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Alzheimer's Genome Project Uncovers New Risk Genes in Large Family-Based Study

NEW YORK (GenomeWeb News) – Researchers with the Alzheimer’s Genome Project have used a family-based genome-wide association approach to identify four new candidate risk genes for Alzheimer’s disease — findings that researchers say may eventually guide treatment for the condition.
 
In a paper appearing online today in the American Journal of Human Genetics, researchers from Harvard Medical School and elsewhere used microarrays to assess half a million SNPs in about 1,400 individuals from more than 400 families. Their search turned up four candidate genes, two of which have already been validated in large replication studies. The work highlights the value of family-based Alzheimer’s studies, researchers say, and opens the door to genetic discoveries that could eventually lead to new treatments.
 
“Virtually all current research into therapies is based on the Alzheimer’s genes that we already know about,” senior author Rudolph Tanzi, a neurologist at Harvard Medical School and director of the Genetics and Aging Research Unit at Massachusetts General Hospital, said in a statement, “so each new gene we find not only enhances our ability to predict and diagnose the disease, but also provides valuable new clues about biochemical events and pathways involved in the disease process.”
 
Previous studies have turned up three genes associated with early-onset Alzheimer’s: amyloid beta (A4) precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2). These mutations are fully penetrant, meaning everyone with these mutations eventually get the disease. But Tanzi, whose lab was involved in discovering all three, told GenomeWeb Daily News that these genes only explain about one to two percent of Alzheimer’s cases.
 
Late-onset Alzheimer’s disease, which accounts for about 95 percent of all Alzheimer’s cases, has been conclusively linked to just one risk gene so far: apolipoprotein E. And this risk variant — APOE ε4 — increases Alzheimer’s risk but does not guarantee disease susceptibility, Tanzi said.
 
Together, he added, known genes account for roughly a third of Alzheimer’s risk, leaving more genetic variants to be discovered. But technologies such as Affymetrix and Illumina microarrays — along with sequence databases and new statistical analysis tools — are helping researchers find more candidate genes, Tanzi said.
 
In an article published in Nature Reviews Neuroscience earlier this month, Tanzi and Massachusetts General Hospital researcher Lars Bertram assessed a handful of the most intriguing risk genes. The duo has also helped to compile information about potential Alzheimer’s risk genes from the published literature on the Cure Alzheimer’s public database AlzGene.org.
 
For the latest paper, Tanzi and his colleagues looked specifically at late-onset Alzheimer’s disease, using the Affymetrix GeneChip Human Mapping 500K Array Set to evaluate 404,604 SNPs in 1,376 individuals from 410 families in what is believed to be the largest family-based genome-wide association study of Alzheimer’s so far. These samples were collected from individuals of European descent since about 1999 as part of the National Institute of Mental Health Genetics Initiative Study, Tanzi said.
 
Next, the team tested genetic associations from this initial screen in replication samples of nearly 2,700 individuals from almost 900 families, which were drawn from three different studies.
 
Their initial screen turned up five loci that were associated with Alzheimer’s. One of these, rs4420638, was about 11 thousand bases away from the APOE-ε4. Two of the four other variants — rs11159647 and rs3826656 — were also significantly associated with Alzheimer’s in the replication study. Meanwhile, a third SNP, rs179943, showed a trend toward association and a fourth was marginally associated with Alzheimer’s. “I think all four of them are worthy of follow-up,” Tanzi said.
 
The researchers found the strongest association between the rs11159647 SNP on chromosome 14 and Alzheimer’s age-of-onset. The SNP doesn’t fall within any characterized genes, Tanzi said, but it does lay in the same part of the genome as PSEN1, one of the characterized early-onset Alzheimer’s genes. “We’re paying attention to the fact that it’s in the neighborhood of presenilin,” Tanzi said.
 
The other genes identified in the screen are intriguing too, he explained. For instance, the rs179943 SNP falls within the intron of a gene called ataxin-1, or ATXN1, on chromosome six. Mutations in ATXN1 cause another neurodegenerative disease called spinocerebellar ataxia, in which the cerebellum, brain stem, and spinal cord progressively degenerate. “Just like in Alzheimer’s, you lose neurons,” Tanzi explained. “But you lose them in the cerebellum and spinal cord.”
 
The researchers also detected a SNP in the CD33 gene, which codes for a cell-surface receptor with a role in fighting bacterial infections in the innate immune system. That has the team thinking more closely about the role that infection might play in Alzheimer’s.
 
The four SNPs identified in the Genetics Initiative Study did not appear to be associated with Alzheimer’s in the small group of African-American families tested. Even so, Tanzi said, there do seem to be other loci that appear to influence Alzheimer’s risk in these families. He is keen to collaborate with other research groups to test these and other associations in a larger set of African-American families.
 
In other efforts, the researchers are currently following up on their initial screen using sequencing to look for additional, rare mutations in their new genes of interest. They are also in the process of following up on additional hits from the screen, taking them into replication studies.
 
In addition, Tanzi noted, the researchers have screened some of the Alzheimer’s families with the Affymetrix 6.0 chip, which uses a million or so probes to look at more than 95 percent of the genome. They are currently analyzing that new data, Tanzi said.
 
As researchers learn more and more about the genes involved in Alzheimer’s onset and progression, they hope to come up with genetic associations that improve the way doctors diagnose and treat the disease. “That’s the hope is that genetics will take us into new pathways,” Tanzi said.
 

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