The genetics of Parkinson's disease

Parkinson's disease (PD) was previously described as the prototypical sporadic disease; however, rapid advances in population and molecular genetics have revealed the existence of a significant number genetic risk factors, prompting its redefinition as a primarily genetic disorder.

Data for this review have been gathered from the published literature.

Multiple haplotypes conveying variable but quantifiable genetic risk, acting concurrently and possibly interacting with one another, provide the basis for a new model of PD. The beginning of this revolution in our understanding came from the clinical observation of parkinsonism with a Mendelian pattern of inheritance in a number of families. The functional work that followed elucidated multiple disease pathways leading to the degeneration of the substantia nigra that characterizes PD. It is however only in recent years, with the emergence of large cohort genome-wide association studies (GWAS), that the relevance of these pathways to so-called sporadic PD has become apparent.

A substantial portion of the presumed genetic inheritance of PD remains at present undefined. Although it is likely that so-called intermediate risk genetic risk factors are the principal component of this 'missing heritability', this is yet to be proved.

Although the picture is by now means complete, the beginnings of rational basis for genetic screening of PD risk have begun to emerge. Equally, this enhanced understanding of the various genetic and in turn biochemical pathways shows promising signs of producing fruitful therapeutic strategies. Technological advances promise to reduce the costs associated with and further increase our capability to understand the complex influence of genetics on the pathogenesis of PD.

The coming years will require the enhancement of current techniques and the development of new ones to define PD's missing heritability. It will also require functional work to define better and in turn potentially reverse the mechanisms that contribute with large effect sizes to the risk of sporadic PD.