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Association of Polygenic Risk Score With Cognitive Decline and Motor Progression in Parkinson Disease.
JAMA Neurol. 2018 03 01; 75(3):360-366.JN

Abstract

Importance

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.

Objective

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.

Results

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.

Authors+Show Affiliations

Department of Epidemiology, UCLA (University of California, Los Angeles) Fielding School of Public Health.Genetic and Molecular Epidemiology Group, Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.Department of Neurology, UCLA David Geffen School of Medicine.Genetic and Molecular Epidemiology Group, Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.Department of Epidemiology, UCLA (University of California, Los Angeles) Fielding School of Public Health. Department of Neurology, UCLA David Geffen School of Medicine.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29340614

Citation

Paul, Kimberly C., et al. "Association of Polygenic Risk Score With Cognitive Decline and Motor Progression in Parkinson Disease." JAMA Neurology, vol. 75, no. 3, 2018, pp. 360-366.
Paul KC, Schulz J, Bronstein JM, et al. Association of Polygenic Risk Score With Cognitive Decline and Motor Progression in Parkinson Disease. JAMA Neurol. 2018;75(3):360-366.
Paul, K. C., Schulz, J., Bronstein, J. M., Lill, C. M., & Ritz, B. R. (2018). Association of Polygenic Risk Score With Cognitive Decline and Motor Progression in Parkinson Disease. JAMA Neurology, 75(3), 360-366. https://doi.org/10.1001/jamaneurol.2017.4206
Paul KC, et al. Association of Polygenic Risk Score With Cognitive Decline and Motor Progression in Parkinson Disease. JAMA Neurol. 2018 03 1;75(3):360-366. PubMed PMID: 29340614.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association of Polygenic Risk Score With Cognitive Decline and Motor Progression in Parkinson Disease. AU - Paul,Kimberly C, AU - Schulz,Jessica, AU - Bronstein,Jeff M, AU - Lill,Christina M, AU - Ritz,Beate R, PY - 2018/1/18/pubmed PY - 2019/9/10/medline PY - 2018/1/18/entrez SP - 360 EP - 366 JF - JAMA neurology JO - JAMA Neurol VL - 75 IS - 3 N2 - Importance: 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. Objective: 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. Results: 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. SN - 2168-6157 UR - https://www.unboundmedicine.com/medline/citation/29340614/Association_of_Polygenic_Risk_Score_With_Cognitive_Decline_and_Motor_Progression_in_Parkinson_Disease_ L2 - https://jamanetwork.com/journals/jamaneurology/fullarticle/10.1001/jamaneurol.2017.4206 DB - PRIME DP - Unbound Medicine ER -