基于GWAS定位的麻风候选区域致病变异的分离及功能分析

Leprosy is a chronic infectious disease caused by Mycobacterium leprae. It affects the skin and peripheral nerves and can cause irreversible impairment of nerve function and consequent chronic disabilities. We have established the genetic resource of leprosy with 20,000 biological samples of leprosy cases collected. In 2009 and 2011, we conducted genome-wide association study (GWAS) and identified nine susceptibility genes associated with leprosy published in <New England Journal of Medicine> and<Nature Genetics>. But it is often the case that those common SNPs identified by GWAS to be associated with the traits are not the causal variants, which shows a limited effect on explaining the risk of diseases. To further identify the causal variants of the LD regions, we are planning to select parts of the case/control samples from GWAS database to conduct the next generation sequencing on the target LD regions. The sequencing data will be integrated with 1000G and HapMap database to obtain one complete reference panel for the imputation of GWAS data. Then after statistical analysis, those SNPs showed suggestive association will be validated in a large cohort of samples and functional analysis will be performed later. This study will do a great benefit for the pathogenesis, risk prediction, clinical diagnosis of leprosy.

麻风是由麻风分枝杆菌感染易感个体、特异性破坏皮肤与外周神经、晚期可致残的慢性传染病。课题组采用全基因组关联分析方法（GWAS）定位了麻风的9个易感基因，结果发表于《New England Journal of Medicine》和《Nature Genetics》上。但由于GWAS是基于"常见疾病-常见变异"理论设计，无法发现罕见变异，且定位的常见变异多为标记位点而不是致病变异，在解释疾病发病风险方面效力有限。因此课题组拟以前期GWAS发现的9个易感基因所在的连锁不平衡区域作为候选区域，从GWAS数据库中选取部分样本，进行目标区域深度测序，测序数据协同1000G及HapMap数据库构建reference panel，通过基因型推算、趋势检验等生物信息学手段筛选阳性位点，在4000麻风病例及6000对照中进行验证并进行功能分析，从而定位麻风的致病变异，为阐述麻风的发病机理奠定基础。

麻风是由麻风分枝杆菌感染易感个体、特异性破坏皮肤与外周神经、晚期可致残的慢性传染病。课题组采用全基因组关联分析方法（GWAS）定位了麻风的9个易感基因，结果发表于《New England Journal of Medicine》和《Nature Genetics》上。但由于GWAS是基于“常见疾病-常见变异”理论设计，无法发现罕见变异，且定位的常见变异多为标记位点而不是致病变异，在解释疾病发病风险方面效力有限。因此课题组按照研究计划，以前期GWAS发现的9个易感基因所在的连锁不平衡区域作为候选区域，从GWAS数据库中选取部分样本，进行目标区域深度测序，测序数据协同1000Genome Project及HapMap数据库构建reference panel，通过基因型推算、趋势检验等生物信息学手段筛选阳性位点，在4000麻风病例及6000对照中进行验证并进行功能分析，从而定位麻风的致病变异，为阐述麻风的发病机理奠定基础。