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

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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.