Genetics of Parkinson's Disease: From Causes to Treatment

The genetic architecture of Parkinson's disease (PD) comprises five autosomal dominantly inherited forms with a clinical picture overall resembling idiopathic disease (PARK-SNCA, PARK-LRRK2, PARK-VPS35, PARK-CHCHD2, and PARK-RAB32) and three recessive types (PARK-PRKN, PARK-PINK1, and PARK-PARK7), several monogenic forms causing atypical parkinsonism, as well as a plethora of known genetic risk factors, most notably SNCA and GBA1 including a recently discovered risk variant unique to individuals of African descent, as well as polygenic scores. The Movement Disorder Society Genetic mutation database (MDSGene) (www.mdsgene.org) provides PD genotype–phenotype relationships, whereas global PD genetics networks, such as the Global Parkinson's Genetics Program (www.gp2.org) elucidate PD genetic factors at an unprecedented scale. Two large studies in relatively unselected, multicenter PD samples estimate the frequency of genetic forms, including PARK-GBA1, at ∼15%. PD genetics are becoming increasingly actionable, with the first gene-targeted clinical trials underway. Furthermore, PD genetics has recently been incorporated into a new biological classification of PD.