Genetic Factors

Although the vast majority of PD cases appear to be sporadic (with no known family history), some cases are familial, defined by at least one relative - usually a parent or sibling - also having PD. Whether this is due to heritable genetic factors or shared environment is not always clear. However, studies of families with a history of PD as well as mono- and di-zygotic twin studies suggest an inherited genetic contribution to PD, although this appears to play a larger role in cases with a younger age of onset (Thacker and Ascherio, 2008; Tanner, 1999).

Computer rendering of DNAImage by Robert Guy, NCIClear evidence for the role of genetics in PD comes from rare families that exhibit a pattern of autosomal dominant or recessive Mendelian disease inheritance (Gasser, 2009). Chromosomal regions identified in these families as pathogenically linked to PD have been designated as 'PARK' genes. Identified loci include: PARK1 and 4 (SNCA/alpha-Synuclein); PARK2 (Parkin); PARK3; PARK5 (UCHL1/ubiquitin carboxyterminal hydrolase 1); PARK6 (PINK1); PARK7 (DJ-1); PARK8 (LRRK2/dardarin); PARK9 (ATP13A2); PARK10; PARK11; PARK12; and PARK13 (Omi/HtrA2).

Clinically, these monogenic forms of PD may include atypical features, such as younger onset, earlier occurrence of dementia, and/or lack of standard neuropathological features (Gasser, 2009). However, in some cases monogenic forms may be indistinguishable from idiopathic PD, suggesting that these genetic factors point to common pathogenic pathways involved in PD (Gupta et al., 2008). Genetic variants linked to monogenic forms of PD do not always result in the onset of PD symptoms, indicating a reduced penetrance and a possible role of other modifying genetic or possibly environmental factors.

Although some genes show a clear causal relationship to PD, a growing list of genetic variants have been associated with increased or reduced risk of PD. These susceptibility factors have been found primarily through gene candidate and genome-wide association studies (Maraganore et al., 2005; Fung et al., 2006; Pankratz et al., 2009; dbGaP; PDGene). Although initially discovered in families, variants in some genes linked to monogenic forms of PD have also been identified in more common sporadic PD, suggesting that they may also act as susceptibility factors. Many susceptibility factors remain insufficiently verified to be certain they hold meaningful risk for PD, often due to limited sample sizes used for genetic studies. To date, few common genetic variants (i.e., those found in more than 5% of the population) can explain much of the genetic contribution to PD, suggesting that many rarer variants may exist undiscovered. New technologies, such as full genome sequencing, will likely be required to complete the full genetic picture for PD (Hardy and Singleton, 2009), but currently remain too expensive for large-scale genetic studies. Studies of gene-gene interactions or the combination of genetic and environmental factors may also be informative.

Much of the genetic variation currently attributed to PD comes from alterations to the genetic code itself (e.g., missense mutations, single-nucleotide polymorphisms, insertions or deletions, or multiplications of whole genes). Genetic variation can lead to altered gene expression and/or protein function (gain or loss of function). Epigenetic factors that regulate DNA condensation, such as DNA methylation or histone protein acetylation, may also play a role in PD risk by altering gene expression, but strong data supporting such mechanisms are lacking (Pieper et al., 2008; Migliore and Copede, 2009).