Abstract
Several studies have investigated the association of the Parkinson’s disease (PD) polygenic risk score (PRS) with several aspects of well-established PD. We sought to evaluate the association of PRS with the prodromal stage of PD. We calculated PRS in a longitudinal sample (n = 1120) of community dwelling individuals ≥ 65 years from the HELIAD (The Hellenic Longitudinal Investigation of Aging and Diet) study in order to evaluate the association of this score with the probability of prodromal PD or any of the established risk and prodromal markers in MDS research criteria, using regression multi-adjusted models. Increases in PRS estimated from GWAS summary statistics’ ninety top SNPS with p < 5 × 10–8 was associated with increased odds of having probable/possible prodromal PD (i.e., ≥ 30% probability, OR = 1.033, 95%CI: 1.009–1.057 p = 0.006). From the prodromal PD risk markers, significant association was found between PRS and global cognitive deficit exclusively (p = 0.003). To our knowledge, our study is the first population based study investigating the association between PRS scores and prodromal markers of Parkinson’s disease. Our results suggest a strong relationship between the accumulation of many common genetic variants, as measured by PRS, and cognitive deficits.
Highlights
Several non-motor symptoms have been associated with an increased risk to develop Parkinson’s disease (PD) in otherwise healthy individuals, while ongoing research aims to validate a variety of candidate PD biomarkers based on imaging, genetic, proteomic, or metabolomic signatures, supplemented by work on tissue markers accessible to minimally invasive biopsies
We excluded from the analysis those participants who were diagnosed with PD or dementia with Lewy bodies (DLB) and participants for whom the presence or absence of these diagnoses could not be ascertained (Maraki et al, 2019b; Giagkou et al, 2020)
Logistic regression models adjusted for MDSC1 and MDSC2 showed that increase in polygenic risk scores (PRS) was associated with increased odds of having 30 or 50% or more pPD probability (OR = 1.033, 95%CI: 1.009–1.057, p = 0.006; OR = 1.052, 95%CI: 1.015–1.089, p = 0.005), while further adjustment for age and sex did not change the results (OR = 1.036, 95%CI: 1.011–1.060, p = 0.004 and OR = 1.056, 95%CI: 1.019–1.096, p = 0.003, respectively)
Summary
Several non-motor symptoms have been associated with an increased risk to develop Parkinson’s disease (PD) in otherwise healthy individuals, while ongoing research aims to validate a variety of candidate PD biomarkers based on imaging, genetic, proteomic, or metabolomic signatures, supplemented by work on tissue markers accessible to minimally invasive biopsies. The recently defined MDS research criteria for prodromal PD include a combination of risk and prodromal markers, in an effort to define target populations of future disease modification trials (Heinzel et al, 2019a). These criteria have been prospectively validated in six independent cohort studies (Fereshtehnejad et al, 2017; Pilotto et al, 2017; Mahlknecht et al, 2018; Mirelman et al, 2018; Giagkou et al, 2020). The aforementioned variable, PRS, has been introduced and likelihood-ratio (LR) is estimated according to its value (Heinzel et al, 2019a)
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