# Progress and Prospects in Parkinson's Research/Causes/Inheritance

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## Background

Diagnosed PD cases can be divided into Sporadic and Familial categories. The second of these categories refers to instances where an onset Mendelianpattern is established or a link to a known PD related mutation has occurred.
The first genetic link to PD was published by Nussbaum et al (1997) and this precipitated an avalanche of similar findings. Currently familial causes are widely quoted as accounting for 5% of diagnosed cases, yet genetic studies account for over 50% of PD research. The reason for this imbalance is:-
* Research is producing more and more genetic links with the disease and 5% is probably a considerable underestimate.
* There are indications that many patients must first have a genetic predilection towards the disease which is then triggered by some external factor.
* If a precursor genetic pattern(s) could be established this might provide a biomarker for the disease.
* Familial cases provide a useful starting point for elucidating the subsequent course of the disease.
* Genetic mutations can be inducted into laboratory animals. Breeding transgenic strains of mice, rats, zebra fish, nematode worms and yeast have been produced successfully to enable aspects of the disease to be studied and the effects of new therapies to be tested.

## Gene association studies

Gene association studies is a technique in widespread use by genetic researchers, who take a cohort of patients with a diagnosed disease and compare their genes with a matching (control) cohort of people without the disease. The control cohort is generally matched for age, gender and ethnicity.
Statistical analysis of the results can identify individual genes, which are deemed to influence the onset of the disease. Further analysis can then isolate the specific SNP and Genotype responsible for the mutation. The results are published in a peer-reviewed journal and can form the basis for further research.
The results of such studies of PD are sometimes questionable because:-
* They are not always borne out by repeat studies.
* The cohorts chosen are small or ill-matched.
* The control cohort may include undiagnosed PD cases such as those that are in the [[Wikipedia:Prodromeprodromal|Prodromeprodromal]] or presymptomatic stage of the disease.
* The PD cohort may contain misdiagnosed cases.
* A single mutation could produce a metabolic chain of events and compromise otherwise healthy genes.
Nevertheless the metaanalysis of repeat studies may identify significant genes.
Other complicating factors are:-
* Many results identify intergenic SNPs as the source of the mutation and the regulatory role of intergenic material in gene expression is still being elucidated.
* Many results show negative results i.e. the mutation reduces the risk of PD.
* Many results show contradictory markers for ethnicity i.e. a SNP may lower the risk for one ethnic group and raise it for another.
A number of public domain web sites are available which summarise the results of PD genetic research to date.

## PD-Gene

PD-Gene is a database for Parkinson’s Disease gene association studies maintained by the Max Planck Institute in Berlin in conjunction with the Michael J. Fox Foundation and the Alzheimer Research Forum.
As of October 2012 it is the distillation of 876 studies and identifies 914 PD-related genes and 3443 SNPs. Search arguments are gene, protein, polymorphism, study and keyword, or one can drill down through the sequence chromosome/ gene/ SNP. Chromosome diagrams show the locus of each identified gene.

## Parkinson Disease Mutation Database

This database, which is curated by Karen Nuytemans, PhD. of the Neurogenerative Brain Diseases Group, Flanders Institute for Biotechnology and the University of Antwerp, aims “to collect all known mutations and non-pathogenic coding variations in the genes related to Parkinson disease”.
The contents summarised at October 2012 are:-
| | | PATHOGENIC | PATHOGENIC | UNCLEAR | UNCLEAR |
| CHROMOSOME | GENE | MUTATIONS | FAMILIES | MUTATIONS | FAMILIES |
| 1 | PINK1 | 28 | 65 | 80 | 125 |
| 1 | PARK7 | 6 | 10 | 17 | 18 |
| 4 | SNCA | 25 | 50 | 1 | 1 |
| 6 | PARK7 | 122 | 607 | 65 | 212 |
| 12 | LRRK2 | 6 | 940 | 68 | 107 |

## Parkinson’s Disease Mutations Database

This is curated by theParkinson's Institute of the Leiden University Medical Centre, Germany. In order to use the service it is necessary to download the LOVD which stands for Leiden Open (source) Variation Database.
The gene variations currently (October 2012) available are for the LRRK2. PARK11, PARK2, PARK7, PINK1 and SNCA genes.

