Genetics of Parkinson Disease

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder second to Alzheimer’s disease, affecting 1-2% of individuals over 60 years of age, with a risk that increases with age. Its phenotypic complexity, characterized by motor (resting tremor, bradikinesia, rigidity and postural instability) and non-motor (autonomic dysfunction and cognitive impairment) symptoms lead to the description of this disorder as a syndrome rather than a monolithic disease. Genetic research in the past 10 years, in particular mapping and cloning of genes which cause the inherited form of the disease, has shown that “Parkinson syndrome” is not one disease entity but rather an atherogeneous group of disorders that are associated with a spectrum of clinical and pathological changes. It is believed to be caused by the interaction of environmental factors and genetic variants acting on the stage of an aging brain. There is a growing body of evidence that genetic risk factors are of major importance in PD. So far 16 loci have been identified involved in PD. PD can be referred mostly as sporadic (90-95%) and to a lesser extent as familial (5%) Familial PD is caused by very rare highly age penetrant mutations, inherited in a Mendelian way (autosomal recessive or dominant). The biological effect of these mutations is sufficient alone for the development of the disease. Sporadic PD is a complex multifactorial disease in which very common genetic variants play a very modest role singularly while taken all together, interacting with other genes and environmental factors, they can exert an important cumulative effect leading to the development of the disease. In the last decade pathogenic mutations in five genes (SNCA, LRRK2, PRKN, DJ-1 and PINK1) have been linked to familial PD. Recently genome wide association studies, GWAS, across different populations identified other 6 loci involved in the sporadic disease (MAPT, SNCA, HLA-DRB5, BST1, GAK and LRRK2). Finally a meta-analysis of the 5 previous GWAS discovered 5 new loci in association with the idiopatic disease (ACMSD, STK39, MCCC1/LAMP3, SYT11 and CCDC62/HIP1R) (International Parkinson Disease Genomics Consortium, 2011)