The complex molecular landscape of Parkinson's disease in Turkey: Genotype-phenotype correlations in a potentially genetic cohort

Parkinson's Disease (PD) is the most common neurodegenerative movement disorder characterised by its cardinal motor signs, bradykinesia, rigidity, tremor, and postural instability. Since age is the significant risk factor, PD is expected to become a worldwide pandemic in 2040 because of rising life expectancy. The disease was considered as sporadic until the mutations in the SNCA gene were associated. Nowadays, it is known that 5-10% of PD cases can be genetically explained with monogenic inheritance. In this thesis, the molecular architecture of PD was investigated in the ethnically heterogeneous yet inbred Turkish population with a potentially genetic cohort comprising 195 index patients and 35 affected family members using state-of-the-art genetic technologies. Whole exome sequencing (WES) is a gold standard method to study PD genetics with a variable diagnostic yield that differs in distinct populations. In the framework of this thesis, WES revealed that 93 out of 230 patients have rare or novel variations in 27 different causative genes and/or known risk factors, GBA and GLUD2 genes. Seven out of 73 index patients were identified with oligogenic inheritance. Additionally, candidate risk factors, heterozygous PRKN/PINK1 and rare TENM4 variants, and the APOE E4 isoform were investigated in the thesis cohort. By re-annotating WES data and analysing two large data portals, AMP-PD and PPMI, ten possible candidate genes for PD were identified. Functional analyses will help to understand the accurate roles of these genes in the pathogenesis of PD. This thesis presents the distribution of mutations in PD-related genes in Turkey and demonstrates that the Turkish cohort under investigation represents with its specific features a mixture of European and Asian populations, further implicating a high gene/variant heterogeneity. The results of the thesis are expected to contribute to the knowledge about the genetic factors underlying Parkinson's disease in the Turkish population, paving the ways for accurate and early diagnosis and to the development of personalized treatments in the era of translational medicine.