基于外显子捕获测序探寻中国汉族偏头痛易感基因

Migraine is a common nervous system disease inflicting millions of people and causing a heavy burden on the society, however, its etiology is still not clear and belived having a strong genetic predisposition. At present the susceptibility genes of migraine is still unclear, more than 20 susceptibility loci has been reported. Now exome sequencing is broadly used to screen disease susceptible genes.Compared with traditional sequencing methods, this technology has short time-consuming, low cost, high flux and so on. Our group concentrated on better identifying of migraine susceptibility genes for a long time, many migraine pedigrees and more than 400 patients with sporadic migraine have been collectted. In the previous case-control study, we have found that there may be a difference between the racial and clinical phenotype for migraine susceptibility genes. And the genotyping have been performed by using fluorescence resonance energy transfer technology and restriction fragment length polymorphism analysis. In this study, migraine pedigrees with aura and without aura were first selected to find the Han-Chinese migraine specific susceptibility genes and loci using exome sequencing, then the gene variation difference between aura and without aura, also the reported 20 susceptibility loci were analyzed in the expanded sporoadic sample, the relationship between clinical phenotype and genotype were also analyzed, these results will provide identifiable ground for screening potential molecular markers for Han-Chinese migraine patients, and lay the foundation for revealing the pathogenesis of this disease.

偏头痛是一种严重威胁健康的神经系统常见疾病，社会负担重，病因仍不明确，具有显著的遗传因素。目前世界上对该病的易感基因定位尚无统一认识，已报道有二十多个易感基因位点。与传统测序方式相比,外显子测序技术具有耗时短、成本低、通量大等特点,已经成为研究疾病致病基因的重要方法。本课题组长期致力于偏头痛的易感基因筛查，目前已经收集到多个家系及400余例散发性偏头痛患者，前期采用病例对照研究，应用荧光能量共振转移、限制性片段多态性分析等技术进行基因分型发现偏头痛的易感基因可能存在种族及临床表型间的差异。本研究拟对收集到的家族性先兆偏头痛、无先兆偏头痛及家系内正常对照，利用外显子测序技术探寻三者间的基因变异差异，进一步在大样本散发性偏头痛中验证并结合已报道位点寻找中国汉族偏头痛特异性易感基因及位点，明确基因型与临床表型的关系，筛选出具有一定特异性的中国偏头痛潜在标志物，为揭示该病的发病机制奠定基础。

偏头痛是一种严重威胁健康的神经系统常见疾病，社会负担重，病因仍不明确，具有显著的遗传因素。目前世界上对该病的易感基因定位尚无统一认识，已报道有二十多个易感基因位点。与传统基因分析技术相比,外显子测序、时间飞行质谱分析技术等具有耗时短、成本低、通量大等特点,已经成为研究疾病致病基因的重要方法。.本研究小组通过厦门大学附属第一医院头痛门诊的开展，成功建立了一个临床评估完善、数据收集充分的大样本偏头痛DNA数据库，病例组、对照组各达600例以上；经过横断面调查研究，明确了厦门地区门诊头痛患者的年龄及性别分布，门诊头痛患者病因分布，原发性头痛的年龄及性别分布，偏头痛与紧张型头痛的人口学特征，偏头痛与紧张型头痛的主要临床特征等。成功应用SNaPshot技术发现GRIA1（rs548294）基因单核苷酸多态性与中国闽南地区汉族女性先兆偏头痛发病相关。GRIA1（rs2195450）基因单核苷酸多态性与中国闽南地区汉族女性偏头痛发病相关。而GRIA3（rs3761555）基因单核苷酸多态性与中国闽南地区汉族人群偏头痛发病无关联。成功应用荧光共振能量转移技术（FRET）发现表明MTHFD1基因多态性位点R134K和R653Q可能与闽南地区偏头痛患者无明显相关性。成功应用iPLEX平台技术进行基因分析发现CALCA和RAMP1基因单核苷酸多态性与中国闽南地区汉族人群偏头痛发病无关联，同时发现ESR1基因与中国汉族偏头痛患者的发病相关。对国外GWAS研究发现的易感基因进行分析发现MEF2D, PRDM16和ASTN2基因可能与中国汉族偏头痛患者的发病相关。这些发现对偏头痛遗传发病机制提供了依据，为提高偏头痛基础与临床认识提供了理论支持。