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GWAS Provides New Clues to Late-Onset Alzheimer's Disease

NEW YORK (GenomeWeb News) – Scientists have identified new variants that are helping to flesh out the genetic signature of late-onset Alzheimer’s disease.
In a paper appearing online today in the American Journal of Human Genetics, a team of American researchers genotyped nearly 500 individuals with late-onset Alzheimer disease at more than 500,000 SNPs. After comparing these with healthy controls, the team found associations with a known risk gene for late-onset Alzheimer’s — apolipoprotein E, or APOE — as well as variants in other parts of the genome, including a strongly associated locus on chromosome 12.
“Detailed functional examination of these signals and genes may lead to a better understanding of the complex pathophysiology of Alzheimer’s disease,” senior author Margaret Pericak-Vance, director of the University of Miami School of Medicine’s Miami Institute for Human Genomics, said in a statement.
Alzheimer’s disease is thought to have both genetic and environmental underpinnings. But so far APOE polymorphisms are the only genetic variants that have been consistently linked to late-onset Alzheimer disease. And APOE only explains part of late-onset Alzheimer’s genetic risk — as much as half remains explained.
That has researchers scrambling to find additional genes associated with the disease. In the past decade or so, Pericak-Vance explained, that has put them on the trail of common variants with smaller effects than APOE.
For the latest research, Pericak-Vance and her co-workers used the Illumina HumanHap550 chip to genotype 492 individuals who were 60 years old or older with late-onset Alzheimer disease and 498 cognitively healthy controls. The samples were collected as part of the University of Miami and Vanderbilt University’s Collaborative Alzheimer Project.
The researchers validated their results using imputation analysis. By imputing their data back to HapMap samples, Pericak-Vance told GenomeWeb Daily News, they could determine whether their results were consistent with those reported by an international research team in Neuron in 2007. Researchers involved in that study assessed SNPs on the Affymetrix 500K GeneChip platform, so comparing the two necessitated such imputation.
Along with six SNPs in APOE, Pericak-Vance and colleagues found another 32 SNPs that fell into 19 regions on 16 chromosomes. After the APOE SNPs, the rs11610206 SNP in chromosome 12 showed the second most significant association with late-onset Alzheimer disease. The team subsequently validated that association by looking at another 238 cases and 220 controls.
Although rs11610206 falls outside of known genes, it lies near a hypothetical gene called FAM113C and candidate genes such as the vitamin D receptor or VDR and the adhesion molecule with Ig-like domain 2 or AMIGO2. Of these, the researchers are currently most intrigued by the potential link to VDR. In the paper, they speculated that the SNP might affect VDR by altering its long-range regulatory mechanisms.
“There is no known connection between this SNP and the vitamin D receptor, but the region between the two is largely uncharacterized, and it is possible that our SNP is in a region that may play some sort of regulatory role,” co-author Jonathan Haines, director of Vanderbilt University’s Center for Human Genetics Research, said in a statement.
Still, they noted, more research is required to get to the bottom of this region and its potential ties to Alzheimer’s. Since this research was completed, Pericak-Vance said her team has been doing functional analyses of VDR that are yielding intriguing results.
The researchers also detected four signals that were “highly associated” with late-onset Alzheimer’s and subsequently validated by imputation analysis. Two of these fell within known genes — one in a chromosome 1 gene called DISC1 that has been previously linked to schizophrenia and other conditions and another in and around a chromosome 19 gene called ZNF224. And, Pericak-Vance noted, the association on 19q13 appears to be genuinely independent of APOE.
The other two signals, which were detected on chromosomes 6 and 4, were not within known genes.
The team also found potential — though less significant — associations between late-onset Alzheimer’s and SNPs in nine genes in the AlzGene Alzheimer candidate gene list. Despite the fact that these signals yielded nominal associations, Pericak-Vance said she is excited about seeing results replicating in several samples.
The team just finished another GWAS looking for common, small genetic effects in additional samples. In the future, Pericak-Vance noted, they will likely do additional research involving extended families that they’ve been studying over several years.
The researchers are also looking at candidate genes and will likely target some for deep sequencing analysis to find rare genetic variants, Pericak-Vance said, particularly genes in which researchers have seen more than one common variant.
Dozens of researchers from across the US and beyond are also coming together as part of an Alzheimer’s consortium to do a meta-analysis on several GWA studies, Pericak-Vance noted. Ultimately, she said, the goal is to find new treatments or therapies for Alzheimer’s or to find a way to identify individuals at highest risk of developing the disease and explore ways to decrease that risk.
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