Celera Discovers Gene Variants Strongly Associated with Alzheimer's Disease
Monday July 17, 7:00 am ET
Findings Could Lead to New Diagnostics and Targeted Therapeutics
Research Published in Human Molecular Genetics and Presented at the International Conference on Alzheimer's Disease in Madrid, Spain
ROCKVILLE, Md.--(BUSINESS WIRE)--July 17, 2006--Celera Genomics (NYSE:CRA - News), an Applera Corporation business, today announced the publication of data from its research studies showing that variants in the death-associated protein kinase 1 (DAPK1) gene on human chromosome 9 correlate strongly with risk for late-onset Alzheimer's disease. These research findings were presented today at the International Conference on Alzheimer's Disease 2006 in Madrid, Spain, and will appear in the August 2006 edition of Human Molecular Genetics, currently available online at hmg.oxfordjournals.org.
In Celera's research studies, two single nucleotide polymorphisms (SNPs) were identified in DAPK1 that showed significant association with late-onset Alzheimer's disease in an analysis of up to six research sample sets with a total of 2,012 cases and 2,336 controls. In addition to the genetic finding, this research study also showed that the disease-associated SNPs directly or indirectly modulate the expression of the DAPK1 gene. This observation provides a potential biological explanation for the association of the DAPK1 variants with Alzheimer's disease.
"This research study provides valuable insights into the genetic contribution to Alzheimer's disease," said Michael Owen, Ph.D., Professor of Psychiatry at Cardiff University, United Kingdom, and a co-author on the paper. "The DAPK1 gene has been a target for drug discovery in other diseases, and a variety of drug compounds can now be tested for their effect on learning and memory in animal models of Alzheimer's disease."
DAPK1 is an enzyme involved in the programmed cell death cascade and evidence suggests that one of its functions is to control the death of nerve cells, and it is predominantly expressed in regions of the brain, such as the hippocampus and cortex, that are most severely affected by Alzheimer's disease. Increased DAPK1 activity or expression has been observed in nerve cell death, and nerves lacking DAPK1 are less susceptible to cell death in cell cultures and in certain animal models. Other evidence suggests that DAPK1 expression is indirectly modified by levels of the precursor form of the protein that forms the senile plaques that are characteristic for Alzheimer's disease. Another recent study reported that mice without DAPK1's kinase activity are more efficient learners and have better spatial memory than normal mice (Yukawa et al. 2006). DAPK1 is therefore believed to be an excellent biological candidate gene for contributing to the development of Alzheimer's disease.
These research findings are the latest in a series of research discoveries made by Celera and its collaborators regarding Alzheimer's. In the past year, Celera's scientists identified novel genetic variants in a homologue of the RPS3a gene (American Journal of Human Genetics, Grupe et al., 2006), the glyceraldehyde-3-phosphate dehydrogenase (GAPD) gene (Proceedings of the National Academy of Sciences, Li et al., 2004) and also in the amyloid beta precursor protein binding family B, member 2 (APPB2) gene (Human Mutation, Li et al, 2005). The previously reported associated markers and this marker in DAPK1 each consistently show an involvement in apoptotic cell death shedding light on the fundamental underlying mechanism of disease, critical to new therapeutic options. Patent applications for these Celera findings are in process.
"These research findings also hold promise for enabling the development of diagnostic tests to identify people who may be at risk for Alzheimer's and would potentially benefit from treatment with DAPK1 inhibitors," said Thomas White, Ph.D., Chief Scientific Officer at Celera. "We intend to partner or license any potential therapeutic value that emerges from this research program."
Study Details
To identify genetic variants associated with Alzheimer's disease in the region on chromosome 9 that is thought to harbor a genetic risk for the disease, SNPs were scanned across the entire chromosome using DNA samples collected from research subjects and similar non-demented individuals. The scan was carried out in a multi-stage fashion (including discovery and replication) and primarily targeted SNPs that may lead to changes in gene or protein function or activity. The DAPK1 SNP survived replication in multiple data sets and was then further tested in three additional validation sets. When analyzing all sample sets combined, individuals with two copies of the risk gene variant were at 1.4-fold greater risk for the development of disease. To identify potential causative variants, additional dense genotyping in the DAPK1 region was then performed.
Following the genetic research study, a biological characterization of DAPK1 gene expression was carried out and it was found that DAPK1 gene expression shows differences between the copies on each of the two chromosomes. The DAPK1 copy-specific expression was then correlated to the genotypes of the Alzheimer's-associated SNPs.
The lead author of this paper was Yonghong Li, Ph.D., Staff Scientist, CNS Discovery Research at Celera. The work was conducted in collaboration with researchers at Washington University, St. Louis, Missouri, Cardiff University in Wales, United Kingdom, the National Institute of Aging, Bethesda, Maryland, Cambridge University, United Kingdom, King's College London, United Kingdom, and the University of California, San Diego, California. |
