Shared Genetics and Risk Factors Between Epilepsy and Psychiatric Disease

癫痫和精神疾病之间的共同遗传学和危险因素

• 批准号: 10324570
• 负责人: Kristen Jennifer Brennand
• 金额: $ 49.08万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324570
• 关键词: Affect; Automobile Driving; Biocompatible Materials; Brain; Clinical; Clinical Data; Clinical Management; Collection; Complex; Convulsions; DNA; Data; Denmark; Development; Diagnosis; Disease; Epilepsy; Event; Focal Seizure; Frequencies; Future; Generalized Epilepsy; Generalized seizures; Genes; Genetic; Genetic Determinism; Genetic study; Genome; Genotype; Heritability; Hospital Records; Hospitals; Human Genetics; Injury; Intervention; Knowledge; Life; Maps; Medical; Medical Records; Mendelian randomization; Mental disorders; Meta-Analysis; Methods; Minority; Mutation; Neonatal; Neurodevelopmental Disorder; Outcome; Partial Epilepsies; Pathogenesis; Pathogenicity; Pathologic; Patient-Focused Outcomes; Persons; Pharmaceutical Preparations; Plant Roots; Population; Prevention strategy; Prognosis; Publishing; Records; Resources; Risk; Sample Size; Sampling; Seizures; Sensory; Testing; Time; Unconscious State; Validation; Variant; biobank; causal variant; cohort; comorbidity; epidemiology study; experience; genetic architecture; genetic risk factor; genetic variant; genome wide association study; genome-wide; high risk; mortality; neuropsychiatric disorder; novel therapeutics; outcome prediction; psychiatric comorbidity; risk variant; treatment response

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.

在美国，每26人中就有1人被诊断为癫痫，其特征是由异常的 大脑中的放电这些癫痫发作具有不同的身体表现（惊厥， 感觉障碍，或意识丧失），并观察到在明显增加的频率， 精神和神经发育障碍者。至少三分之一的癫痫患者 在治疗期间经历额外的癫痫发作。我们不了解常见形式的发病机制 癫痫不是由于明显的损伤或严重的突变;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）与其他疾病共享， 从而驱动所观察到的共变量。这限制了临床管理选择和准确的预后，包括 共病精神疾病的可能性，以及新疗法的开发。 癫痫的流行病学研究可以揭示结果预测因子，人类遗传学研究可以 揭示致病基因以及这些基因是否也会导致其他疾病的风险;这些结果将 为发现致病机制和预测患者结果提供了基础。 然而，这些活动需要拥有终身医疗数据和DNA材料的大型队列，而这并不容易。 在美国可用。我们有一个独特的机会，利用人口资源克服这一障碍， 在丹麦可用：我们可以检索和基因型DNA从新生儿血斑约12,000人， 通过丹麦国家医院登记册，收集癫痫患者的临床资料，并将其与终身临床数据和生活事件相匹配。通过 结合以前癫痫和神经精神疾病遗传研究的数据，并使用我们的 国家的最先进的方法，以确定因果基因从这样的数据，我们因此可以（1）执行一个良好的动力 癫痫的遗传学研究，并确定致病基因;（2）测试和验证结果的预测因子，包括 癫痫患者的共病精神疾病，以及它们是否是因果关系;（3）确定是否共病 精神疾病与癫痫具有共同的遗传性，因而具有共同的病理基础。具体而言，我们将： 1.识别易患癫痫的遗传变异及其影响的基因。利用遗传性 全基因组变异的信息，以评估癫痫亚型是否由相同的致病性 机制，以及这些是否与共病精神疾病共享。 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， 复杂的癫痫病也有这些机制。我们的发现将对未来的任何预防或干预至关重要 战略，因为他们将使临床医生预测的可能性，共病精神疾病的人， 癫痫在诊断时，并建议开发新的抗癫痫药物的目标。