Todorova M T, Mantis J G, Le M, Kim C Y, Seyfried T N
Biology Department, Boston College, Chestnut Hill, MA 02467, USA.
Genes Brain Behav. 2006 Oct;5(7):518-27. doi: 10.1111/j.1601-183X.2006.00204.x.
Gene identification has progressed rapidly for monogenic epilepsies, but complex gene-environmental interactions have hindered progress in gene identification for multifactorial epilepsies. We analyzed the role of environmental risk factors in the inheritance of multifactorial idiopathic generalized epilepsy in the EL mouse. Seizure susceptibility was evaluated in the EL (E) and seizure-resistant ABP/LeJ (A) parental mouse strains and in their AEF1 and AEF2 hybrid offspring using a handling-induced seizure test. The seizure test was administered in three environments (environments I, II and III) that differed with respect to the number of seizure tests administered (one test or four tests) and the age of the mice when tested (young or old). The inheritance of seizure susceptibility appeared dominant after repetitive seizure testing in young or old mice, but recessive after a single test in old mice. Heritability was high (0.67-0.77) in each environment. Significant quantitative trait loci (QTL) that were associated with environments I and III (repetitive testing) were found on chromosomes 2 and 9 and colocalized with previously mapped El2 and El4, respectively. The El2 QTL found in environment I associated only with female susceptibility. A novel QTL, El-N, for age-dependent predisposition to seizures was found on proximal chromosome 9 only in environment II. The findings indicate that environmental risk factors determine the genetic architecture of seizure susceptibility in EL mice and suggest that QTL for complex epilepsies should be defined in terms of the environment in which they are expressed.
单基因癫痫的基因鉴定进展迅速，但复杂的基因-环境相互作用阻碍了多因素癫痫基因鉴定的进展。我们分析了环境风险因素在EL小鼠多因素特发性全身性癫痫遗传中的作用。使用处理诱导癫痫发作试验，在EL（E）和抗癫痫发作的ABP/LeJ（A）亲代小鼠品系及其AEF1和AEF2杂交后代中评估癫痫发作易感性。癫痫发作试验在三种环境（环境I、II和III）中进行，这三种环境在癫痫发作试验的次数（一次试验或四次试验）和试验时小鼠的年龄（年轻或年老）方面有所不同。在年轻或年老小鼠中进行重复癫痫发作试验后，癫痫发作易感性的遗传表现为显性，但在年老小鼠中进行单次试验后则表现为隐性。在每种环境中，遗传力都很高（0.67 - 0.77）。在染色体2和9上发现了与环境I和III（重复试验）相关的显著数量性状位点（QTL），分别与先前定位的El2和El4共定位。在环境I中发现的El2 QTL仅与雌性易感性相关。仅在环境II中，在近端染色体9上发现了一个新的QTL，即El-N，用于年龄依赖性癫痫发作易感性。研究结果表明，环境风险因素决定了EL小鼠癫痫发作易感性的遗传结构，并表明复杂癫痫的QTL应根据其表达的环境来定义。
