Objective: To identify genetic variants associated with impulse control disorders (ICD) in Parkinson’s disease (PD)

Background: ICD is frequently associated with dopamine agonist (DA) therapy in PD. There are growing evidence of a high heritability for ICD in general population and PD. Previous candidate gene association studies showed that variants on genes belonging to the reward pathway are involved in this genetic susceptibility.

Methods: We selected 36 PD patients on DA therapy with (n=18) and without (n=18) ICD, matched for age and gender. Whole exome sequencing was performed using MedExome SeqScape EZ kit (Roche) and NexSeq 500 sequencer (Illumina). Variants with a strong functional impact (Cadd-score≥12.37) and in brain-expressed genes were selected. Allele frequencies, and their distribution in genes and pathways were analyzed respectively with single variant test and Optimized Sequence Kernel Association Test (SKAT-O). For this pilot study, pathways with p-value < 0.01 and genes and variants with p-value < 0.001 were retained for replication in the Parkinson’s Progression Markers Initiative (PPMI) cohort.

Results: From the 6,953 variants selected for the analysis, we identified 5 pathways associated with ICD below the 0.01 p-value threshold: Localization of the PINCH-ILK-PARVIN complex to focal adhesions (p=1.6×10^-3), adenylate cyclase activating pathway (p=1.6×10^-3), LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production (p=2.2×10^-3), AMPK inhibits chREBP transcriptional activation activity (p=2.7×10^-3), and IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (p=7.8×10^-3). The association with the adenylate cyclase activating pathway was replicated in PPMI cohort (p=2.0×10^-2), resulting in a combined significant p-value taking into account multiple testing (p=3.7×10^-4, Fisher’s combined test). None of the most associated genes nor variants in the discovery cohort were found associated in PPMI cohort.

Conclusions: Our results suggest that genes implicated in the signaling pathways linked to G protein-coupled receptors participate to genetic susceptibility to ICD in PD. These results are in accordance with the pharmacology of dopamine agonists, and the importance of ERK and cAMP signaling pathways in the dopamine-dependent plasticity in the striatum. Results from this pilot study need however to be replicated in independent cohorts.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/exome-sequencing-in-patients-with-impulse-control-disorders-in-parkinsons-disease-a-pilot-study/