Genetic biomarkers
The diagnosis of idiopathic PD has become more complex thought the discovery of Mendelian genes which cause monogenic forms of the disease such as autosomal dominant mutations in the SNCA, LRRK2 or VPS35 genes and autosomal recessive Parkin or PINK1 mutations. Taken together these account for a small percentage of PD cases seen in clinical practice, but asymptomatic carriers of dominant PD mutations like LRRK2 are obvious candidates when trying to study the preclinical phase of PD. In addition,several other genes have been identified which contribute to an increased risk for the sporadic form of thedisease [95]. Derived from careful clinical observations of parkinsonism in patients with Gaucher’s disease and their relatives, heterozygous mutation in the glucocerebrosidase (GBA) gene has been found to associate with PD risk with an odds ratio of 5.4 [96]. Penetrance of this mutation seems to be high [97] and the prevalence of GBA mutations in PD populations has been between 3 and 20% in different studies, with the highest rates found in PD patients of Ashkenazi Jewish ancestry [96–99]. Importantly, pathogenic GBA variants are found in 1–3% of the population [96] and are associated with deterioration in clinical markers of PD consistent with prodromal PD [99]. A more recent discovery is the association of mutations in the GTP cyclohydrolase 1 gene, representing the most common cause of DOPA-responsive dystonia, with sporadic PD with an odds ratio of 7.5 [100]. Pathogenic variants of this gene, however, seem to be rather rare in the population. Many more common low-risk susceptibility variants in other loci have only recently been identified and confirmed in large meta-analysis of datasets from genome-wide association studies (GWAS) in PD (Table 3). Although the effects of single genetic susceptibility factors seem to be small with odds ratios for each locus ranging from 0.7 to 1.8, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk with odds ratio of 2.5 (95% CI 2.2–2.8) in one [101] and 3.3 (95% CI 2.6–4.3) in a more recent study [102] (Table 3). Many of the reported genes such as SNCA and LRRK2 are also known to encode for key-player proteins in PD pathogenesis [95]. A dedicated online database has recently been created, where results of all published genetic association studies in PD and meta-analysis are freely available (http://www.pdgene.org) [103]. In addition, a polygenic risk score, consisting of small effect allels, has recently been identified in a discovery GWAS dataset and replicated in 3 independent GWAS datasets [104]. The average polygenic score in patients with an early disease age at onset was significantly higher than in those with a late age at onset [104], substantiating the hypothesis that accumulation of common polygenic alleles with relatively low effect sizes may considerably enhance overall PD risk and anticipate disease onset.
However, the true value of genetic risk scores (GRS) in the prediction of incident ‘sporadic’ PD is currently unknown. A recent study combined a GRS from 30 genetic risk factors with other PD markers using stepwise logistic regression analysis to identify PD cases in the Parkinson Progression Marker Initiative (PPMI) cohort as a training dataset [105]. The final model included GRS, olfactory function, family history of PD, age, and sex and was associated with an excellent separation of PD cases from controls in 5 independent validation cohorts (AUCs >0.92) [105]. When looking at the single markers however, olfactory assessment was most responsible for the explained variance (63%), followed by the GRS (14%), family history (11%), sex (6%), and age (6%) underlining the importance of olfactory testing for clinical and research purposes. Future prospective studies will have to assess the true value of this or similar models for the identification of prodromal PD.