Age at onset as stratifier in idiopathic Parkinson's disease - effect of ageing and polygenic risk score on clinical phenotypes

Abstract

Several phenotypic differences observed in Parkinson's disease (PD) patients have been linked to age at onset (AAO). We endeavoured to find out whether these differences are due to the ageing process itself by using a combined dataset of idiopathic PD (n = 430) and healthy controls (HC; n = 556) excluding carriers of known PD-linked genetic mutations in both groups. We found several significant effects of AAO on motor and non-motor symptoms in PD, but when comparing the effects of age on these symptoms with HC (using age at assessment, AAA), only positive associations of AAA with burden of motor symptoms and cognitive impairment were significantly different between PD vs HC. Furthermore, we explored a potential effect of polygenic risk score (PRS) on clinical phenotype and identified a significant inverse correlation of AAO and PRS in PD. No significant association between PRS and severity of clinical symptoms was found. We conclude that the observed non-motor phenotypic differences in PD based on AAO are largely driven by the ageing process itself and not by a specific profile of neurodegeneration linked to AAO in the idiopathic PD patients.

Fig. 1. Forrest plot with estimated coefficients and corresponding confidence intervals (±1.96 × standard error) for AAO, from linear/logistic regression of numerical/binary outcome on disease duration and AAO.

The colour blue indicates significant negative effects of AAO on the clinical outcome, and the colour red indicates significant positive effects at the Bonferroni-adjusted 5% level. The binary variables are annotated by asterisk. Clinical symptoms and scales are described in Supplementary Material.

Fig. 2. Pairwise association between age at onset (AAO), age at assessment (AAA) (y-axis) and polygenic risk score (PRS) (x-axis) with Kendall correlation coefficient.

Significant inverse association was determined between AAO and PRS and AAA and PRS indicating the younger the AAO of PD, the higher cummulative burden of small effect size variants (represented by PRS).

Fig. 3. Description of the study design and study dataset.

PD individuals with Parkinson’s disease, HC healthy control.