Rare variant analysis of the PPMI dataset to uncover the complex genetic architecture of Parkinson’s disease

Objective: To unravel the genetic factors that play a role in PD we used the whole exome sequencing data available as a part of Parkinson Progression Markers Initiative (PPMI). Background: Parkinson’s disease (PD) is a complex disease. Besides variants in high-risk genes such as LRRK2 and PARK2, multiple genes associated to sporadic PD were discovered via genome-wide association studies. Yet, there is a large number of genetic factors that need to be deciphered. Methods: To unravel the genetic factors that play a role in PD we used the whole exome sequencing data available as a part of Parkinson Progression Markers Initiative (PPMI). The dataset comprised of 435 PD cases and 162 ethnically matched controls, respectively. We performed burden tests at single variant, gene and geneset levels on common and rare exonic and splice-variants. We also looked for severity of rare highly deleterious variants (CADD phred score>30) using the CADD score as well as singleton (variants seen in only one individual across cases and controls) rare variants. Additionally, we performed the functional enrichment analysis with the genes harboring rare highly deleterious variants (case uniq genes) that are only present in cases. Results: We observed an increased mutational burden of singleton variants in PD cases compared to the controls in nonsynonymous+LOF variants (empirical P-value 0.005) but not in the synonymous variants (empirical P-value 0.09). We observed a higher significant burden (P-value 0.028) as well as higher significant severity (empirical P-value 0.027) of rare, highly deleterious nonsynonymous variants, but not in the synonymous variants of the candidate genes (P-value 0.686, empirical P-value 0.556 for burden and severity respectively). The network analysis of genes having deleterious variants only present in cases (Case uniq) showed a significant increase in connectivity compared to random networks (P-value 0.0002). Pathway analysis of those genes showed a significant enrichment of pathways and biological process implicated in the nervous system functioning and the etiology of PD. Conclusions: Our study supports the complex disease notion of PD by highlighting the convoluted architecture of PD where case uniq genes including LRRK2 are implicated in several biological processes and pathways related to PD. The main finding of this study is to discover the complex genetics of PD at an exome wide level