Genetic analysis of Parkinson's disease using Next-generation sequencing

Abstract

Neurological diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Epilepsy and Multiple Sclerosis are included in the Global burden of disease study as these disorders have a high impact on public health. Lack of effective treatment has motivated the researchers to perform early diagnostics, by identifying new gene mutations, which can improve the therapies. The aim of this thesis was a genetic analysis of PD using next-generation sequencing data. In this thesis, whole genome sequencing (WGS) and whole exome sequencing (WES) using DNA from familial PD patients and healthy individuals was performed in order to identify the PD causal genes. A large repository of sporadic PD WES data and a genotyping array was used to replicate our findings. The PD patients from Germany were stratified for clinical trials on the basis of mitochondrial endo-phenotype by performing risk profiling of associated Single Nucleotide Polymorphisms (SNPs) using exome genotyping array. The sporadic PD WES and genotyping array data from International Parkinson’s disease Genomics Consortium was used to perform association tests, to determine the burden of rare variants in candidate genes of interest. Furthermore, mRNA sequencing of all the genes under the PD GWAS loci after knockdown with short hairpin RNAs was performed, to identify the actual genes contributing to PD risk and the novel pathways involved in PD. Finally, an epistatic interaction of a Mendelian PD gene and associated locus was performed to understand the joint contribution to PD risk. Taking everything into account, we identified pathogenic variants in known and some novel genes causing PD in families. On the basis of risk profiling some of the German PD patients will undergo clinical trials with coenzyme Q10 and vitamin K2. The association tests using sporadic PD data helped to identify some novel genes significantly associated with PD risk. The knockdown experiments facilitated the identification of genes contributing to PD risk in some of the PD GWAS loci.