Mov Disord: Genetic risk score helps stratify Parkinson's disease

Age is one of the strongest known risk factors for Parkinson's disease (PD)
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Therefore, as more and more people live to old age, the incidence of Parkinson's disease is expected to rise sharply in the next few decades

Precision GWAS

In the linear regression model, the variants detected by PD GWAS are also related to the age of onset of PD
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Only a few common variants have reached the age-associated signal of individual onset in a genome-wide sense, but models based on the polygenic risk score (PRS) have consistently found that a higher cumulative burden of hereditary PD risk is associated with earlier onset

Polygenic risk scores (PHSs) using time-event or survival frameworks have been successful in Alzheimer's disease (AD) and prostate cancer (both are complex diseases that are highly age-related)
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This approach integrates the association with disease risk and age of onset into a common concept, with the hypothesis that genetic variation acts as a regulator of age-related risk

In this way, Lasse Pihlstrøm and others of the University of Oslo applied this PHS method to PD for the first time
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Although the incidence of PD is closely related to age, some problems need to be paid attention to from the beginning
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A small proportion of PD patients have a single-gene cause, which was recently estimated to be about 1% in the UK, but it is higher in certain populations

Using the personal-level case-control genotype data with age of onset information provided by the International Parkinson's Disease Genomics Consortium (IPDGC), they established a PHS model based on reference data of sporadic PD patients and healthy controls in the 40 to 75-year-old age group.
And verified in two independent data sets
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It further proves that the hazard ratio obtained by this method can be directly explained by the stratified annual incidence rate, which has potential significance for clinical trial design

They used the Cox regression framework to establish a polygenic risk score model in the training data set of 11693 PD patients and 9841 controls
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The score was then verified in an independent test data set of 5112 PD patients and 5372 controls, and a small single study sample of 360 patients and 160 controls

Polygenic risk score can predict the onset of PD

Combined with the epidemiological data of incidence, they applied the score to estimate the instantaneous PD risk of the genetic stratification of each age group
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The study proved the feasibility of the PD polygenic hazard approach, integrating genetic influences on disease risk and age of onset in a model
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Combined with other predictive biomarkers, this method may bring hope for risk stratification in future clinical trials of disease-modifying therapies that are designed to delay the onset of PD

This study proved the feasibility of the PD polygenic hazard method, integrating the genetic influence on disease risk and age of onset in a model

Genetic Stratification of Age‐Dependent Parkinson's Disease Risk by Polygenic Hazard Score.

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