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Exome Sequencing Study Unearths Rare Variants in New Alzheimer's Risk Gene

NEW YORK (GenomeWeb News) – In a study published online today in Nature, researchers reported on rare variants in a newly identified Alzheimer's disease risk gene, including at least one variant that appears to raise risk of the disease by around two-fold.

A Washington University-led team used a family-based approach to track down low-frequency Alzheimer's risk variants, sequencing the exomes of individuals from more than a dozen families impacted by late-onset Alzheimer's disease. The search led to a rare variant in a phospholipase D3 gene called PLD3 that was subsequently shown to double Alzheimer's risk.

The researchers' targeted look at PLD3 in thousands more individuals with or without the condition turned up other late-onset Alzheimer's disease-associated alleles in the gene as well, while follow-up experiments hinted that PLD3's role in the disease may be related to its influence on amyloid beta precursor processing.

"[W]e were surprised to find that the effect of the gene was so large," corresponding author Carlos Cruchaga, a Washington University psychiatry researcher, said in a statement.

"After adjusting for other factors that can influence risk for the disease, we found that people with certain gene variants were twice as likely as those who didn’t have the variants to develop Alzheimer's," Cruchaga said.

Past research has uncovered risky mutations in notorious Alzheimer's disease genes such as APOE, he and his colleagues noted, as well as numerous common variants that notch up individuals' risk of developing late-onset Alzheimer's disease.

Fewer studies have focused on rare variants contributing to the condition, though two papers published in the New England Journal of Medicine last year linked a low-frequency variant in a gene called TREM2 to significantly higher risk of late-onset Alzheimer's disease.

To look for additional contributors at the low frequency end of the variant spectrum, authors of the new study started by looking at mutation patterns in more than 850 late-onset Alzheimer's disease families collected as part of a National Institute of Aging study.

After classifying families based on age-at-Alzheimer's disease onset, APOE genotypes, and so on, the researchers focused in on 14 families affected by late-onset Alzheimer's disease that could not be explained by known genetic culprits.

Using Agilent SureSelect kits, they captured protein-coding sequences from the genomes of 29 Alzheimer's-affected and 11 unaffected individuals in those families, sequencing each exome with the Illumina HiSeq 2000.

In two of the families, the team found the same suspicious PLD3 variant in Alzheimer's-affected individuals. That variant was not detected in members of those families who remained Alzheimer's-free in old age.

By looking at the presence or absence of the rare PLD3 variant in data from more than 11,000 individuals with or without Alzheimer's disease, meanwhile, the researchers estimated that the version of PLD3 detected in the families bumps up Alzheimer's disease risk by about two-fold compared to the risk of the disease in the general population.

As such, Cruchanga noted, "[t]his PLD3 variant, like the recently identified rare variant in the TREM2 gene, appears to confer more risk for Alzheimer’s disease than other genes identified by the latest genome-wide association studies."

But other alterations in PLD3 appeared to dial up Alzheimer's disease risk, too. Through targeted sequencing on coding regions of the gene in almost 4,400 cases and controls of European descent and more than 300 African-American cases and controls, authors of the study found 14 PLD3 variants that were more common in those with Alzheimer's disease than those without.

Moreover, such variants appeared to confer elevated Alzheimer's risk in individuals with European or African-American ancestry.

Although more research is needed to delve into the role that PLD3's protein product plays in Alzheimer's disease, results from the team's expression analysis and follow-up experiments supported the notion that it could have Alzheimer's-related functional effects in the brain.

In mouse brain cell experiments, for example, researchers saw that enhanced PLD3 activity is associated with lower levels of intracellular precursors to — and extracellular components of — amyloid beta proteins, which are generally believed to build up and aggregate in plaques in the brain during Alzheimer's disease development. On the other hand, PLD3 knockdown led to a boost in extracellular amyloid beta peptides.

"[N]ow that we’ve found that this gene is involved, we need to figure out its precise role in the body and how particular variants contribute to the development of Alzheimer’s disease," co-author Alison Goate, a psychiatry, neurology, and genetics researcher at Washington University, said in a statement.