The genetic background of Parkinson's disease: current progress and future prospects

Almost two decades of genetic research in Parkinson's disease (PD) have remarkably increased our knowledge regarding the genetic basis of PD with numerous genes and genetic loci having been found to cause familial PD or affect the risk for PD. Approximately 5–10% of PD patients have monogenic forms of the disease, exhibiting a classical Mendelian type of inheritance, however, the majority PD cases are sporadic, probably caused by a combination of genetic and environmental risk factors. Nowadays, six genes, alpha synuclein, LRRK2, VPS35, Parkin, PINK1 and DJ‐1, have definitely been associated with an autosomal dominant or recessive PD mode of inheritance. The advent of genome‐wide association studies (GWAS) and the implementation of new technologies, like next generation sequencing (NGS) and exome sequencing has undoubtedly greatly aided the identification on novel risk variants for sporadic PD. In this review, we will summarize the current progress and future prospects in the field of PD genetics.     

Complete screening for glucocerebrosidase mutations in Parkinson disease patients from Greece

Mutations in β-glucocerebrosidase gene (GBA) have been implicated in Parkinson disease (PD). A Greek cohort of 172 PD patients and 132 control individuals were screened for GBA mutations by complete sequencing of the gene's exons. Four mutations previously associated with Gaucher disease and/or Parkinson's disease (L445P, D409H, E326K, H255Q) were detected, as well as five newly identified variants (R329H, L268L, S271G, T428K, V460L), providing for the first time data regarding the frequency of GBA mutations among PD patients and controls, in the Greek population. H255Q was the most common GBA mutation among Greek PD patients (4/172). V460L was only found in control individuals (2/132). Overall, GBA mutations were significantly overrepresented in a subgroup of early onset PD patients, compared to controls (P = 0.019, OR = 4.2; 95%CI = 1.28–13.82), suggesting that GBA mutations may modify age of onset for PD.     

Association of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism with Parkinson's disease in a Greek population

Brain-derived neurotrophic factor (BDNF) enhances survival of dopaminergic neurons in the substantia nigra, whereas in patients with Parkinson's disease (PD), the expression of BDNF mRNA is decreased, thus making BDNF a candidate gene for PD susceptibility. The association between BDNF Val66Met polymorphism and PD has been evaluated in several studies with controversial results. Thus, we determined the distribution of BDNF Val66Met polymorphism in 184 Greek patients with sporadic PD and 113 control participants using polymerase chain reaction-restriction fragment length polymorphism, and explored the association of the polymorphism with certain clinical parameters of the disease. Our results do not support a major role for the BDNF Val66Met polymorphism in PD in the Greek population.     

Lack of Association of the PICALM rs3851179 Polymorphism With Parkinson's Disease in the Greek Population

ABSTRACT Parkinson's disease (PD) is a complex, heterogeneous neurodegenerative disorder, affecting approximately 1% of the population over 60?years of age. The molecular and cellular mechanisms underlying PD pathogenesis are still unknown. Clathrin-mediated endocytosis (CME) is a procedure closely related to the intracellular trafficking of multiple molecules in the cell, including proteins, lipids, and neurotransmitters. Recently, variations in the gene encoding the phosphatidylinositol binding clathrin assembly protein (PICALM) has been associated with Alzheimer's disease (AD), suggesting a possible role of CME in the pathogenesis of neurodegenerative diseases. In this study, we examined for the first time the potential role of the PICALM rs3851179 polymorphism in PD. We studied the PICALM rs3851179 polymorphism in 191 Greek patients with sporadic PD and 118 control subjects, using a PCR-RFLP method. Our results do not provide evidence that the PICALM rs3851179 polymorphism increase susceptibility of PD, in the Greek population.     

GSK3β polymorphisms, MAPT H1 haplotype and Parkinson's disease in a Greek cohort

To determine whether polymorphisms in the microtubule-associated protein tau (MAPT) and/or glycogen synthase kinase-3β (GSK3β) genes underpin susceptibility to Parkinson's disease (PD), we conducted a case-control association study in a Greek cohort of 196 PD cases and 163 healthy controls. In our study, the MAPT H1 haplotype was found to be significantly associated with PD, no association was detected between the intronic rs6438552 (−157 T/C) GSK3β polymorphism and PD, whereas the C/C genotype of the promoter rs334558 (−50 T/C) GSK3β polymorphism was found to exert a protective role. The C/C genotype of the rs334558 GSK3β polymorphism was also found to have an additional protective role in our MAPT H1/H1 PD subgroup. Haplotype analysis revealed that, the T-T haplotype of both GSK3β polymorphisms was over-represented in PD patients compared to controls, and this association was independent of MAPT H1 haplotype.     

Pharmacogenetics and levodopa induced motor complications

Aim: L-dopa remains the most effective symptomatic therapy for Parkinson's disease (PD) but unfortunately, its chronic use is often associated with motor complications. This review highlights the importance of pharmacogenetics in an individualised PD therapeutic approach.

Material and Methods: review of the literature was done.

Results: PD patients show remarkable heterogeneity in their response to L-dopa and this profound interindividual heterogeneity suggests that there is a genetic predisposition.

Conclusions: The impact of the genetic makeup of every individual on PD treatment appears to be of great importance in order to achieve not only the optimum therapeutic effect, but also with minimal side effects.     

Assessment of Parkinson's disease risk loci in Greece

Genome-wide association studies (GWAS) have been shown to be a powerful approach to identify risk loci for neurodegenerative diseases. Recent GWAS in Parkinson's disease (PD) have been successful in identifying numerous risk variants pointing to novel pathways potentially implicated in the pathogenesis of PD. Contributing to these GWAS efforts, we performed genotyping of previously identified risk alleles in PD patients and control subjects from Greece. We showed that previously published risk profiles for Northern European and American populations are also applicable to the Greek population. In addition, although our study was largely underpowered to detect individual associations, we replicated 5 of 32 previously published risk variants with nominal p values <0.05. Genome-wide complex trait analysis revealed that known risk loci explain disease risk in 1.27% of Greek PD patients. Collectively, these results indicate that there is likely a substantial genetic component to PD in Greece, similarly to other worldwide populations, that remains to be discovered.     

From 1997 to 2007: a decade journey through the H1 haplotype on 17q21 chromosome

The H1 haplotype was first identified 10 years ago. Initially, a dinucleotide polymorphism was detected in the tau (MAPT) gene and was subsequently found to be in linkage disequilibrium (LD) with other polymorphisms, forming the MAPT H1 haplotype, a risk factor for many neurological diseases, considered as tauopathies. Genetic and histopathologic data are in agreement that MAPT and its encoded protein have a pivotal role in the normal function of neurons. Currently, the H1 haplotype extends beyond the outer edges of MAPT encompassing multiple genes on chromosome 17 and thus increasing the number of candidate genes implicated in the pathogenesis of tauopathies. This review highlights the milestones and basic events in the journey towards uncovering the significance of the H1 haplotype.