Here you'll find some general background information on PD and genetics as well as some of our current collaborators and potential studies of interest based on the PD GEN DNA bank.
Parkinson’s disease affects around 100,000 patients in the United Kingdom and is the most common neurodegenerative condition after Alzheimer’s disease. With an exponential rise in its prevalence with age, the ageing of the UK population over the next 20 years will significantly increase the burden of this neurodegenerative condition. The aetiology of PD is unknown. Family studies continue to suggest a strong genetic component with the possibility of autosomal dominant inheritance with incomplete penetrance. Twin studies have been hampered by the short duration of follow-up of the potentially affected co-twin and thus have given variable results.
Two genes for PD have been identified in a number of large kindreds: a‑synuclein has autosomal dominant inheritance and parkin has autosomal recessive inheritance. Other identified loci in familial kindreds are either rare or cause atypical disease.
Most PD is sporadic and genetic defects such as those in a-synuclein and parkin are only very rarely seen in sporadic disease. Thus, most work to date on genetic factors in PD has focussed on studies of genetic markers hypothesised to predispose susceptibility to the disease. Such genetic association studies have, to date, failed to produce replicable results.
The collection will have immediate use as part of existing collaborations such as the European Consortium on Genetic Susceptibility in Parkinson's disease (Dr NW Wood) and the European Study Group on Atypical Parkinsonism (ESGAP; Dr D Nicholl & Professor AC Williams). In addition, the collection will have a direct wider relevance to the global PD genetics research community.
Potential Genetic Studies Using a Parkinson's Disease DNA Bank
The creation of a Parkinson's Disease DNA Bank will allow a considerable number of novel research projects to be performed which will have significant implications regarding the understanding of the disease and its treatment.
Susceptibility genotyping studies
The pathogenesis of the majority of cases of sporadic PD is believed to be multifactorial, but certain genes may confer increased susceptibility to the condition. Examples include the apolipoprotein e4 allele and a recently identified mutation in the promoter of a synuclein.14 The size of the PD GEN study will enable large association studies of sufficient power to be performed which will enable more definitive analysis of candidate loci such as CYP2D6,6 where previous smaller studies have given inconclusive results.
Pharmacogenomic studies will enable genotype-phenotype correlations with drug response in the PD MED trial. Such studies may help identify genetic variation in genes involved in the metabolism and pharmacology of anti-parkinsonian drugs, as well as genes involved in generating an oxidative response and mitochondrial uncoupling. Examples of these include: catechol-O-methyltransferase,15 monoamine oxidase B, N-acetyltransferase (NAT 1 and 2), glutathione S-transferase (GSTT 1, M1, M3, P1) and members of the cytochrome P450 super-family. Similarly, the ability to remain on dopamine agonist monotherapy in early disease without adverse events may be predictable genetically. If so, then it may be possible to target the more expensive agonist therapy only to those who will benefit.
Genotype-phenotype association studies
There may be genetic markers for the dementia, depression, and psychosis seen in some patients with PD which could inform better therapeutic decisions. The DNA collection proposed here will also allow study of genetic predictors of the rate of disease progression and the incidence of levodopa-induced motor complications (i.e. dyskinesias and motor fluctuations) in relation to the medication to which patients are randomised (e.g. polymorphism in the DRD2 gene).
Studies in atypical Parkinsonian syndromes
Although PD MED will recruit only patients who clinically have idiopathic PD, the error rate in this diagnosis is up to 24%.17 We will inevitably collect DNA from patients with alternative diagnoses such as Progressive Supranuclear Palsy (PSP) and Multiple System Atrophy (MSA). This will allow studies of genetic aspects of these conditions and link with the work of the European Study Group on Atypical Parkinsonism (ESGAP). Dr D Nicholl (Birmingham) is a founder member of ESGAP and has a Wellcome Clinician Scientist Fellowship application pending to study the genetic basis of the tau haplotype in PSP. This type of work will also link in with the large epidemiological study underway in Newcastle under the auspices of Professor DJ Burn.
Known Parkinsonian loci
Although the majority of Mendelian forms of PD are exceedingly rare, recent work has identified that mutations in the parkin gene are responsible for up to 77% of cases of juvenile PD, and have a much broader phenotype and age of presentation than previously thought. The DNA bank would enable prevalence studies to be performed on parkin and other, as yet unidentified, Mendelian forms of PD to establish whether they have a wider role in sporadic PD in a large population of patients and controls. We may then be able to better characterise PD patients by genotype rather than phenotype.
The PD GEN genetic database will enable the performance of complex gene-environment studies, such as interactions between smoking use and susceptibility to PD.
Familial PD studies
The PD GEN study will enable the recruitment of further PD families as part of the ongoing European Consortium on Genetic Susceptibility in Parkinson's disease collaboration.