Parkinson's disease: from monogenic forms to genetic susceptibility factors.

Research in Parkinson's disease (PD) genetics has been extremely prolific over the past decade. More than 13 loci and 9 genes have been identified, but their implication in PD is not always certain. Point mutations, duplications and triplications in the alpha-synuclein (SNCA) gene cause a rare dominant form of PD in familial and sporadic cases. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a more frequent cause of autosomal dominant PD, particularly in certain ethnic groups. Loss-of-function mutations in Parkin, PINK1, DJ-1 and ATP13A2 cause autosomal recessive parkinsonism with early-onset. Identification of other Mendelian forms of PD will be a main challenge for the next decade. In addition, susceptibility variants that contribute to PD have been identified in several populations, such as polymorphisms in the SNCA, LRRK2 genes and heterozygous mutations in the beta-glucocerebrosidase (GBA) gene. Genome-wide associations and re-sequencing projects, together with gene-environment interaction studies, are expected to further define the causal role of genetic determinants in the pathogenesis of PD, and improve prevention and treatment.