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

基本信息

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
项目类别：
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

项目摘要

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.

美国有16人在美国有癫痫病的诊断，其特征是癫痫发作异常大脑中的电气排放。这些癫痫发作具有异质的身体表现（抽搐，感觉干扰或意识丧失），在明显增加的频率下观察到患有精神病和神经发育障碍的人。至少三分之一的患有癫痫的人在治疗时会经历其他癫痫发作。我们不了解共同形式的发病机理癫痫病的疾病并不是由于明显的损伤或严重的突变；是否由不同形式的癫痫驱动不同的致病机制；或这些机制是否（部分）与其他疾病共享因此驱动观察到的合并症。这限制了临床管理选择，准确的预后包括合并精神病的可能性和新疗法的发展。癫痫的流行病学研究可以揭示结果预测因子，人类遗传研究可以揭示因果基因以及这些因果基因是否也造成其他疾病的风险；这些结果将是提供用于发现致病机制和预测患者预后的底物。但是，这些活动需要终身医学数据和DNA材料的大量队列，而不是在美国可用。我们有一个独特的机会使用人口资源来克服这一障碍丹麦可用：我们可以从约有12,000人的新生儿血点检索和基因型DNA 通过丹麦国家医院登记册进行癫痫，并将其与终身的临床数据和人生事件相匹配。经过结合先前关于癫痫和神经精神疾病的遗传研究的数据，并通过使用我们从此类数据中识别因果基因的最新方法，我们可以（1）执行良好的动力癫痫中的遗传研究并鉴定因果基因；（2）测试和验证结果的预测指标，包括患有癫痫患者的合并症精神病，以及它们是否是因果关系；（3）确定是否合并精神病具有遗传力，因此具有癫痫病。具体来说，我们将： 1。鉴定易感癫痫及其影响的基因的遗传变异。使用遗传力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驱动机制，如果这些机制与合并症的精神病共享。 2。确定癫痫患者及其遗传决定因素的结果预测因子。这些研究将发现驱动癫痫发病机理的基因，并确定常见的亚型是否是复杂的癫痫分享这些机制。我们的发现对于未来的预防或干预至关重要策略，因为它们将使临床医生能够预测患有合并症的精神病的可能性诊断时癫痫病，并建议开发新的抗塞氏菌药物的靶标。