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

帕金森氏病（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。单核苷酸变异（snv）和以拷贝数变异（cnv）形式存在的结构变异（SV）已在约15种不同的基因中被确定为PD的病因。然而，到目前为止，单基因形式的帕金森病只能解释全世界约10%的患者。尽管遗传力估计显示PD的遗传成分约为30%，但很大一部分PD的遗传仍未得到解决。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），可以预测帕金森病风险增加高达6倍。虽然重复扩增（RE）已经被发现了几十年，但它们在PD中很大程度上被忽视了，特别是在下一代测序技术中。现在，新的生物信息学工具和技术进步正在神经退行性疾病领域播种新的RE疾病发现的复兴。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、SVs和snv，从而缩小PD缺失遗传力的差距。该计划将有四个目标：1)对至少120例经短读外显子组或基因组测序后致病变异阴性的PD患者进行长读基因组测序；2)将创新的生物信息学工具应用于另外400例PD患者新生成的短读测序数据；3)使用独立的方法和在额外的PD患者中进行遗传验证；4)比较短读和长读测序的诊断率。申请人在运动障碍领域具有互补的专业知识，重点是PD和包括系统生物学方法在内的大规模数据分析。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队列中应用新技术进步（第三代测序）来研究PD缺失的遗传性。

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.