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Paul KC, Schulz J, Bronstein JM, Lill CM, Ritz BR. Association of Polygenic Risk Score With Cognitive Decline and Motor Progression in Parkinson Disease. JAMA Neurol. 2018;75(3):360–366. doi:10.1001/jamaneurol.2017.4206
Do genome-wide association study–identified susceptibility risk loci for Parkinson disease modify cognitive and motor symptom progression?
In this population-based study of 285 patients with Parkinson disease, a higher polygenic risk score based on 23 Parkinson disease genome-wide association study–identified single-nucleotide polymorphisms was associated with faster cognitive decline and progression of motor symptoms. Results did not change after removing GBA loci from the risk score.
Susceptibility risk alleles had a cumulative association with cognitive and motor decline in Parkinson disease; these alleles may influence not only Parkinson disease susceptibility but also disease progression in multiple domains.
Genetic factors have a well-known influence on Parkinson disease (PD) susceptibility. The largest genome-wide association study (GWAS) identified 26 independent single-nucleotide polymorphisms (SNPs) associated with PD risk. Among patients, the course and severity of symptom progression is variable, and little is known about the potential association of genetic factors with phenotypic variance.
To assess whether GWAS-identified PD risk SNPs also have a cumulative association with the progression of cognitive and motor symptoms in patients with PD.
Design, Setting, and Participants
This longitudinal population-based cohort study of 285 patients of European ancestry with incident PD genotyped 23 GWAS SNPs. One hundred ninety-nine patients were followed up for a mean (SD) of 5.3 (2.1) years for progression (baseline: June 1, 2001, through November 31, 2007; follow-up: June 1, 2007, through August 31, 2013, with mortality surveillance through December 31, 2016); 57 patients had died or were too ill for follow-up, and 29 withdrew or could not be contacted. Movement disorder specialists repeatedly assessed PD symptom progression.
Main Outcomes Measures
The combined association of PD risk loci, after creating a weighted polygenic risk score (PRS), with cognitive decline, motor progression, and survival, relying on Cox proportional hazards regression models and inverse probability weights to account for censoring.
Of the 285 patients undergoing genotyping, 160 were men (56.1%) and 125 were women (43.9%); the mean (SD) age at diagnosis was 69.1 (10.4) years. The weighted PRS was associated with significantly faster cognitive decline, measured by change in the Mini-Mental State Examination (hazard ratio [HR] per 1 SD, 1.44; 95% CI, 1.00-2.07). The PRS was also associated with faster motor decline, measured by time to Hoehn & Yahr Scale stage 3 (HR, 1.34; 95% CI, 1.00-1.79) and change in Unified Parkinson’s Disease Rating Scale part III score (HR, 1.42; 95% CI, 1.00-2.01).
Conclusions and Relevance
Susceptibility SNPs for PD combined with a cumulative PRS were associated with faster motor and cognitive decline in patients. Thus, these genetic markers may be associated with not only PD susceptibility but also disease progression in multiple domains.
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