Identification of pathogenic structural variants and repeat expansions in Parkinson's disease

帕金森病致病性结构变异和重复扩增的鉴定

• 批准号: 458958659
• 负责人: Professor Dr. Hauke Busch
• 金额: --
• 依托单位: Institut für Neurogenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/458958659?language=en
• 关键词: Identification; pathogenic; structural; variants; repeat

Parkinson's disease (PD) is the fastest growing neurological disease and is very heterogeneous clinically as well as in its course. Currently, treatment only provides temporary symptomatic relief. Single nucleotide variants (SNVs) and structural variants (SV) in the form of copy number variations (CNVs) have been identified in ~15 different genes as a cause of PD. However, thus far, monogenic forms of PD explain only ~10% of patients worldwide. A large part of PD still remains genetically unsolved, despite heritability estimates showing that the genetic component of PD is ~30%. Common variants in monogenic and PD risk genes as well as in the mitochondrial DNA constitute polygenic risk scores (PRS), which can predict an up to 6-fold increased risk of PD.Although repeat expansions (RE) have been known for decades, they have been largely neglected in PD, especially with next generation sequencing techniques. Now, novel bioinformatic tools and technical advances are seeding a renaissance of discoveries of novel RE disorders in the field of neurodegenerative diseases. We aim to close the gap of missing heritability for PD by comprehensive genome sequencing for the simultaneous detection of RE, SVs, and SNVs in individual PD patients. This proposal will have four objectives: 1) perform long-read genome sequencing in at least 120 PD patients negative for pathogenic variants after short-read exome or genome sequencing, 2) apply innovative bioinformatic tools to newly-generated short-read sequencing data of 400 additional PD patients, 3) perform genetic validations with independent methods and in additional PD patients, and 4) compare the diagnostic yield of short- and long-read sequencing.The applicants have complementary expertise in the field of movement disorders with a focus on PD and large-scale data analysis including Systems biology methods. Given the applicants’ expertise in genomics and transcriptomics, we will apply new technological advances (third generation sequencing) on unique patient cohorts to investigate the missing heritability in PD.

帕金森病 (PD) 是发展最快的神经系统疾病，其临床和病程具有很大的异质性。目前，治疗只能暂时缓解症状。拷贝数变异 (CNV) 形式的单核苷酸变异 (SNV) 和结构变异 (SV) 已在约 15 个不同基因中被确定为 PD 的病因。然而，迄今为止，单基因形式的 PD 只能解释全球约 10% 的患者。尽管遗传力估计显示帕金森病的遗传成分约占 30%，但很大一部分帕金森病的遗传问题仍未得到解决。单基因和帕金森病风险基因以及线粒体 DNA 中的常见变异构成多基因风险评分 (PRS)，它可以预测帕金森病风险增加高达 6 倍。尽管重复扩增 (RE) 已为人所知数十年，但在帕金森病中它们在很大程度上被忽视，尤其是使用下一代测序技术。现在，新型生物信息学工具和技术进步正在为神经退行性疾病领域新型 RE 疾病的发现注入复兴的种子。我们的目标是通过全面的基因组测序来同时检测个体 PD 患者的 RE、SV 和 SNV，从而缩小 PD 遗传性缺失的差距。该提案将有四个目标：1）在短读长外显子组或基因组测序后，对至少 120 名致病性变异呈阴性的 PD 患者进行长读长基因组测序，2）将创新的生物信息学工具应用于另外 400 名 PD 患者新生成的短读长测序数据，3）使用独立方法在其他 PD 患者中进行遗传验证，4）比较短读长和长读长的诊断率 申请人在运动障碍领域拥有互补的专业知识，重点是帕金森病和大规模数据分析，包括系统生物学方法。鉴于申请人在基因组学和转录组学方面的专业知识，我们将在独特的患者群体中应用新技术进步（第三代测序），以调查 PD 中缺失的遗传性。