Open AccessAxial Impairment Following Deep Brain Stimulation in Parkinson’s Disease: A Surgicogenomic Approach
Author(s) -
Naomi P. Visanji,
Mahdi Ghani,
Eric Yu,
Erfan Ghani Kakhki,
Christine Sato,
Danielle Moreno,
Taline Naranian,
YuYan Poon,
Maryam Abdollahi,
Maryam Naghibzadeh,
Rajasumi Rajalingam,
Andrés M. Lozano,
Suneil K. Kalia,
Mojgan Hodaie,
Mélanie Cohn,
Marta Statucka,
Alexandre Boutet,
Gavin J B Elias,
Jürgen Germann,
Renato P. Munhoz,
Anthony E. Lang,
Ziv GanOr,
Ekaterina Rogaeva,
Alfonso Fasano
Publication year - 2022
Publication title -
journal of parkinson's disease/journal of parkinson's disease (online)
Language(s) - English
Resource type - Journals
eISSN - 1877-718X
pISSN - 1877-7171
DOI - 10.3233/jpd-212730
Subject(s) - deep brain stimulation , medicine , linkage disequilibrium , parkinson's disease , subthalamic nucleus , disease , levodopa , allele , genetics , biology , haplotype , gene
Background: Postoperative outcome following deep brain stimulation (DBS) of the subthalamic nucleus is variable, particularly with respect to axial motor improvement. We hypothesized a genetic underpinning to the response to surgical intervention, termed “surgicogenomics”. Objective: We aimed to identify genetic variants associated with clinical heterogeneity in DBS outcome of Parkinson’s disease (PD) patients that could then be applied clinically to target selection leading to improved surgical outcome. Methods: Retrospective clinical data was extracted from 150 patient’s charts. Each individual was genotyped using the genome-wide NeuroX array tailored to study neurologic diseases. 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 grouped using a priori defined cut-offs. We analyzed common variants, burden of rare coding variants, and PD polygenic risk score. Results: NeuroX identified 2,917 polymorphic markers at 113 genes mapped to known PD loci. The gene-burden analyses of 202 rare nonsynonymous variants suggested a nominal association of axial impairment with 14 genes (most consistent with CRHR1, IP6K2, and PRSS3). The strongest association with surgical outcome was detected between a reduction in levodopa equivalent daily dose and common variations tagging two linkage disequilibrium blocks with SH3GL2. Conclusion: Once validated in independent populations, our findings may be implemented to improve patient selection for DBS in PD.