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Alzheimer's Meta-analysis Leads to New Risk Loci

NEW YORK (GenomeWeb News) – Using a massive meta-analysis genome-wide association study approach, a large international team has unearthed 11 new loci with ties to late-onset Alzheimer's disease.

As they reported online this weekend in Nature Genetics, members of the International Genomics Alzheimer's Project, or IGAP, consortium brought together data for tens of thousands of individuals with or without late-onset Alzheimer's disease. Through GWAS and meta-analyses of the data, they tracked down 19 risk loci for the neurodegenerative condition, including 11 not found previously.

"Here we greatly increased the list of possible drug target candidates for Alzheimer's disease, finding as many new significant genes in this one study as have been found in the last 15 years combined," co-senior author Gerard Schellenberg, a pathology and laboratory medicine researcher at the University of Pennsylvania's Perelman School of Medicine, said in a statement.

"We can add these new genetic clues to what we already know and try to piece together the mechanism of this complex disease," he said.

Genetic studies conducted over the past few years have led to the discovery of 11 regions with links to late-onset Alzheimer's disease. Despite such efforts, though, there is still a ways to go in accounting for the apparent heritability for the condition.

To that end, authors of the current analysis decided to start by assessing samples collected for four past GWAS.

The first phase of their meta-analysis included information for 17,008 individuals with Alzheimer's disease and 37,154 unaffected controls, originally profiled for studies by the Alzheimer's Disease Genetic Consortium, the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, the European Alzheimer's Disease Initiative, and the Genetic and Environmental Risk in Alzheimer's Disease Consortium.

Based on genotyping information at more than 7 million SNPs, the researchers narrowed in on variants at several new and known sites suspected of contributing to late-onset Alzheimer's disease risk.

They went on to verify genome-wide significant associations for SNPs at 19 loci through follow-up and combined analyses that included 8,572 more samples from individuals with Alzheimer's disease and 11,312 control samples.

Along with variants in and around the well-known Alzheimer's contributor APOE, the team saw association involving SNPs in other genes pinpointed through past studies of the disease.

But new candidate genes were detected as well, including genes falling in amyloid and tau protein-related pathways and pathways involved in immune response, inflammation, cellular migration and transport processes.

Among the newly detected immune contributors, for example, were genes in a region coding for the human leukocyte antigen genes HLA-DRB5-HLA-DRB1.

That region, which contributes to the function of the major histocompatibility complex, has been implicated in inflammation- and immune-related conditions such as multiple sclerosis and Parkinson's disease, the study authors noted, pointing to potential overlap between the neurological conditions.

"We know that healthy cells are very good at clearing out debris, thanks in part to the immune response system," Schellenberg said. "[B]ut in these neurodegenerative diseases where the brain has an inflammatory response to bad proteins and starts forming plaques and tangle clumps, perhaps the immune response can get out of hand and do damage."

In addition to variants with statistically significant Alzheimer's disease associations, members of the consortium also identified more tenuous ties to SNPs in more than a dozen other genes.

"Each gene we implicate in the disease process adds new knowledge to our understanding of disease mechanism and provides insight into developing new therapeutic approaches," co-author Lindsay Farrer, biomedical genetics chief with Boston University School of Medicine, said in a statement.

"[U]ltimately these approaches may be more effective in halting the disease since genes are expressed long before clinical symptoms appear and brain damage occurs," he said.

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