Shared Genetics and Risk Factors Between Epilepsy and Psychiatric Disease

在美国，每26人中就有1人被诊断为癫痫，其特征是异常导致的癫痫发作 大脑中的电放电。这些癫痫发作具有不同的物理表现(抽搐、 感觉障碍或意识丧失)，并以显著增加的频率观察到 有精神和神经发育障碍的人。至少三分之一的癫痫患者 在治疗过程中经历额外的癫痫发作。我们不了解常见形式的发病机制 指不是由于明显的损伤或严重的突变引起的癫痫；不同形式的癫痫是否由 不同的致病机制；或者这些机制是否(部分)与其他疾病和 从而推动观察到的共病。这限制了临床治疗选择和准确的预后，包括 合并精神疾病的可能性，以及新疗法的开发。 癫痫的流行病学研究可以揭示预后预测因素，而人类基因研究可以 发现两个原因基因以及这些基因是否也会增加其他疾病的风险；这些结果将 为发现致病机制和预测患者预后提供了底物。 然而，这些活动需要拥有终身医学数据和DNA材料的大量队列，而这些数据并不是 在美国上市。我们有一个独特的机会来克服这个障碍，利用人口资源 在丹麦可用：我们可以从新生儿血斑中提取DNA并对其进行基因分型，适用于约12,000名患有 通过丹麦国家医院登记簿，并将这些数据与终身临床数据和生活事件进行匹配。通过 整合了先前癫痫和神经精神疾病基因研究的数据，并使用我们的 最先进的方法从这样的数据中识别因果基因，因此我们可以(1)执行强大的 癫痫的遗传学研究和确定致病基因；(2)测试和验证结果的预测因素，包括 癫痫患者的共病精神疾病及其是否有因果关系；(3)确定是否有共病 精神疾病与癫痫有共同的遗传性，因此也是一个病理学基础。具体来说，我们会： 1.确定易患癫痫的基因变异及其影响的基因。利用可遗传性 全基因组变异中的信息以评估癫痫亚型是否由相同的致病因素驱动 机制，如果这些与共病的精神疾病共享。 2.确定癫痫患者的预后预测因素及其遗传决定因素。 这些研究将揭示驱动癫痫发病机制的基因，并确定常见的、 复杂的癫痫有相同的机制。我们的发现对未来的任何预防或干预都是至关重要的 策略，因为它们将使临床医生能够预测患有以下疾病的人并发精神疾病的可能性 在诊断时癫痫，并建议为开发新的抗癫痫药物的目标。

1 in 26 people in the US have a diagnosis of epilepsy, characterized by seizures resulting from abnormal electrical discharges in the brain. These seizures have heterogeneous physical manifestations (convulsions, sensory disturbances, or loss of consciousness) and are observed at markedly increased frequencies in persons with psychiatric and neurodevelopmental disorders. At least a third of persons with epilepsy experience additional seizures whilst on treatment. We do not understand the pathogenesis of common forms of epilepsy not due to obvious injury or severe mutations; whether different forms of epilepsy are driven by different pathogenic mechanisms; or whether these mechanisms are (partly) shared with other diseases and thus drive the observed comorbidity. This limits clinical management options, accurate prognosis including the likelihood of comorbid psychiatric disease, and development of new therapies. Epidemiological studies of epilepsy could uncover outcome predictors, and human genetic studies could uncover both causal genes and whether these also contribute risk of other diseases; these results would provide a substrate both for discovering pathogenic mechanisms and for predicting patient outcomes. However, these activities require large cohorts with both lifelong medical data and DNA material, which are not available in the US. We have a unique opportunity to overcome this barrier using the population resources available in Denmark: we can retrieve and genotype DNA from neonatal bloodspots for ~12,000 persons with epilepsy via the Danish National Hospital Register, and match these to life-long clinical data and life events. By incorporating data from previous genetic studies of epilepsy and of neuropsychiatric disease, and by using our state-of-the-art methods to identify causal genes from such data, we can thus (1) perform a well-powered genetic study in epilepsy and identify causal genes; (2) test and validate predictors of outcomes, including comorbid psychiatric disease in persons with epilepsy, and whether they are causal; (3) establish if comorbid psychiatric disease shares heritability, and thus a pathological basis, with epilepsy. Specifically, we will: 1. Identify genetic variants predisposing to epilepsy and the genes they affect. Use the heritability information in genome-wide variation to assess if epilepsy subtypes are driven by the same pathogenic mechanisms, and if these are shared with comorbid psychiatric disease. 2. Identify outcome predictors for persons with epilepsy, and their genetic determinants. These studies will uncover genes driving epilepsy pathogenesis, and establish if the subtypes of common, complex epilepsy share these mechanisms. Our findings will be crucial to any future preventive or intervention strategies, as they will enable clinicians to predict the likelihood of comorbid psychiatric disease in persons with epilepsy at the time of diagnosis, and suggest targets for developing new anti-seizure medications.