Initial studies focused on early-onset and familial Parkinson’s disease (PD) discovered rare mutations in 16 loci (PARK1-20). Recent, genome-wide association studies (GWAS) have found 26 PD risk loci with small effect size. However, most of the “GWAS hits” contain multiple genes that are equally likely to be affected by associated polymorphisms. Therefore, the currently identified genetic factors explain only 6-7% of the phenotypic variability associated with PD. The most significant GWA signals account for only 3-5% of PD genetic variability. Thus, a significant portion of the genetic contribution in PD remains to be discovered.

PD is a clinically, pathologically and genetically heterogeneous disorder. Recently, genetic studies in complex diseases have provided evidence that clinical phenotypes (categorical classification) can be addressed as a collection of multiple phenotypes. Focusing on specific traits (e.g. biomarkers) of the disease has facilitated its correlation with a genetic signature. Thus, analyzing groups of patients that share heritable clinical features improves ability to identify underlying genetic architecture and uncover novel genes or pathways involved in PD.


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