Genetic risk-factors for the development of sporadic PD. In addition to the identification of monogenic causes of PD, the use of genome- wide association studies (GWAS) has identified a number of genetic polymorphisms which have been found to enhance the probability of developing PD. GWAS allow associations to be made between specific genetic variants and PD, as they provide the necessary, large sample size to find correlations between relatively infrequent mutations and disease prevalence. Some of the genes considered risk factors for sporadic PD are the same genes responsible for the development of monogenic PD. For example, mutations in the SNCA promoter have been shown to increase the risk of developing PD but are not directly causative (Pals et al. 2004, Xxxxxxxxxx et al. 2006). Furthermore, a single nucleotide polymorphism (SNP) of the SNCA gene has also been linked to increased PD susceptibility (Xxxxx et al. 2007). This SNP, called rs356219, has also been found to synergise with particular haplotype of mictrotubule-associated protein tau (MAPT), a gene normally associated with Alzheimer’s disease (Xxxxx et al. 2005). When these 2 polymorphisms are found together, Xxxxx et al. (2007) determined that they approximately doubled the chance of developing PD. LRRK2 has also been implicated as a susceptibility factor in idiopathic PD via SNPs known as rs1491942 and rs11564273 (Xxxxx et al. 2011). In addition, 2 other risk- enhancing polymorphisms (G2385R and R1628P), which are particularly prevalent in Asian populations, appear to confer up to 3-fold increased susceptibility to PD (Xxxxxx & Xxxxx 2009). Despite the association of various established PD-genes with an increased susceptibility to the disease, mutations in the glucocerebrosidase (GBA) gene are thought to be the most common risk factors for the development of PD (Xxxxxx et al. 2011). Homozygous mutations of GBA are responsible for the development of the autosomal-recessive Gaucher’s disease (GD), a disorder characterised by abnormal storage and accumulation of glycolipids within lysosomes that most commonly occurs outside of the CNS (Zimran 2011). Some homozygous GD patients have been shown to go on to develop early-onset PD (Xxxxxx et al. 2003). Interestingly, heterozygotes for GBA mutations don’t develop GD but have, nevertheless, been found to have approximately a 5-fold greater chance of developing PD compared with people with wild type GBA (Sidransky et al. 2009), strongly suggesting that the GBA enzyme could be involved in the pathogenesis of ...
