Abstract
Mutations in the LRRK2 and GBA genes are the most common inherited causes of Parkinson's disease (PD). Studies exploring phenotypic differences based on genetic status used hypothesis-driven data-gathering and statistical-analyses focusing on specific symptoms, which may influence the validity of the results. We aimed to explore phenotypic expression in idiopathic PD (iPD) patients, G2019S-LRRK2-PD, and GBA-PD using a data-driven approach, allowing screening of large numbers of features while controlling selection bias. Data was collected from 1525 Ashkenazi Jews diagnosed with PD from the Tel-Aviv Medical center; 161 G2019S-LRRK2-PD, 222 GBA-PD, and 1142 iPD (no G2019S-LRRK2 or any of the 7 AJ GBA mutations tested). Data included 771 measures: demographics, cognitive, physical and neurological functions, performance-based measures, and non-motor symptoms. The association of the genotypes with each of the measures was tested while accounting for age at motor symptoms onset, gender, and disease duration; p-values were reported and corrected in a hierarchical approach for an average over the selected measures false discovery rate control, resulting in 32 measures. GBA-PD presented with more severe symptoms expression while LRRK2-PD had more benign symptoms compared to iPD. GBA-PD presented greater cognitive and autonomic involvement, more frequent hyposmia and REM sleep behavior symptoms while these were less frequent among LRRK2-PD compared to iPD. Using a data-driven analytical approach strengthens earlier studies and extends them to portray a possible unique disease phenotype based on genotype among AJ PD. Such findings could help direct a more personalized therapeutic approach.
Highlights
Mutations in the LRRK2 and GBA genes are the most common known genetic risk factors of Parkinson’s disease (PD) [1, 2]
A total of 1525 Ashkenazi Jewish (AJ) patients with PD participated in this study: 1142 idiopathic PD (iPD), 161 carriers of the G2019S-LRRK2 mutation and 222 carriers of the 7 common AJ mutations in the GBA gene
Differences between iPD, LRRK2-PD, and GBA-PD were found in multiple domains
Summary
Mutations in the LRRK2 and GBA genes are the most common known genetic risk factors of Parkinson’s disease (PD) [1, 2]. The phenotype of genetic-associated PD has been described mainly compared to idiopathic PD (iPD). Previous explorations were based on a hypothesis driven approach, comparing specific features or data summaries between groups, and adjusting (in best case scenarios) for a limited number of multiple comparisons. The magnitude of variables measured and the breadth of domains are often large. Such abundance of data requires accounting for multiple comparisons and selective inference in order to maintain results replicability [15, 16], and avoid loss of information because of summation into means and total scores. The aim of this study was to explore phenotypic expression in iPD, LRRK2-PD and GBA-PD using a well-guarded datadriven approach
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