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Alzheimer's Disease Potential Risk Variants Identified in Study of APOE4 Carriers, Noncarriers

NEW YORK (GenomeWeb) – Using exome sequence data, an international team has identified variants outside of the APOE locus that appear to mediate Alzheimer's disease (AD) risk in individuals with or without the well-known APOE risk allele epsilon-4 (APOE4).

Members of the Alzheimer's Disease Sequencing Project and the Alzheimer's Disease Exome Sequencing-France Project began by digging into exome sequence data for more than 16,000 AD cases and 17,500 unaffected controls, searching for variants contributing to AD risk in the context of individuals' APOE epsilon-4 status. The findings, published online today in JAMA Neurology, pointed to a handful of variants that may eventually help stratify risk in individuals who appear to be prone to AD.

The associations uncovered in the analyses "reinforce known and suggest additional pathways leading to AD," senior and corresponding author Lindsay Farrer, a biomedical genetics researcher at Boston University, and his colleagues wrote.

Although late-onset AD has been linked to APOE4, targeting that allele does not seem to thwart the neurodegenerative disease, the authors noted. That has prompted speculation that the high-risk APOE genotype "might act as a proxy or biomarker for the causal mechanism," they explained, or that the epsilon-4 allele "may have a role in multiple pathways leading to AD or is dependent on other genetic or non-genetic factors."

In an effort to find new contributors to AD, the researchers brought together exome sequence data for 5,522 unrelated individuals with AD and more than 4,900 cognitively normal control individuals, all with non-Hispanic white ancestry. After quality controls steps, they were left with data for 2,377 AD cases and 706 yet-unaffected controls who carried the APOE4 allele, along with data representing 3,145 individuals with AD and more than 4,200 control individuals who did not carry the AD-related version of APOE.

The team attempted to validate potential AD contributors using data for two more cohorts: exome data for another 1,766 individuals with AD and 2,906 without, as well as 8,728 AD-affected individuals and 9,808 controls assessed by array-based genotyping.

Depending on the type of association analysis used, the researchers tracked down as many as 22 variants with potential ties to AD risk. From the discovery group and a meta-analysis done in combination with data from the replication cohorts, for example, they saw a potentially protective SNP at the ISYNA1 locus for those carrying the AD-related APOE allele.

In the APOE4-free group, on the other hand, the team's analyses highlighted potential AD-associated SNPs in AC099552 and in GPAA1, among others, including a variant called rs138412600 that appears to influence the expression of GPAA1 and a related repressive transcription factor called FOXG1 in the brain.

"Bioinformatics and functional studies of the GPAA1 rs138412600 variant, which was the most robust novel association signal, demonstrated that it may also be associated with global cognition function and expression in [the] brain of GPAAA1 and its repressive transcription factor, FOXG1," the authors reported.

In the group of cases and controls lacking the high-risk APOE4 allele, the researchers also flagged SNPs with shakier associations in or around genes previously implicated in AD risk, including MAPT and TREM2.

Still, the authors cautioned that the specific genes implicated in their analyses "should be considered tentative," since "the replication data sets were not suitable for replication testing because the sentinel variants accounting for the associations were either not present or not well imputed in these samples."

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