知，生物学功能也有待鉴定。申请人前期利用初筛芯片数据综合数据库进行基因型填补，根据m6A修饰位点保守序列在全基因组范围内筛选结合连锁不平衡进行分析，发现了4个与先天性间隔缺损发生风险显著相关独立的m6A修饰遗传变异。本研究将首先对上述4个独立遗传变异在大样本人群中对进行独立验证，挖掘潜在致病变异。在此基础上，进一步设计功能实验证实致病变异在细胞和动物模型中通过m6A的水平改变影响关键基因生物学功能，导致先天性心脏间隔缺损易感。本研究结果将有助于阐明中国汉族人群先天性心脏间隔缺损发生的分子遗传学机制。同时研究结果可用于先天性心脏病高危人群筛查，对于疾病的早期诊断、预防和治疗具有重要意义。

Congenital heart disease (CHD) is currently the leading cause of infant mortality worldwide and the most common subtype of CHD is septal defect(SD). Our previous genome-wide association study (GWAS) identified several susceptibility loci for CHD in Han Chinese. However, the causal variants for SD and their potential biological function need to be investigated. We previous imputed our existing genome-wide scan data , then achieved the associations between single nucleotide polymorphisms (SNPs) modified by m6A and SD risk by annotating genome-wide m6A motif and conducting linkage disequilibrium (LD) analysis .We found 4 independent m6A modified SNPs showed significant associations with SD risk. In the current study, we will perform a validation of the 4 SNPs in a case-control study to investigate the potential causal variants. On basis of the validation, molecular biology and animal model experiments are designed to identified the functions of the SD associated m6A modified causal variants. The results in this study may provide insight into pathogenic mechanism of SD and be used to screen high-risk CHD populations for early prevention, diagnosis and treatment strategy.