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Genetic and Environmental Modifiers for LRRK2-Associated PD

In the last decades, mutations of several genes have been found to cause familial Parkinson’s disease (PD) and variants of these genes can also increase the risk for developing sporadic parkinsonism which account for more than 90% of the cases. Particular interest has been focused on the leucine-rich repeat kinase 2 (LRRK2), alpha-synuclein and tau genes. It has been postulated that genetic variation on disease risk and phenotype might depend on the co-occurrence of multiple genes and environmental exposures. However, convincing evidence is still lacking. This project aims to establish cross sectional and longitudinal cohorts of LRRK2 carriers and to investigate how LRRK2 gene changes interact with other genes as well as environmental exposure in causing PD.

Project Description: 
This project will build on two existing cohorts — the Chinese National Consortium of PD (CNCPD) and the Beijing Longitudinal Study on Aging (BLSA) cohort. We will first genotype and screen for subjects with LRRK2 risk variants to expand the cohorts. Neurological exams will then be carried out in non-PD subjects positive to LRRK2 risk variants to identify PD patients and non-motor symptoms including olfactory function, heart rate variability and RBD by questionnaire will be investigated to identify potential risk factors for or pre-motor stage of PD. The genetic polymorphisms of SNCA (rs356219 and Rep-1) and MAPT (rs2435207 and rs242562) will be genotyped on all subjects screened positive for LRRK2 risk variants, aiming to investigate their effects on the penetrance and clinical manifestations in LRRK2-positive PD. Moreover, environmental exposures and habits on the penetrance and clinical manifestations of LRRK2-positive PD will also be investigated independently and in combination with other genetic variants.

Relevance to Diagnosis/Treatment of PD:  
Understanding LRRK2-associated PD is likely to provide critical insights of the cause of the more common idiopathic form of PD. It could provide evidence of influencing factors for penetrance and clinical manifestations for LRRK2-associated PD, and therefore provide biomarkers and clinical markers for screening susceptible individuals and pre-clinical patients. In addition, results of the study may help to develop potential therapeutic targets for PD.

Anticipated Outcome:
We anticipate establishing the largest and unique cohorts and tissue bank of Chinese with LRRK2-positive PD and non-PD, including clinical, genetic and environmental information. We will answer whether variants of alpha-synuclein and tau genes and environmental exposures might modify the penetrance and expressivity of LRRK2-positive PD.


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