Determining the genetic aetiology of early onset Parkinson's disease

Parkinson?s disease (PD) is a common degenerative brain disease in which loss of nerve cells leads to slowness of movement, tremor, stiffness and difficulty walking. As the disease progresses some patients develop dementia and become increasingly incapacitated. There are no treatments that reverse the damage to the brain or halt the disease process. Some younger patients with PD have autosomal recessive genetic disease. We all carry two copies of about 20,000 genes. In autosomal recessive disease two faulty copies of a gene lead to loss of gene function. In this form of genetic inheritance there is usually no increased risk of disease for children or parents of affected patients. To date three genes have been identified for autosomal recessive PD which have been important in leading to new genetic tests for PD, and in helping us to understand the disease processes. We suspect that PD is a heterogeneous disease, with many different processes leading to a similar clinical syndrome. The main goal of this work will be to identify new disease genes which will enable more accurate genetic testing for this condition, the appropriate targeting of new treatments to the correct patients and the development of new treatments in cell and animal models. In our work we have shown that among early onset PD patients there is strong evidence for the existence of further autosomal recessive genes and we have identified a set of 71 early onset PD patients (EOPD) who are likely to have this type of gene change, causing PD. We will identify new genes that cause PD by detailed study of these 71 patients using a recently developed technique called next generation sequencing. This allows a rapid scan for gene changes across all 20,000 genes in the human genome. This will identify a series of possible new genes. The second stage will be to try to confirm these findings in a large representative set of 1300 EOPD patients. The identification of new genes for PD will lead to new diagnostic tests, a better understanding of various forms of PD and the development of new cell and animal models for the disease. This will allow the development of new treatments that we hope will improve the outlook for people with PD.

Although Parkinson?s disease (PD) is a common age dependant neurodegenerative condition about 5% of all PD patients develop disease before the age of 50 (Early onset PD ? EOPD). Three autosomal recessive EOPD genes (parkin, PINK1 and DJ1) have been identified and their discovery has led to new diagnostic tests and insights into the pathogenesis of PD. Many groups have developed cell and animal models of PD based on these genes. There is compelling evidence that there are further autosomal recessive (AR) genes to be identified for EOPD, based on segregation analyses, comprehensive mutation screening and on our own work on homozygosity mapping. We have ascertained over 250 UK patients with EOPD and are members of the International Consortium for PD Genomics (ICPDG), which has collated samples and data on 1400 EOPD patients. Previous gene identification has been based on linkage in known consanguineous families. The advances in next generation sequencing (NGS) mean that we are now in a position to resolve the genetic architecture of EOPD, in a ?linkage-free? approach. Our work indicates that a two-stage approach will be the most efficient. We have demonstrated an excess of genomic homozygosity in EOPD, largely contributed to by a subset of 71 patients in our sample set who carry an 8 Mbp or longer run of homozygosity (ROH). In stage 1 we will examine the entire exome of each of these 71 patients to identify genes that contain a homozygous rare putative loss of function (LOF) mutation. We anticipate that this will identify approximately 20 candidate genes. In stage 2 the exonic sequence of each of these 20 genes will be screened for homozygous and compound heterozygous mutations in the remaining 1300 EOPD patients and 4000 controls (via the UK10K and 1000 genomes projects). Case control analysis of rare bi-allelic LOF mutations will identify which loci are new AR PD genes. This two-stage approach provides a powerful (power 0.99) and efficient approach to identifying new genes for EOPD. Identifying the genetic basis of PD in these patients is the first step in understanding disease heterogeneity and appropriately designing and targeting disease modifying therapies. This work will also inform the design and provision of new diagnostic genetic screening panels.