Self-report data as a tool for subtype identification in genetically-defined Parkinson\u2019s Disease

Ashley R Winslow,Paul Cannon,Jemma B Wilk,Craig L Hyde,Warren D Hirst,Melissa R Miller,Nicholas Eriksson

doi:10.1038/s41598-018-30843-6

Abstract

Through a targeted recruitment 23andMe has collected DNA and patient-reported symptoms from more than 10,000 subjects reporting a physician-verified diagnosis of PD. This study evaluated the potential of self-report, web-based questionnaires to rapidly assess disease natural history and symptomology in genetically-defined PD populations. While average age-at-diagnosis was significantly lower in GBA mutation carriers compared to idiopathic PD, or iPD (idiopathic PD, defined as no GBA mutations and no LRRK2 G2019S mutation), there were no significant differences in symptoms. Conversely, LRRK2 G2019S carrier status significantly associated with reporting of milder daily symptoms of lightheadedness and several differences were observed at a false discovery rate < 0.1, including increased reporting of changes in walking as an initial symptom of disease, decreased reporting of lightheadedness upon standing, and milder symptoms related to daily functioning. The subclinical differences in symptoms reported by LRRK2 G2019S carriers suggest differences in underlying pathophysiology and/or disease progression in LRRK2 carriers compared to iPD. Importantly, we confirm previous findings in PD genetic subsets where disease characteristics were ascertained through clinical exam. Overall, these data support the effective use of self-report and genetic data to rapidly analyze information from a large disease population or difficult to identify genetic subgroups.

Highlights

While recent genome-wide association studies (GWAS) have identified more than 40 loci associated with Parkinson’s disease (PD) susceptibility[1,2], most of our current biological understanding of the disease stems from research on rare mutations associated with PD
To better understand if carriers of GBA and LRRK2 mutations with PD represent a specific disease subtype, we evaluated differences in disease natural history and manifestation in three genetically-defined groups: LRRK2 G2019S carriers, carriers of 17 mutations in GBA (Table 1), and idiopathic PD (iPD)
While GBA mutation carriers had an earlier age-at-diagnosis on average, only the LRRK2 G2019S carriers presented with significant differences in motor phenotypes and daily functioning, GBA mutation carriers were indistinguishable from the iPD group

Summary

Introduction

While recent GWAS have identified more than 40 loci associated with Parkinson’s disease (PD) susceptibility[1,2], most of our current biological understanding of the disease stems from research on rare mutations associated with PD. Two such genes, LRRK2 (leucine rich repeat kinase 2) and GBA (glucosidase beta acid, glucocerebrosidase), are recognized risk loci and known causes of autosomal dominant PD. The hope is that these same cellular processes are the basis of disease for all forms of Parkinson’s disease Despite this progress, the utility of rare, single gene mutations to model complex disorders has been called into question. Gaining a better clinical and genetic understanding of carriers of LRRK2 and GBA mutations will help elucidate similarities in pathogenic events in PD as well as identify disease subtypes that may have distinct biology or distinct clinical manifestation

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Conclusion