Objective: To explore, using a data driven statistical analysis method, discriminating phenotype features of disease in a large group of patients with Parkinson’s disease (PD) with or without genetic mutations associated with the disease.  

Background: Recent studies investigated genotype-phenotype relation in PD patients carriers of genetic mutations in the LRRK2 and GBA genes. These studies explored specific features in relation to genetic status. Data driven analysis utilizes methods of big-data analytics to explore the relation of multiple features across domains while accounting for multiple comparisons to provide a more accurate and unbiased presentation of  the findings.

Methods: Data was collected from 1,724 participants diagnosed with PD; 163 G2019S-LRRK2 carriers,  201 GBA carriers and 1360 Idiopathic PD. Data included 778 measures; demographic information questionnaires, cognitive assessments, physical and neurological examination, performance based measures and non-motor symptoms questionnaires. Statistical analysis was conducted by testing each of the measures and its association with genotype accounting for age, gender and disease duration resulting in more than 3000 tested comparisons. P-values were corrected for hierarchical multiple comparisons.

Results: 49 (out of 778) measures passed the significance threshold. Differences were found between groups in presenting motor symptoms, existence of psychiatric manifestations and response to dopaminergic treatment. PD carriers of the G2019S-LRRK2 mutation were more likely to present with gait difficulty as first motor symptom (adjusted p-value <0.0001), had more severe gait involvement and were more likely to experience freezing of gait within 3 years from diagnosis (p=0.004), compared to the 2 other groups. PD GBA mutation carriers had more cognitive involvement (p<0.0001), more autonomic dysfunction and hyposmia (p=0.0013), higher risk for psychiatric involvement (p=0.002) and for developing hallucination related to pharmacological treatment (p<0.0001).

Conclusions: The findings support a characteristic phenotypic disease based on genotype. Using a robust analytical approach strengthens earlier studies and extends them to portray a possible unique disease progression based on genotype. Such findings could help direct a more personalized therapeutic approach.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/data-driven-analysis-for-exploring-phenotypic-differences-in-patients-with-parkinsons-disease-with-or-without-genetic-mutations/