GENETIC EPIDEMIOLOGY OF FAMILIAL EPILEPSY

在本申请中，我们建议扩大我们对 通过进行遗传连锁分析识别癫痫的遗传 并在染色体上定位对基因有重大影响的特定基因 易患癫痫。大约有32个家庭在 项目的初始资助阶段，已知至少包含三个 癫痫患者(先证者和至少两名一级患者 (亲属)，将包括在关联研究中。计算机模拟 将被用来评估(1)哪些家系可能产生 最高Lod得分，(2)个人需要接受采访才能获得 其他家族历史信息，以及(3)哪些个人需要 在每个谱系内取样。根据这些模拟的结果， 将进行更多的面谈，并从 见多识广的家庭成员。抽样的个体的基因类型将是 在被检测为限制性的一系列遗传标记中的每一个处确定 片段长度多态。那么联动的几率和最大 每个遗传标记与一个基因之间的似然重组分数 癫痫的可能易感基因将被估计。异质性 重组分数中的家庭之间将进行测试，两者都没有 关于哪些家庭可能表现出联系的假设，以及 比较不同发病年龄、病因和年龄的家庭 先证者的癫痫类型。这种表型是由 易感基因将通过比较以下结果进行研究 对受影响亲属的几种不同定义，包括所有 癫痫，仅特发性癫痫，仅全身性癫痫，部分 仅癫痫，癫痫和热性惊厥，以及两者 以及孤立的无缘无故癫痫发作。最后，如果演示了链接，则 连锁不平衡的存在将通过比较标记进行调查 研究中受影响和未受影响的个体的等位基因频率 人口作为一个整体。 确定癫痫的易感基因将有助于早期 识别易感人群，这将是 分子研究旨在确定其生理机制 敏感度提高。这样的研究可能会导致 对癫痫发病机制的基本因素的认识 对新的治疗和预防战略的相应影响。

In this application, we propose to extend our investigations of the role of inheritance in epilepsy by performing genetic linkage analysis to identify and chromosomally locate specific genes that have a major influence on susceptibility to epilepsy. Approximately 32 families ascertained in the initially funded stage of the project, and known to contain at least three individuals with epilepsy (the proband and at least two first-degree relatives), will be included in the linkage study. Computer simulations will be used to assess (1) which pedigrees are likely to produce the highest lod score, (2) which individuals need to be interviewed to obtain additional family history information, and (3) which individuals need to be sampled within each pedigree. Based on the results of these simulations, additional interviews will be conducted and blood samples collected from informative family members. The genotypes of sampled individuals will be determined at each of a series of genetic markers detected as restriction fragment length polymorphisms. Then the odds of linkage and the maximum likelihood recombination fraction between each genetic marker and a putative susceptibility gene for epilepsy will be estimated. Heterogeneity between families in the recombination fraction will be tested both without assumptions about which families are likely to show linkage, and by comparing families defined by different ages at onset, etiologies, and seizure types in the probands. The phenotype that results from the susceptibility gene will be investigated by comparing the results under several different definitions of affected relatives, including all epilepsy, idiopathic epilepsy only, generalized epilepsies only, partial epilepsies only, both epilepsy and febrile convulsions, and both epilepsy and isolated unprovoked seizures. Finally, if linkage is demonstrated, the presence of linkage disequilibrium will be investigated by comparing marker allele frequencies in affected and unaffected individuals in the study population as a whole. Identification of a susceptibility gene for epilepsy would facilitate early identification of susceptible individuals, and would be a first step in molecular studies designed to identify the physiological mechanism by which susceptibility is raised. Such studies could lead to increased understanding of fundamental factors in the pathogenesis of epilepsy, with corresponding implications for new strategies of treatment and prevention.