|Researchers Identify Gene Mutations Underlying
Risk for Most Common Form of Parkinson's Disease
International study reveals common gene variants in people of
Two genes containing mutations known to cause rare familial forms
of parkinsonism are also associated with the more common, sporadic
form of the disease where there is no family history, researchers
The finding came in the largest genome-wide association study
(GWAS) reported to date involving Parkinson's disease. GWAS studies
look in the DNA on all of the chromosomes in a specific population
of individuals for common genetic associations with a disease.
To date, such studies have been done on relatively small numbers
of samples and have not been able to identify genetic variations
of smaller effect in Parkinson's disease. But now, GWAS studies
in very large sample sets are able to identify these elusive genetic
Collaborating scientists in the United States and Europe pooled
nearly 14,000 DNA samples and data to confirm that mutations in
the alpha-synuclein (SNCA) gene and microtubule associated protein
tau (MAPT), both present in the general population, are risk factors
for sporadic Parkinson's disease.
In an independent study from Japan, researchers also identified
a different combination of genetic variants as risk factors in
people of Japanese descent, a finding that highlights the power
of GWAS in comparing risk factors among different populations.
The findings presented in the Nov. 15, 2009, online issue of Nature
Genetics were supported in part by the National Institute on Aging
(NIA), National Institute of Neurological Disorders and Stroke,
National Cancer Institute, and the National Institute of Environmental
Health Sciences, all components of the National Institutes of Health.
Parkinson's disease, which affects about 1.5 million Americans,
is a progressive neurologic disorder caused by the degeneration
of nerve cells in the portion of the brain that controls movement.
The likelihood of developing the disorder increases with age and
involves a combination of environmental risk factors and genetic
susceptibility. GWAS studies require large numbers of DNA samples — a
hurdle the international team of researchers overcame through collaboration.
"Because previous Parkinson's GWAS were too small and lacked power,
we worked together to compile and analyze the large data sets needed
to identify the elusive genetic variations that play a role in
this complex disease," said Andrew B. Singleton, Ph.D., chief of
the NIA Laboratory of Neurogenetics, who co-led the study with
Thomas Gasser, M.D., of the Hertie Institute for Clinical Brain
Research, University of Tubingen, and the German Center for Neurodegenerative
Disease, of Tubingen, Germany. "With this better understanding
of the underlying genetic variants involved in the progress of
this disorder, we have more insight into the causes and underlying
biology of this disease. We hope this new understanding will one
day provide us with strategies to delay, or even prevent, the development
of Parkinson's disease."
The two-phase GWAS first analyzed DNA samples of 1,713 people
with the disease and 3,978 free of the disorder, all of whom were
Europeans. The findings were then replicated in a similar group
of 3,361 people with Parkinson's disease and 4,573 without the
disorder. Following the initial findings implicating SNCA and MAPT
variants as risk factors for typical Parkinson's disease, the team
then compared results with researchers performing a GWAS study
in a group of Japanese people (2,816 with Parkinson's disease and
3,401 free of the disorder). This second GWAS also revealed the
strong association for SNCA but not for MAPT. Additionally, both
GWAS studies found evidence for two additional risk variants; the
first, which was strongest in the Japanese population, was named
Park16; the second is close to a gene, LRRK2, which Dr. Singleton's
and Dr. Gasser's groups previously found contains mutations that
cause an inherited form of Parkinson's disease.
"These findings support the notion that the sporadic and rare
familial forms of the disease are related and that common genetic
variability plays a role in developing the disorder," said NIA
Director Richard J. Hodes, M.D. "Future GWAS involving greater
numbers of DNA samples will likely reveal additional common genetic
risk factors. As we continue to use these and other novel approaches
to understand complex diseases, we move closer to a complete understanding
of the genetic basis of Parkinson's disease."
The study also received funding from the German Federal Ministry
of Education, Science, Research and Technology through the National
Genome Network and the Medical Research Council, United Kingdom.
Other collaborators include: Center for Neurosciences and Cell
Biology, University of Coimbra, Coimbra, Portugal; Institute of
Neurology, University College London, London, England; Helmholtz
Center, Munich, Germany; Department of Neurology, University of
Luebeck, Luebeck, Germany; Department of Psychiatry and Department
of Neurology, Washington University School of Medicine, St. Louis;
Institute of Medical Biometry, Informatics and Epidemiology, University
of Bonn, Bonn, Germany; Movement Disorders Center, University of
Florida, Gainesville, Fl.; Klinik for Neurologie and Institut fur
Klinische Molekularbiologie, Christian-Albrechts-Universitat Kiel,
Kiel, Germany; Department of Molecular and Human Genetics, Baylor
College of Medicine, Houston; AARP, Washington, D.C.; Pennsylvania
State University-Milton S. Hershey Medical Center, Hershey, Pa.
The NIA (www.nia.nih.gov) leads the federal effort supporting
and conducting research on aging and the health and well-being
of older people. Part of its research program focuses on the aging
brain and age-related cognitive change. NINDS (www.ninds.nih.gov)
is the nation's primary supporter of biomedical research on the
brain and nervous system. NCI (www.cancer.gov) leads the National
Cancer Program and the NIH effort to dramatically reduce the burden
of cancer and improve the lives of cancer patients and their families,
through research into prevention and cancer biology, the development
of new interventions, and the training and mentoring of new researchers.
NIEHS (www.niehs.nih.gov) supports research to understand the effects
of the environment on human health.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.