Abstract
Parkinson's disease (PD) is a sporadic progressive neurodegenerative brain disorder with a relatively strong genetic background. We have reviewed the current literature about the genetic factors that could be indicative of pathophysiological pathways of PD and their applications in everyday clinical practice. Information on novel risk genes is coming from several genome-wide association studies (GWASs) and their meta-analyses. GWASs that have been performed so far enabled the identification of 24 loci as PD risk factors. These loci take part in numerous cellular processes that may contribute to PD pathology: protein aggregation, protein, and membrane trafficking, lysosomal autophagy, immune response, synaptic function, endocytosis, inflammation, and metabolic pathways are among the most important ones. The identified single nucleotide polymorphisms are usually located in the non-coding regions and their functionality remains to be determined, although they presumably influence gene expression. It is important to be aware of a very low contribution of a single genetic risk factor to PD development; therefore, novel prognostic indices need to account for the cumulative nature of genetic risk factors. A better understanding of PD pathophysiology and its genetic background will help to elucidate the underlying pathological processes. Such knowledge may help physicians to recognize subjects with the highest risk for the development of PD, and provide an opportunity for the identification of novel potential targets for neuroprotective treatment. Moreover, it may enable stratification of the PD patients according to their genetic fingerprint to properly personalize their treatment as well as supportive measures.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative brain disease after Alzheimer’s disease
A few of these loci, 24 in particular, harboring single nucleotide polymorphisms’ (SNPs) that were found to be associated with PD were validated in the replication phase of the latest and largest meta-analysis of genome-wide association studies (GWASs) performed by Nalls et al in 2014
We focus on the largest meta-analysis of GWASs on PD risk so far (Nalls et al, 2014), but we searched the PubMed database and GWAS catalog (Welter et al, 2014) for studies that pointed out the same loci as the above-mentioned meta-analysis
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative brain disease after Alzheimer’s disease. At early stages of research on genetics of PD, only linkage studies were performed, which means that families with PD history were included in the study These studies identified mutations in six genes that conclusively cause monogenic PD—SNCA, LRRK2, Parkin, PINK1, DJ-1, ATP13A2 (Klein and Westenberger, 2012). Genome-wide association studies (GWASs) that compared single nucleotide polymorphisms’ (SNPs) frequencies between sporadic PD patients and healthy individuals have identified several loci as Parkinson’s disease susceptibility genes (Klein and Westenberger, 2012; Nalls et al, 2014). A few of these loci, 24 in particular, harboring SNPs that were found to be associated with PD were validated in the replication phase of the latest and largest meta-analysis of GWASs performed by Nalls et al in 2014. This review highlights the main functions of these genes’ products and their role in the PD pathogenesis
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