Celera Identifies Novel Genes Associated with Late-Onset Alzheimer's Disease

Business Wire, Feb 27, 2007

Findings May Form Part of a Genetic Risk Score to Identify Individuals at Risk for Alzheimer's Disease and Aid in Better Understanding of Treatment Response

ROCKVILLE, Md. -- Celera (NYSE: CRA), an Applera Corporation business, today announced the publication of data from its research studies identifying several candidate genetic markers associated with late-onset Alzheimer's disease (LOAD), including markers in multiple genes that have never been associated with LOAD. Two of these genes are PCK1, a gene that regulates blood glucose levels, and GALP, a gene that is modulated by insulin and regulates food intake, suggesting a link between Alzheimer's disease and irregular glucose/insulin levels. This research paper has been accepted for publication in Human Molecular Genetics and is currently available on the publication's website at http://hmg.oxfordjournals.org.

This is the first report of a genome-wide association study in LOAD focused on testing genetic variants that are likely to change the function of a gene or protein. There were 19 single nucleotide polymorphisms (SNPs) that showed significant association with LOAD in an analysis of five independent case control sample sets, totaling 1,808 cases and 2,062 controls. Three of the identified markers were located close to the APOE gene, a known risk factor for LOAD. An additional 16 markers mapped to biological candidate genes, such as PCK1 and GALP, to chromosome segments that are considered to harbor genetic mutations that lead to a higher risk for LOAD, or to novel genes.

"This research study identifies genes that are likely risk factors for Alzheimer's disease, allowing us to narrow our biological focus as we strive toward an even better understanding of how these genes contribute to the development of this disease," said Julie Williams, Ph.D., Professor of Neuropsychological Genetics at Cardiff University's School of Medicine, and a lead author on the paper. "Identifying susceptibility genes for Alzheimer's disease provides a knowledge base for the development of potential new diagnostic tests and novel therapies. These findings need to be looked at in other research samples to explore the consistency and the strength of these findings."

Celera intends to combine these markers with other previously identified markers into a Genetic Risk Score for late-onset Alzheimer's disease that may identify individuals at elevated risk to develop the disease. Identification of individuals at elevated risk may also lead to more timely and cost-effective clinical drug trial designs. Other genetic variants that correlate strongly with LOAD previously identified by Celera are in the death-associated protein kinase 1 (DAPK1) gene1, in a homologue of the RPS3a gene2, in members of the GAPD(3) (glyceraldehyde-3-phosphate dehydrogenase) gene family, and in the APPB2(4) (amyloid beta precursor protein binding family B member 2) gene. Several of these previously reported markers play a role in programmed cell death, supporting this as one of the underlying disease mechanisms of LOAD. Patent applications for these Celera findings have been filed.

"This research holds promise for the development of diagnostic tests as well as new targets for drug discovery," said Thomas White, Ph.D., Chief Scientific Officer at Celera. "As with our Genetic Risk Scores in other complex diseases such as risk of cirrhosis in hepatitis C virus infected individuals, and coronary heart disease and stroke that are currently in development, we now plan to combine these markers with others, and develop a predictive test that determines who might be at higher risk for Alzheimer's disease."

Study Details

To identify novel genetic variants that predispose individuals to LOAD, the collaborators tested 17,343 SNPs from 11,221 genes in up to five independent case-control sample sets, totaling 1,808 LOAD cases and 2,062 normal controls. SNPs that met previously defined significance criteria in the first tested sample set were typed in DNA pools from a second set of cases and controls. There were 119 markers that satisfied criteria from these first two rounds of pooled genotyping and these were individually genotyped in four sets of cases and controls. Finally, 19 markers showing the most evidence of association (p < 0.01) were genotyped in a fifth sample set. In summary, this genome-wide scan of putative functional variants has identified novel susceptibility genes for LOAD and provides new guidance in the understanding of Alzheimer's pathogenesis.

The lead authors of this paper were Andrew Grupe, Ph.D., Director of CNS Discovery Research at Celera, and Julie Williams, Ph.D., Professor of Neuropsychological Genetics at Cardiff University's School of Medicine, United Kingdom. The study was performed in collaboration between researchers from Celera, Cardiff University (Cardiff, U.K.), Washington University (St. Louis, MO), Rosetta Inpharmatics (Seattle, WA), Cambridge University (Cambridge, U.K.), Trinity College (Dublin, Ireland), King's College London (London, U.K.), and University of California, San Diego (San Diego, CA).