Genome wide analysis of Young Onset Parkinson disease in Wales

Parkinson disease (PD) involves wearing down of brain cells, which leads to tremor and slowness of movement. At the moment there are no treatments which prevent the damage to nerve cell function. Although PD is not usually a familial disease we now know that genetic variation can be important in some patients. This is probably particularly important in people who develop PD at a young age.

The genetic code contains the information which controls the development and function of all the cells in the body and variation in this code can increase the risk of developing disease.

We have access to new technology (DNA chips) which allows the measurement of a large number of DNA variants (over 550,000) every 5000 letters, through the entire human genome. We will use these chips to map variation that occurs frequently in patients with young onset PD in an attempt to discover new genes that can cause PD.

This information will be useful for the diagnosis of PD and in advising patients on the risk to family members. Ultimately we hope that the identification of the disease pathway, through disease genes, will lead to new treatments.

Parkinson disease (PD) is a common age dependant neurodegenerative disease and about 5% of PD patients develop disease before the age of 45. Epidemiological data suggest that many patients with Young Onset PD have autosomal recessive disease. To date, three autosomal recessive genes for PD have been identified, parkin, DJ-1 and PINK-1 but together these genes account for no more than 25% of young onset European PD patients. Mutations identified in parkin, in the non-consanguineous European population include homozygous point mutations and exonic deletions and multiplications. We believe that patients with Young Onset PD are an extremely important resource for understanding the development of PD, and that there are further genes to be identified in this group. We have established a community-based study of Young Onset PD in Wales. This stable and relatively homogenous outbred population has great advantages for genetic analysis - we predict that there will be a restricted number of mutations responsible for PD in the Welsh group. We propose genome wide single nucleotide polymorphism analysis (using the Illumina HumanHap550 chip) in 75 Welsh young onset PD patients and 75 Welsh controls, following preliminary analysis of known PD genes. The Illumina genotyping chip used contains over 550,000 SNPs spaced on average every 5.5 kb across the genome. In addition to the A/B genotype assignment, metrics generated in the chip analysis can be used to determine the presence of genomic deletions and duplications. This analysis will be undertaken in collaboration with Dr. Andrew Singleton laboratory at the US National Institutes of Health, who have carried out similar analysis on late onset PD sample sets. The identification of common non-polymorphic variation in Welsh young onset PD patients will be used to map novel disease genes. Candidate genes will be analyzed in further detail in our large PD cohort which by the end of 2007 will include over 400 PD patients, and in collaboration with Dr. Andrew Singleton using their PD patient sample. This novel approach to mapping disease genes will lead to new insights into the pathogenesis of PD, which in the long term will pave the way for new disease modifying therapies. More immediately, identifying new genes for PD will improve our understanding of the disease nosology, genetic counseling and
will lead to the development of new diagnostic and predictive tests.