Parkinson’s disease (PD) is the fastest-growing neurological disease and currently affects close to twelve million patients worldwide with no cure available. The disease risk is closely linked to specific environmental exposures and lifestyle. Only in a minority of ~15% of PD patients, the disease is caused by a genetic variant of a single gene. However, the role of pathogenic variants is more prominent in patients with an early disease onset. Mitochondrial dysfunction is a key player in PD pathogenesis. PD-causing variants are located on the nuclear genome; still, variants of the mitochondrial genome have also been associated with PD risk. Out of the estimated ~29% of PD heritability, there are ~15% unexplained. We aim to fill some of the gaps by investigating small point mutations and larger genetic events along with extra-nuclear genetic variants. Still, ~70% of PD cases are attributable to the environment.
We hypothesize that variants of the nuclear genome and mitochondrial genome shape the susceptibility and age at onset (AAO) of PD. Furthermore, environmental and lifestyle factors affect the risk of disease. By jointly assessing genetics and environment/lifestyle, we will be able to better predict the risk and AAO of PD.
Aim 1: To analyze the nuclear genome of early-onset PD patients (i.e., PD patients <50 years AAO, thus, presumably having a higher genetic load compared to typical late-onset PD) to find causal genes underlying PD pathogenesis.
Aim 2: To investigate the mitochondrial genome and explore interactions with nuclear-encoded mitochondrial genes and their association with PD risk and AAO.
Aim 3: To connect environmental and lifestyle factors that are already known to be relevant in PD (i.e., smoking, pesticide exposure, non-steroidal anti-inflammatory drugs (NSAIDs), caffeine, physical exercise, medication, comorbidities), for potential gene-environment interactions.