Genetics of Parkinson's disease

Abstract

Fifteen years of genetic research in Parkinson's disease (PD) have led to the identification of several monogenic forms of the disorder and of numerous genetic risk factors increasing the risk to develop PD. Monogenic forms, caused by a single mutation in a dominantly or recessively inherited gene, are well-established, albeit relatively rare types of PD. They collectively account for about 30% of the familial and 3%-5% of the sporadic cases. In this article, we will summarize the current knowledge and understanding of the molecular genetics of PD. In brief, we will review familial forms of PD, basic genetic principles of inheritance (and their exceptions in PD), followed by current methods for the identification of PD genes and risk factors, and implications for genetic testing.

Figure 1.

Pedigrees showing different inheritance patterns. (A) Autosomal dominant disease inheritance pattern. Every affected person in the pedigree has one affected parent, one affected individual is present in every generation, and on average, an affected individual transmits the mutant gene (and thus the disease) to half of his or her children. (B) Autosomal recessive disease inheritance pattern. The affected individuals have two unaffected parents (both heterozygous mutation carriers), children of the affected individual are also unaffected and heterozygous, and only one of the four siblings (25%) is affected. (C) Autosomal dominant pedigree complicated by the presence of reduced penetrance (not all individuals with a mutation are affected), variable expressivity (not all individuals with a mutation show the expected disorder phenotype), and phenocopies (some individuals show clinical symptoms of the disorder without carrying the disease-causing mutation). Black symbols - affected individuals; white symbols - unaffected individuals; half-filled symbols - individuals with only resting tremor and/or bradykinesia.

Figure 2.

Pedigree of a PD family that comprises affected members with and without the LRRK2 p.G2019S mutation. Five mutation carriers are unaffected, showing reduced penetrance, two mutation carriers are affected with dystonia, showing variable expressivity, and one affected family member does not have the p.G2019S mutation in LRRK2. Black symbols - affected individuals; white symbols - unaffected individuals; half-filled symbols - individuals with dystonia; + - mutation carriers.