Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data
Fung HC, Scholz S, Matarin M, Simon-Sanchez J, Hernandez D, Britton A, et al.;
Commented by , 24 Nov 2006
Background
In the past decade, seven genes have been identified which underly monogenic forms of familial Parkinson’s disease (PD). Although epidemiological data suggest a role for genetics also in sporadic PD, few genetic variants have been unequivocally linked to this more common form of the disease.
Genome-wide screens can be a suitable method to identify common genotypic variants which may be associated with sporadic PD, without the necessity of identifying target proteins or candidate genes.
Objectives
The objective of this study was to identify any common genetic variability exerting a large effect in risk for Parkinson’s disease in a population cohort. In addition the authors attempted to produce publicly available genome-wide genotype data for SNPs that can be openly mined by other researchers and can further be augmented by genotyping of additional subjects available in publicly accessable repositories.
Methods
The authors performed a genome-wide, single-nucleotide-polymorphism (SNP) genotyping of publicly available samples from a cohort of PD patients (n=267) and neurologically normal controls (n=270). For the PD cohort blood was obtained from unique and unrelated white individuals with idiopathic PD, age range was 55-84 years, no patients were included who had three or more relatives with parkinsonism, nor those with Mendelian inheritance of PD.
< p> Controls were neurologically normal, unrelated, white individuals from different sites within the USA. More than 408,000 unique SNPs were used from two specific assays. Genotype and allele association tests were performed comparing the patient population with normals.
Results
Close to 220 million genotypes were produced in 537 subjects. Genotype and allele association tests did not identify any significant differences between patients and controls. Tha data suggested that there is no common genetic variant that exerts large genetic risk for late-onset PD in white North Americans.
The raw genotype data has now been publicly posted and became the first publicly accessible high-density SNP data outside of the International HapMap Project. These genotype data for PD patients and controls can now be screened and augmented by other researchers to identify common genetic variability that results in minor and moderate risk for sporadic PD.
Professor Emre's comments
The discovery of genetic mutations leading to monogenic forms of PD provided a substantial impetus to the understanding of potential pathophysiological mechanisms involved in PD, as such they were also instrumental in creating the hypothesis of abnormal protein accumulation as a plausible mechanism of the disease process.
In addition to these monogenic forms of familial PD, epidemiological evidence suggests that genetics play a role also in the more common, sporadic form of the disease: The risk of developing PD increases by 70% for all ages if a sibling has the disease, this increase is more than seven times for those younger than 66 years (ref. 1). These data strongly suggest a genetic contribution to the disease risk.
Genome-wide screening is a powerful tool to identify common genetic variations associated with an increased disease risk. In this method common genomic variations are compared between a patient and normal control population and those variations are sought, which are more frequent in the patient population.
The strength of this method is that there is no need for an a priori hypothesis with regard to disease mechanisms and potentially involved proteins, nor for candidate genes. Larger samples would be required for smaller effects exerted on risks, large effects can be identified even in smaller populations.
Previous attempts of genome-wide screening in PD and control populations yielded some positive results, 13 SNPs were found to be associated with risk for PD (ref. 2). These results met with justified excitement, unfortunately these associatons could not be confirmed in this study. This does not exclude, however, common genetic variations or SNPs associated with increased risk for PD, which have a small to moderate effect.
Despite negative results, an important aspect of this study is that the authors made publicly available a large database which can be tested and augmented by others. New investigational teams interested in genome-wide screening do not have to start from scratch, they can build upon the available data. This is a very good example of how selfless, truely universal collaboration should be, if we want to advance our knowledge without unnecessary replications and with rational use of resources.
References
1. de Rijk MC, Breteler MM, Graveland GA, Ott A, Grobbee DE, van der Meche FG, et al. Prevalence of Parkinson's disease in the elderly: the Rotterdam Study. Neurology 1995; 45 (12); 2143-2146
2. Maraganore DM, de Andrade M, Lesnick TG, Strain KJ, Farrer MJ, Rocca WA, et al. High-resolution whole-genome association study of Parkinson disease. American Journal of Human Genetics 2005; 77 (5); 685-693. [Epub 2005 Sep 9]