Parkinson disease (PD) is the most common neurodegenerative movement disorder with age-related prevalence. Approximately 1% of the population is affected at 65 years, increasing to 4–5% in 85-year-olds. The mean age of onset is 70 years although 4% of patients develop disease before the age of 45. The burden to patients, families, caregivers and society is steadily increasing with population aging.
LRRK2 p.G2019S mutation is responsible for an autosomal-dominant form of familial PD. LRRK2 mutations accounts for up to 40% of sporadic PD in Tunisia, 18% in Ashkenazi Jewish populations, 1-2% in Caucasian populations. To date, LRRK2 is the gene with the most pathogenic mutations for PD. These include missense mutations R1441C/G/H, N1437H, I2020T, Y1699C in addition to G2019S. More common polymorphisms that contribute to risk of disease include A419V, R1628P and G2385R.
The most common pathology of LRRK2 parkinsonism is Lewy bodies. However, four different pathologies are also present including neurofibrillary tangles, ubiquitin-immunopositive inclusions, TDP-43 inclusions, nigral neuronal loss and gliosis without Lewy body inclusions(Ross et al. 2006a). Alternate pathologies are possible within the same family. Despite the pleomorphic pathology, LRRK2 manifests clinically as typical Parkinson disease.
Overall, the clinical presentation of idiopathic Parkinson’s disease (iPD) and LRRK2 parkinsonism are similar. However, pilot studies suggest some disparities in terms of motor and non-motor dysfunction. In a smaller sample we reported LRRK2 mutation carriers have less postural tremor, but more severe motor symptoms and dyskinesia, compared with iPD. Depression, hallucinations and sleep disorders are reportedly more common and LRRK2 p.G2019S patients may have more drug induced side-effects and premorbid affective disorders. Postural instability and gait disorders may be more prominent in early onset LRRK2 p.G2019S patients . However, LRRK2 p.G2019S carriers have also been reported with slower disease progression and lower MMSE scores.
Penetrance estimates from most North American and Western European family-based analyses have been conspicuously lower than in North Africa. However, within LRRK2 p.G2019S carrier patients there is incomplete penetrance. Twelve subjects who are healthy LRRK2 p.G2019S carriers have been right-censored and included in the cumulative incidence graph.This leads us to hypothesize that there are genetic factors that can modulate phenoconversion of LRRK2 p.G2019S. Modifier genes can modulate and fine-tune expression of other genes. They contain variants that affect the phenotypic outcome of a disease. Identification of modifier genes is essential in fully understanding the pathology of disease. The results will provide a foundation for subsequent translational neuroscience and therapeutic development. Knowledge of these modifier genes can provide better and more accurate diagnoses for the disease. MAPT and SNCA have recently been implicated in influencing the onset of motor symptoms of LRRK2 p.G2019S carriers. However, replication of the association of these modifier genes has been lacking.
We postulate that the novel genes and DNA variants that are identified in this study will advance our understanding of the biological mechanisms of LRRK2. Second, these genetic factors may prove to be useful therapeutic targets that could be used to delay the onset of PD among those with LRRK2 mutations. Third, screening of these genetic variants could be included as part of LRRK2 genetic testing and results provided as part of genetic counseling to yield better estimates of the likely onset of PD for a particular at-risk individual.
We hypothesize that there is a genetic modifier that can modulate the phenoconversion of LRRK2 p.G2019S, and the identification of this modifier will provide insight for developing treatments for PD patients.
Aims & Expected Results
We will test for association of genes already implicated in Parkinson’s disease on age of onset. This will involve examination of regression models on age of onset in LRRK2 p.G2019S carriers and idiopathic PD. For LRRK2 p.G2019S families, we will apply linkage analysis to identify the region the genetic modifier may lie and ascertain the array of genetic variation. Lastly, we will also employ imputation of whole genome sequencing data and collapsing variant association analyses to narrow down the variants of interest within the linkage regions. A separate cohort will be used to replicate the findings in Aim 3 with a different Tunisian and Norwegian cohort of LRRK2 p.G2019S.
We have recently published the clinical differences of LRRK2 and idiopathic PD and discovered that there is a gender difference in age-of-onset that seems to be LRRK2-specific. LRRK2 also has a more unified progression regardless of other PD symptoms compared to idiopathic PD. Using genetic linkage; we have narrowed down regions that are important in age-of-onset on chromosome 1, 11, 21 and X. We have already started to employ imputation with our whole genome sequencing data to identify these. SNCA and MAPT variants do not influence age of onset in LRRK2 parkinsonism.