Objective: To assess the role of monogenic forms of PD and polygenic risk scores (PRS) on the motor and cognitive outcome of deep brain stimulation (DBS) surgery in Parkinson’s disease patients.

Background: Several studies have reported on genetic background and outcome of DBS in PD patients. PRS has been shown to predict both risk and progression of PD.  Apolipoprotein E e4 (APOE e4) allele carrier status, a well-known risk factor for Alzheimer’s disease, has also been associated with increased risk of cognitive decline in Parkinson’s disease. This study aims to assess the role of both monogenic forms of PD and genetic risk factors on DBS outcome.

Method: Forty-nine PD patients who had undergone DBS at the NIH were genotyped on Illumina’s Neurochip or NeuroX custom-designed genotyping array. After quality control (call rates <95%, sex mismatches, heterozygous outliers), patients were screened for GBA, LRRK2, PRKN, APOE, and MAPT mutations. In addition, genetic risk scores were calculated for patients with whole genome sequencing using the ninety genetic risk loci identified in the latest PD meta-GWAS[1]. Multivariate linear regression was performed on the differences in pre- and 3-months and 24-months post-operative motor (UPDRS) and cognitive scores (Mattis Dementia Rating Scale-2, Beck Depression Inventory, Verbal Fluency) and genetic status, while controlling for sex, age at surgery, disease duration, DBS target, and ethnicity.

Results: Baseline cognitive and motor measures were not significantly different between the GBA, LRRK2, PARK2, MAPT H2, and APOE e4 carrier and non-carrier groups. After controlling for sex, age at surgery, disease duration, and ethnicity, GBA carriers had significantly worse cognitive outcome than non-carriers (p<0.05), and the change in phonemic fluency score was negatively associated with APOE e4-carrier status (p<0.05). PRS was not significantly associated with DBS outcome.

Conclusion: This study suggests that specific genotypic variants such as GBA mutations and APOE e4 rather than a polygenic risk score based on common risk variants serve as stronger predictors of DBS cognitive outcome.

References: [1] Nalls, Mike A, et al. “Expanding Parkinson’s Disease Genetics: Novel Risk Loci, Genomic Context, Causal Insights and Heritable Risk.” BioRxiv, Cold Spring Harbor Laboratory, 1 Jan. 2019, www.biorxiv.org/content/10.1101/388165v2.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/determining-outcome-of-deep-brain-stimulation-surgery-in-parkinsons-disease-patients/