## Mutation Database for Parkinson’s Disease

This is curated by the Institute for Infocomm Research in Singapore. In August 2011 it contained 2,391 entries for 202 genes extracted from 576 publications. The contents of the web site are:-
| Function | Contents |
| Browse | Alphabetic list of gene symbols Chromosome location of the gene Entry point to variation report Links to Entrez Gene and SWISS-PROT database |
| Search | Search by Gene symbol (including partial name), aliases, Gene ID, SWISS-PROT accession number Search by Geographic regions of the study Search by Author's name of the primary reference |
| Summary | About the gene Number of records in MDPD Number of variants reported in SWISS-PROT database Link to OMIM database |
| Variation report | List of Variation Impact List of Variation Type List of studied country Variation sequence (position in amino acid and nucleic acid level) List of PubMed reference for the gene Entre to individual record covering sample size, age, gender, variation, impact, geographic, and comments Number of variants reported in SWISS-PROT database Link to OMIM database |
| Comparison | Comparing genetic data from any two geography regions |
| Statistics | Key statistics in MDPD Top 10 genes with most literature reports Top 10 genes with most reported negative variants Top 10 countries / regions with most studies done |

## Where is genetic research going?

Genetic research in relation to the disease is still in its infancy and currently raises more questions than answers. It is a reasonable assumption that gene association studies will throw up many more PD-related SNPs and each one brings with it the questions - what activates the SNP and what happens consequentially inside the affected cell to invoke PD? The observed variable effects of ethnicity and recent work on Alzheimer’s Disease indicate that single SNPs may not work in isolation and that different SNP permutations may have different outcomes. There are also indications that intergenic SNPs may influence the workings of otherwise healthy genes. This accords with observation that Parkinson’s Disease is a very personalised complaint. No two patients exhibit the same mix of symptoms or react to medication in the same way. Patterns of symptoms associated with patterns of SNPs may emerge and, as gene sequencing becomes economical and commonplace, genetic profiling can be expected to become a useful tool for diagnosis and prescription.
The following table summarises the current state of kmowledge of the PARKxx series of mutations.
| PARK locus | GENE | MAP POSITION | CLINICAL PHENOTYPE | PATHOLOGY |
| PARK1/4 | SNCA | 4q21 | Parkinsonism with common dementia | Lewy bodies |
| PARK2 | PARKIN | 6q25-q27 | Early onset slowly progressing Parkinsonism | Lewy bodies |
| PARK3 | Unknown | 2p13 | Late onset Parkinsonism | Lewy bodies |
| PARK5 | UCHL1 | 4p14 | Late onset Parkinsonism | Unknown |
| PARK6 | PINK1 | 1p35-p36 | Early onset slow progressing Parkinsonism | One case exhibiting Lewy bodies |
| PARK7 | DJ1 | 1p36 | Early onset Parkinsonism | Unknown |
| PARK8 | LRRK2 | 12q12 | Late onset Parkinsonism | Lewy bodies usually |
| PARK9 | ATP13A2 | 1p36 | Early onset Parkinsonism with Kufor-Rakh syndrome | Unknown |
| PARK10 | Unknown | 1p32 | Unclear | Unknown |
| PARK11 | GIGYF2 | 2q36-q37 | Late onset Parkinsonism | Unknown |
| PARK12 | Unknown | Xq | Unclear | Unknown |
| PARK13 | Omi/HTRA2 | 2p13 | Unclear | Unknown |
| PARK14 | PLA2G6 | 22q13.1 | Parkinsonism with additional features | Lewy bodies |
| PARK15 | FBX07 | 22q12-q13 | Early onset Parkinsonism | Unknown |
| PARK16 | Unknown | 1q32 | Late onset Parkinsonism | Unknown |
| FTDP-17 | MAPT | 17q21. | Dementia sometimes Parkinsonism | Neurofibrillary tangles |
| SCA2 | Ataxin2 | 22q12-q13 | Usually ataxia sometimes Parkinsonism | Unknown |
| SCA2 | Ataxin3 | 12q24.1 | Usually ataxia sometimes Parkinsonism | Unknown |
| Gaucher's locus | GBa | 1q21. | Late onset Parkinsonism | Lewy bodies |