LRRK2 G2019S Disease Penetrance Modifiers
MJFF Research Grant, 2010
The most commonly found mutation in Parkinsonís disease patients is LRRK2 G2019S.† This mutation can lead to the development of Parkinsonís disease at very different ages, from early thirties to late eighties. In this proposal, we attempt to identify genetic factors influencing the age at which a person with the LRRK2 G2019S mutation develops Parkinsonís disease.
By sequencing the entire genome, this study aims to identify all genetic variation in 16 individuals from three different families that present the LRRK2 G2019S mutations.† These families represent the two extremes of the spectrum regarding the age at onset of disease, and are divided in two groups; family members who developed Parkinsonís disease at the age of 40 years or younger, and those that developed disease at the age of 76 or older. The variants common to one group of patients (early or late onset) and lacking in the other will be the candidates for altering the age at disease onset. These variants will be selected for further screening and correlation with age at disease onset in additional LRRK2 G2019S carriers from the same population.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:††
The identification of genetic factors that alter the age at onset for those patients with LRRK2 G2019S mutations will provide novel targets for therapeutic intervention with potential to halt or delay the onset of disease.
We anticipate the identification of genes containing genetic variants that affect the age at which patients develop Parkinsonís disease. These genetic modifiers will then be used towards the development of novel therapeutics with potential to slow and even halt the development of disease. We expect these novel therapies to be effective in patients with LRRK2 G2019S mutations, but efficacy for idiopathic patients is not unexpected since the pathways towards disease may be common.
Fourteen Tunisian Arab-Berber subjects provided informed consent and DNA samples for whole genome sequencing (WGS). Individuals/DNA samples are all LRRK2 G2019S carriers, half with early onset disease (mean onset 34.9 years (SDĪ7.2, range 22-42)) whereas half were clinically asymptomatic elderly carriers (mean age 77 years (SDĪ6.9, range 68-90)). All were clinically assessed. Each sample has ~3,994,481 single nucleotide variants called of which ~91% are in dbSNP (34% are within genes (using refGene start and end positions) and ~1.5% are within exons). In addition each sample generated ~325,750 insertions (67% within dbSNP, 36% within and ~1.1% within exons), 349,189 deletions (58% within dbSNP, 35% within and ~1.0% within exons) and 41,903 breakpoints (8.7% within dbSNP, 37% within and ~0.8% within exons). Based on sequencing all individuals were unequivocally identified/confirmed as LRRK2 G2019S carriers. Comparison of these two sets of data generated an initial list of 277autosomal non-synonymous/missense variants with significantly different genotype distributions. These are now prioritized for genotypic validation in a larger series of LRRK2 G2019S carriers and in the LRRK2 Cohort Consortium. WGS analysis of additional samples has been proposed to more meaningfully assess coding changes, non-coding variants, in/dels and larger structural genomic rearrangements.
Professor at University of British Columbia (UBC)
Location: Vancouver, Canada