ROCHESTER, Minn. -- Mayo Clinic researchers in collaboration withscientists at Perlegen Sciences, Inc. and funded by the Michael J. FoxFoundation for Parkinson's Research have produced the first large-scalewhole genome map of genetic variability associated with Parkinson'sdisease. Their results highlight changes in 12 genes that may increasethe risk for Parkinson's disease in some people. Parkinson's disease isa disabling and currently incurable disease that affects millions ofpeople worldwide.
Mayo Clinic and Perlegen Sciences will report their findings in TheAmerican Journal of Human Genetics. The paper was published onlineFriday, Sept. 9 (www.ajhg.org) and will appear in the November 2005print issue.
"This represents one of the first large-scale whole genome associationstudies of any disease," said the study's first author, Mayo Clinicneurologist Demetrius Maraganore, M.D. "It is something we've wanted todo for years, and now we finally had the technology and funding to makeit happen. If confirmed, the findings may lead to new insights aboutthe causes of Parkinson's disease."
Significance of the Findings
Both the findings and the technology that produced them aregroundbreaking, representing one of the most comprehensive geneticstudies of Parkinson's disease to date with nearly 200 million genetictests (genotypes) completed. To accomplish this, researchers initiallystudied the association of about 200,000 single-letter variations inthe genome known as single nucleotide polymorphisms, or "SNPs"(pronounced "snips") in patients with Parkinson's disease. The studyexamined DNA from 775 people with Parkinson's disease (cases) and from775 people without Parkinson's disease (controls).
"To be most effective, a whole genome association study requiresaccurate testing of a large number of SNP markers that are distributedacross the human genome in a dense and informative pattern," says Dr.Maraganore. "In this respect, our collaborators at Perlegen have set anew standard."
"In one year, the Michael J. Fox Foundation and Mayo Clinic havegenerated results that will greatly focus future research efforts inParkinson's disease," explained David Cox, M.D., Ph.D., chiefscientific officer of Perlegen Sciences. "If replication of only one ofthese findings leads to a better understanding of the causes of thedisease or improvements in the early detection or treatment ofpatients, we will have made significant progress."
Noteworthy findings include:
- Confirmation that variation in two previously known regions of the genome, PARK10 and PARK11, are likely associated with Parkinson's disease susceptibility.
- Identification of 10 additional SNPs that appear to be associated with Parkinson's disease susceptibility. Some of these are in or near genes with direct biological relevance to the disease. For instance, one of these, the SEMA5A gene, may play an important role in both the development and programmed death of dopamine-producing nerve cells in the brain. Selective degeneration of dopamine neurons in the brain is a hallmark feature of Parkinson's disease.
Susceptibility genes are genes that may make some people more or lesslikely to develop a disease but that do not necessarily cause thedisease directly. The authors note that in this study, the size of theeffect was small for any single SNP; combinations of gene variants orinteractions with environmental factors may be necessary to developParkinson's disease.
"This study represents the first large-scale attempt to assess thecontribution of genes to susceptibility and development of Parkinson'sdisease," said Kenneth Olden, Ph.D., Sc.D., chief scientific advisorfor the Michael J. Fox Foundation and former director of the NationalInstitute of Environmental Health Sciences (NIEHS) of the NationalInstitutes of Health. "If confirmed, the finding of 12 potentialsusceptibility genes is significant. However, equally significant isthe fact that this comprehensive study found no strong single geneticdeterminant of Parkinson's disease." The Michael J. Fox Foundation isorganizing a large-scale validation study of the initial findings.
The Mayo Clinic/Perlegen Sciences study was funded by a one-year, $2.8million grant under the Michael J. Fox Foundation's LEAPS program. Thework also benefited from long-standing funding from the NIEHS.
About Parkinson's Disease
Parkinson's disease is a disabling, progressive disorder that affectsabout six million people worldwide. It involves degeneration of braincells, particularly those that make the chemical dopamine. The diseaseis characterized by uncontrolled shaking (tremor), slowed movements,muscle stiffness and imbalance. Parkinson's disease is estimated tocost society billions of dollars per year. While there are availabletreatments to reduce the burden of symptoms, their benefit is limiteddue to side effects and loss of efficacy. There is no proven method toslow or halt the progression of Parkinson's disease.
Cite This Page: