Genetics of parkinsonism

Ten years ago, α-synuclein mutations were discovered as the first genetic cause of Parkinson's disease (PD). In the following years, linkage mapping and positional cloning studies revealed further highly-penetrant (Mendelian) PD-causing mutations in the parkin, DJ-1, PINK1, LRRK2, and ATP13A2 genes, delineating a highly heterogeneous etiological scenario. Perhaps even more importantly, a low-penetrance LRRK2 mutation (Gly2019Ser) and polymorphic variants in α-synuclein and LRRK2 are emerging as relevant genetic determinants for sporadic PD in several populations. Other Mendelian genes remain to be found, but the complete resolution of the genetic architectures of the common PD forms represents the main challenge for the next decade.