Objective: We aimed to identify genetic variants associated with clinical heterogeneity in deep brain stimulation outcome of Parkinson’s Disease patients with an overall objective of identifying factors that could be applied clinically to inform patient and target selection, leading to improved surgical outcome. 

Background: Postoperative outcome following deep brain stimulation of the subthalamic nucleus is variable particularly with respect to axial motor improvement. We hypothesised a genetic underpinning to the response to surgical intervention, termed “surgicogenomics”.

Method: Retrospective clinical data was extracted from 150 patient’s charts and genomic DNA from corresponding blood samples genotyped using NeuroX. Genetic data were clustered based on surgical outcome assessed by comparing pre- and post-operative scores of levodopa equivalent daily dose and axial impairment at one and five years post surgery. Allele frequencies were compared between patients with excellent vs. moderate/poor outcomes as defined using a priori defined cut-offs. Burden of rare coding variants, combined annotation dependent depletion and polygenic risk scores were calculated.

Results: NeuroX identified 2917 polymorphic markers at 113 genes mapped to known Parkinson’s Disease loci, including 202 rare nonsynonymous variants. The gene-burden analyses suggested the association of axial impairment with CRHR1, IP6K2 and PRSS3, while SH3GL2 was linked to reduction in levodopa equivalent daily dose. The strongest association with surgical outcome was detected within a 150K region of intron 1 of SH3GL2.

Conclusion: Once validated in independent populations, our findings may be implemented to improve patient selection for deep brain stimulation in Parkinson’s disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/axial-impairment-following-deep-brain-stimulation-in-parkinsons-disease-a-surgicogenomic-approach/