Objective: Motor and cognitive progression in Parkinson’s is heterogeneous. Our aim is to identify single nucleotide polymorphisms (SNPs) associated with disease progression.

Background: Rare genetic variants, such as GBA, have been shown to predict mortality and motor progression in Parkinson’s disease. There is early evidence from small studies that common genetic variants and the cumulative Genetic Risk Score are also associated with motor and cognitive decline [1,2].

Methods: 1987 patients with recent-onset Parkinson’s disease were recruited to the Tracking Parkinson’s study in the UK. DNA samples were genotyped using the Illumina HumanCore Exome array with custom content and imputed using the Haplotype Reference Consortium panel v1.1. Motor progression was defined as annual change in the MDS-UPDRS Part III scores from baseline to 18 months (on/off medication) and 24 months (off medication). Cognitive progression was defined as annual change in Montreal Cognitive Assessment (MoCA) scores from baseline to 18 months. We conducted unbiased Genome Wide Association Studies (GWASs) with linear regression models to search for associated variants across the genome. Age at onset, sex and population structure (10 principal components) were included as covariates.

Results: 33 patients were excluded because they received a different diagnosis other than Parkinson’s. Early results from the motor progression GWAS showed that one loci in Chromosome 3 is significantly associated with change in MDS-UPDRS Part III score (on or off medication) at 18 months, p<5x10^-8. When we conducted a GWAS using MDS-UPDRS Part III data in the ‘off’ medication state, several loci in Chromosomes 3, 10, 7 and 11 reached nominal significance (p<5x10^-5) but none reached genome-wide significance. For cognitive progression, no SNPs reached genome-wide significance. However several loci in Chromosome 7, 4 and 11 reached nominal significance. We will take these variants forward for replication in independent cohorts and investigate the biological plausibility using gene expression analysis, pathway analysis and comparison with exome data.

Conclusions: Our pilot analyses show early evidence that common genetic variants may be associated with motor and cognitive progression but longer follow-up is required. Genetic variants that are associated with progression could potentially be investigated as targets for new therapies to stop or slow disease progression.

References: 1. 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. doi:10.1001/jamaneurol.2017.4206. 2. Latourelle JC, Beste MT, Hadzi TC, et al. Large-scale identification of clinical and genetic predictors of motor progression in patients with newly diagnosed Parkinson’s disease: A longitudinal cohort study and validation. Lancet Neurol. 2017;16(11):908-916. doi:10.1016/S1474-4422(17)30328-9.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genome-wide-association-studies-of-motor-and-cognitive-progression-in-parkinsons-disease/