Objective: To examine the extent to which single nucleotide polymorphisms (SNPs) are associated with motor phenotype and progression in Parkinson’s disease (PD).

Background: Tremor-dominant (TD) and postural-instability-gait-disturbance (PIGD), the most commonly reported motor phenotypes, are associated with differential treatment response and prognosis. The etiology between these differences in phenotype is unknown. SNPs provide genetic variation that can be associated with disease risk and phenotype. The potential for PD phenotype to be associated with genetic variation has not been explored.

Methods: In a discovery cohort of 251 established PD subjects, we used linear regression to evaluate associations between motor phenotype and 10 SNPs previously reported to confer PD risk; SNPs with significant associations in the discovery cohort were then tested for replication of associations in an additional cohort of 559 PD subjects from three sites (PANUC-Seattle, PANUC-Portland, Univ. of Cincinnati). TD/PIGD ratios were calculated using the Unified Parkinson’s disease Rating Scale motor subscale (UPDRS-III). Primary outcomes included TD/PIGD ratio, tremor and PIGD subscores, and UPDRS-III score. Covariates in the model included age, sex, disease duration, and levodopa equivalent daily dose (LEDD). SNPs that showed a cross-sectional association with the TD/PIGD ratio were then examined in a longitudinal mixed-effects model to look for potential association between the SNP and the rate of motor progression. Longitudinal data of up to 7 years was available for 230 of the discovery cohort subjects. Covariates in the longitudinal analysis included age, sex, years from baseline visit, LEDD, and baseline UPDRS-III total.

Results: In our discovery cohort, we found a significant association between genotype at rs356182, near SNCA, and TD/PIGD ratio (FDR-corrected p = 0.04). This relationship was confirmed in the replication cohort (p = 0.02). Moreover, the minor allele (G) at rs356182 was associated with a higher TD/PIGD ratio and with slower motor progression (p = 0.01).

Conclusions: A common genetic variant near SNCA is associated with a tendency towards a TD phenotype and a slower rate of motor progression. SNPs may provide valuable insight into the mechanisms underlying phenotypic heterogeneity in PD.

An abstract with the discovery cohort results is submitted to the AAN 2016 annual conference in Vancouver.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-variation-near-the-snca-gene-associates-with-parkinsons-disease-motor-phenotype-and-progression/