Common and pleiotropic genetic factors in epileptogenesis

癫痫发生的常见和多效性遗传因素

• 批准号: 490911581
• 负责人: Professor Dr. Michael Nothnagel, Ph.D.
• 金额: --
• 依托单位: Statistical Genetics and Bioinformatics Group
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/490911581?language=en
• 关键词: Common; pleiotropic; genetic; factors; epileptogenesis

Previous studies on identifying genetic risk loci implicated in epileptogenesis have usually employed standard genetic risk models under which these variants act, namely single common variants under a multiplicative (i.e. additive in the number of alleles) model (GWAS studies) or several subsets of rare variants acting together as a genetic burden (exome studies). In the 1st funding period, we (1) identified 2 novel suceptibility loci for GGE (NCAM1, MAP3K9), (2) described an aberrant ALDH5A1 promoter regulation, and (3, formerly P2) conducted a benchmarking study for common-variant pleiotropy detection and applied such methods to GWAS datasets from ILAE2. In the 2nd period, project P3 will pursue different statistical and bioinformatic approaches in parallel to identify epilepsy-related genetic variants that act under non-standard risk models or those which require additional information, including external epigenomic data or information on related traits, to achieve sufficient power for their successful identification. This involves widened pleiotropy detection, Bayesian GWAS, polygenic risk scores (PRS) profiling and improved epilepsy sub-phenotype delineation, systematic investigation of compound heterozygous risk models and of pairwise epistasis as well as several approaches based on integration of transcriptional and epigenetic data. We will focus on generalized genetic epilepsies (GGEs) while also considering focal epilepsies (FEs) as well as developmental and epileptic encephalopathies (DEEs). Project P3 will share novel candidate loci with P1, P2 and the experimental projects P4-P8.

先前关于确定与癫痫发生有关的遗传风险位点的研究通常采用这些变异作用的标准遗传风险模型，即单个常见变异在倍增（即等位基因数量的加性）模型下（GWAS研究）或几个罕见变异子集共同作为遗传负担（外显子组研究）。在第一个资助期内，我们(1)确定了2个新的GGE易感位点（NCAM1, MAP3K9），(2)描述了一个异常的ALDH5A1启动子调控，（3，以前的P2）进行了一项共同变异多效性检测的基准研究，并将这些方法应用于ILAE2的GWAS数据集。在第二阶段，P3项目将采用不同的统计和生物信息学方法，同时识别在非标准风险模型下或需要额外信息（包括外部表观基因组数据或相关性状信息）的癫痫相关遗传变异，以获得足够的能力来成功识别它们。这包括扩大多效性检测，贝叶斯GWAS，多基因风险评分（PRS）分析和改进癫痫亚表型描述，系统调查复合杂合风险模型和成对上位性，以及基于转录和表观遗传数据整合的几种方法。我们将重点关注广泛性遗传性癫痫（GGEs），同时也考虑局灶性癫痫（FEs）以及发育性和癫痫性脑病（dee）。P3项目将与P1、P2和实验项目P4-P8共享新的候选基因座。