Common and pleiotropic genetic factors in epileptogenesis

以前关于鉴定癫痫发生中涉及的遗传风险基因座的研究通常采用标准遗传风险模型，在该模型下这些变体起作用，即在倍增（即等位基因数量的加性）模型下的单个常见变体（GWAS研究）或作为遗传负担一起起作用的罕见变体的几个子集（外显子组研究）。在第一个资助期，我们（1）鉴定了2个新的GGE易感性位点（NCAM 1，MAP 3 K9），（2）描述了异常的ALDH 5A 1启动子调控，（3，以前的P2）进行了一项针对常见变异多效性检测的基准研究，并将这些方法应用于ILAE 2的GWAS数据集。在第二阶段，项目P3将同时采用不同的统计和生物信息学方法，以识别在非标准风险模型下起作用的癫痫相关遗传变异，或需要额外信息的遗传变异，包括外部表观基因组数据或相关性状的信息，以获得足够的成功识别能力。这涉及扩大多效性检测，贝叶斯GWAS，多基因风险评分（PRS）分析和改善癫痫亚表型描绘，复合杂合风险模型和成对上位性的系统研究，以及基于转录和表观遗传数据整合的几种方法。我们将重点关注全身性遗传性癫痫（GGEs），同时也考虑局灶性癫痫（FEs）以及发育性和癫痫性脑病（DEEs）。项目P3将与P1、P2和实验项目P4-P8共享新的候选基因座。

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.