Objective: The aim of the study is to use genome-wide approach to elucidate genetic variability that influences LRRK2 G2019S penetrance in Parkinson’s Disease (PD).

Background: Mutations in Leucine-rich repeat kinase 2 (LRRK2) mutation G2019S are the most frequently reported monogenic cause of PD among them, the glycine to serine substitution (G2019S) is the most common (1% of sporadic and 4% of familial PD patients worldwide, international LRRK2 consortium). This frequency varies greatly between ethnic groups, from 30-40% in North African countries to 0-3% in northern countries. Some carriers have early-onset Parkinsonism whereas others remain asymptomatic despite advanced age suggesting the influence of additional genetic variations.

Method: We recruited a clinic-based cohort of LRRK2 G2019S carriers including 289 participants from North Africa (224 unrelated carriers and 65 related carriers). LRRK2 carrier status was confirmed by Sanger sequencing or TaqMan SNP assays-on-demand. All samples were genotyped using Infinium OmniExpress-24-v1 array. We used genome-wide association analysis (GWAS) for related/unrelated G2019S carriers to find out loci of interest.

Results: When using age at onset (AAO) as quantitative trait, we identified two suggestive SNPs (rs1762792, pvalue = 8.70E-08; rs1360821 pvalue = 1.00E-07) by GWAS within the intergenic region between FABP5P4 and GPC6 (chromosome 13q31.3).These findings where confirmed when AAO was used as a categorical variable (dichotomised by median onset, 52 years, rs1762792 – pvalue = 1.20E-07; rs1360821 – pvalue = 2.00E-07). By using Kaplan–Meier analysis we compared how AAO varied with rs1762792 genotypes in all 276 G2019S carriers analysed. The CC homozygotes had a median AAO of 47 years while TT homozygotes had a median AAO of 57 years ; this suggests a protective role of the wild type allele. GWAS did not show any significant association with the DNM3 locus (rs2901600, pvalue = 0.8624) and the AAO in 276 North African related and unrelated affected G2019 carriers.

Conclusion: Our data suggests that genetic variability in 13q31.3 region may influence AAO for LRRK2 G2019S parkinsonism. These findings need to be replicated in other cohort of patients with a different ethnical background. This replication study is currently undergoing through an international collaboration.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-role-of-genetic-modifiers-in-parkinsons-disease-associated-lrrk2-g2019s-mutation/