Abstract
BackgroundThe genetic architecture of Parkinson’s Disease (PD) is complex and not completely understood. Multiple genetic studies to date have identified multiple causal genes and risk loci. Nevertheless, most of the expected genetic heritability remains unexplained. Polygenic risk scores (PRS) may provide greater statistical power and inform about the genetic architecture of multiple phenotypes. The aim of this study was to test the association between PRS and PD risk, age at onset and cerebrospinal fluid (CSF) biomarkers (α-synuclein, Aβ1–42, t-tau and p-tau).MethodsThe weighted PRS was created using the genome-wide loci from Nalls et al., 2014 PD GWAs meta-analysis. The PRS was tested for association with PD status, age at onset and CSF biomarker levels in 829 cases and 432 controls of European ancestry.ResultsThe PRS was associated with PD status (p = 5.83×10−08) and age at onset (p = 5.70×10−07). The CSF t-tau levels showed a nominal association with the PRS (p = 0.02). However, CSF α-synuclein, amyloid beta and phosphorylated tau were not found to be associated with the PRS.ConclusionOur study suggests that there is an overlap in the genetic architecture of PD risk and onset, although the different loci present different weights for those phenotypes. In our dataset we found a marginal association of the PRS with CSF t-tau but not with α-synuclein CSF levels, suggesting that the genetic architecture for the CSF biomarker levels is different from that of PD risk.
Highlights
The genetic architecture of Parkinson’s Disease (PD) is complex and not completely understood
The Polygenic risk scores (PRS) was significantly associated with PD status in the joint analysis (p = 5.83×10−08, beta = 5.24), as well as in each individual dataset [Parkinson’s Progression Markers Initiative (PPMI) (p = 3.45×10−05, beta = 5.84); Washington University in Saint Louis (WUSTL) (p = 1.82×10−04, beta = 4.85)] (Table 3, Fig. 1 Panels A and B)
This study aimed to test if the known genetic variants associated with PD risk have a cumulative effect on PD risk, age at onset or cerebrospinal fluid (CSF) biomarker levels
Summary
The genetic architecture of Parkinson’s Disease (PD) is complex and not completely understood. Multiple genetic studies to date have identified multiple causal genes and risk loci. Polygenic risk scores (PRS) may provide greater statistical power and inform about the genetic architecture of multiple phenotypes. The aim of this study was to test the association between PRS and PD risk, age at onset and cerebrospinal fluid (CSF) biomarkers (α-synuclein, Aβ1–42, t-tau and p-tau). The PRS was tested for association with PD status, age at onset and CSF biomarker levels in 829 cases and 432 controls of European ancestry. Results: The PRS was associated with PD status (p = 5.83×10−08) and age at onset (p = 5.70×10−07). The genetic architecture of PD is complex and not completely understood. Several genetic studies have identified multiple causative genes as well as common and rare variants.
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