The Neurogenetics of Parkinson's Disease and Putative Links to Other Neurodegenerative Disorders

Two decades after the identification of SNCA as the first causative gene in Parkinson's disease (PD) and the subsequent understanding that genetic factors play a substantial role in PD development, our knowledge of the genetic architecture underlying PD has vastly improved. The identification of mutations in at least six genes (. SNCA, LRRK2, VPS35, Parkin, PINK1, and DJ-1) causing "classical PD" and several others involved in related parkinsonian phenotypes have broadened our understanding of the pathophysiological and molecular mechanisms underlying PD. While about 5% of patients suffer from these monogenic forms of the disease, the majority of PD ("idiopathic PD") is genetically complex, that is, it is caused by the combined action of comparatively common DNA sequence variants (eg, single-nucleotide polymorphisms [SNPs]) of low penetrance in concert with environmental factors. Via utilizing genome-wide screening methods, 26 PD risk variants have been established to date. Similar to other genetically complex diseases, these show only moderate effects on PD risk. Increasing this etiologic complexity, many of the involved genetic and environmental risk factors likely interact in an intricate fashion. In this chapter, we summarize the most important findings in PD genetics including those that are the result from next generation sequencing studies, and outline future challenges in PD genetics research.