Elucidating monogenic causes and genetic modifiers of Parkinson’s disease at a global scale

About 15% of Parkinson’s disease (PD) has a monogenic cause. Remarkable progress has been made in the understanding of monogenic neurological diseases within previous decades due to rapidly advancing technologies, the most recent of which are so-called third-generation technologies like long-read sequencing (LRS). LRS is a sequencing technique with the capacity to sequence much longer reads compared to traditional short-read whole-genome sequencing (WGS), thus allowing the detection of complex structural variants (SVs). SVs represent a major source of genetic variation in the human genome; however, they are currently understudied in PD genetics. Another important limitation of PD research is that most studies were performed in White/European populations, thereby severely limiting our insights into monogenic PD and genotype-phenotype correlations at a global scale. To address these gaps, the overall aim of this project is to further elucidate monogenic causes of PD in diverse ancestries. The projects will be performed under the umbrella of the Global Parkinson’s Genetics Program (GP2). The first aim is to better understand known monogenic forms of PD and their genetic spectrum in diverse ancestries. We will generate genome-wide genotyping and short-read WGS data for up to 100,000 individuals with PD. These data will be used to investigate the genetic spectrum and perform genotype-phenotype correlations across diverse populations, and further, to investigate genetic modifiers of penetrance and expressivity in selected monogenic forms of PD by using a genome-wide association study approach. The second aim is to systematically analyze structural variants as a monogenic cause of PD. As a first step, this will be done on a cohort level by using short-read WGS data and a specialized bioinformatics pipeline. Next, these findings will be validated by performing LRS in a subset of individuals and identified SVs will be further characterized. The third aim is to potentially identify novel monogenic causes of PD by using LRS primarily in prioritized individuals in whom a monogenic cause of disease is more likely based on a young age at disease onset or a positive family history, but in whom no causative genetic variant was previously identified using short-read WGS. In summary, this project aims to better understand the known monogenic forms of PD by investigating a multi-ancestry cohort and performing genotype-phenotype correlations and modifier studies at a global scale. Further, it aims to identify potential novel causes of monogenic PD by applying new 'state-of-the-art' genetic methods such as LRS. The project therefore intends to close two important gaps in PD research by i) addressing the lack of diverse ancestries, particularly those from historically underrepresented or underrecognized populations, and ii) applying advanced methods to identify genetic causes of PD that could not be detected previously.

DFG Programme WBP Fellowship

International Connection USA

Host Professor Andrew Singleton, Ph.D.