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Association of Polygenic Risk Score With Cognitive Decline and Motor Progression in Parkinson Disease.

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.

SUBMITTER: Paul KC

PROVIDER: S-EPMC5885856 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Association of Polygenic Risk Score With Cognitive Decline and Motor Progression in Parkinson Disease.

Paul Kimberly C KC Schulz Jessica J Bronstein Jeff M JM Lill Christina M CM Ritz Beate R BR

JAMA neurology 20180301 3

<h4>Importance</h4>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.<h4>Objective</h4>To assess whether GWAS-identified PD risk SNPs also have a cumulat ...[more]

PMID: 29340614

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Project description:Background and objectivesEvidence suggests that either family history or polygenic risk score (PRS) is associated with developing Parkinson disease (PD). However, little is known about the longitudinal prognosis of PD according to family history and higher PRS.MethodsFrom the Parkinson's Progression Markers Initiative database, 395 patients with PD who followed up for more than 2 years were grouped into those with family history within first-degree, second-degree, and third-degree relatives (N = 127 [32.2%]) vs those without (N = 268 [67.8%]). The PRS of 386 patients was computed using whole-genome sequencing data. Longitudinal assessment of motor, cognition, and imaging based on dopaminergic degeneration was conducted during the regular follow-up period. Effects of family history, PRS, or both on longitudinal changes of cognition, motor severity, and nigrostriatal degeneration were tested using a linear mixed model. The risk of freezing of gait (FOG) according to family history was assessed using the Kaplan-Meier analysis and Cox regression models.ResultsDuring a median follow-up of 9.1 years, PD with positive family history showed a slower decline of caudate dopamine transporter uptake (β estimate of family history × time = 0.02, 95% CI = 0.002-0.036, p = 0.027). Family history of PD and higher PRS were independently associated with a slower decline of Montreal Cognitive Assessment (β estimate of family history × time = 0.12, 95% CI = 0.02-0.22, p = 0.017; β estimate of PRS × time = 0.09, 95% CI = 0.03-0.16, p = 0.006). In those 364 patients without FOG at baseline, PD with positive family history had a lower risk of FOG (hazard ratio of family history = 0.57, 95% CI = 0.38-0.84, p = 0.005).DiscussionHaving a family history of PD predicts slower progression of cognitive decline and caudate dopaminergic degeneration, and less FOG compared with those without a family history independent of PRS. Taken together, information on family history could be used as a proxy for the clinical heterogeneity of PD.Trial registration informationThe study was registered at clinicaltrials.gov (NCT01141023), and the enrollment began June 1, 2010.

Project description:Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets.To determine whether GBA mutations and the E326K polymorphism modify PD symptom progression.The entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state.Linear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site.Of the total sample of 733 patients who underwent successful genotyping, 226 (30.8%) were women and 507 (69.2%) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (??=?4.65; 95% CI, 1.72-7.58; P?=?.002), E326K (??=?3.42; 95% CI, 0.66-6.17; P?=?.02), and GBA variants combined as a single group (??=?4.01; 95% CI, 1.95-6.07; P?=?1.5?×?10-4) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (??=?0.38; 95% CI, 0.23-0.53; P?=?.01) and E326K (??=?0.64; 95% CI, 0.43-0.86; P?=?.002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6%]; P?=?.01) and GBA variant carriers (15 of 39 [38.5%]; P?=?.04) progressed to mild cognitive impairment or dementia.GBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.

Project description:Studies of Alzheimer's disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (emPRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain A?-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory was determined individually for 27 genetic variants in a reference sample (n = 151). These were then summed to generate a emPRS either including APOE (emPRSc?APOE) or excluding APOE (emPRSs?APOE ). Resultant emPRS were then evaluated, in a test sample (n = 75), against decline in global cognition, verbal episodic memory and a pre-Alzheimer's cognitive composite (AIBL-PACC) over 7.5 years. The mean (SD) age of the 226 participants was 72.2 (6.6) years and 116 (51.3%) were female. Reference and test samples did not differ significantly demographically. Whilst no association of emPRSs were observed with baseline cognition, the emPRSc? APOE was associated with longitudinal global cognition (-0.237, P = 0.0002), verbal episodic memory (-0.259, P = 0.00003) and the AIBL-PACC (-0.381, P = 0.02). The emPRSs? APOE was also associated with global cognition (-0.169, P = 0.021) and verbal episodic memory (-0.208, P = 0.004). Stratification by APOE ?4 revealed that the association between the emPRS and verbal episodic memory was limited to carriage of no ?4 or one ?4 allele. This was also observed for global cognition. The emPRS and rates of decline in AIBL-PACC were associated in those carrying one ?4 allele. Overall, the described novel emPRS has utility for the prediction of decline in cognition in preclinical AD. This study provides evidence to support the further use and evaluation of phenotype weightings in PRS development.

Dataset Information

Association of Polygenic Risk Score With Cognitive Decline and Motor Progression in Parkinson Disease.

Publications

Association of Polygenic Risk Score With Cognitive Decline and Motor Progression in Parkinson Disease.

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