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Rare Variants in Three Genes Tied to Alzheimer's Disease Risk in New Study

NEW YORK (GenomeWeb) – An international team of researchers has connected rare coding variants in three microglial-expressed genes to Alzheimer's disease risk.

While some 30 genetic loci have been associated with risk of developing late-onset Alzheimer's disease, those loci only explain a portion of disease risk. To uncover rare variants that may also contribute to Alzheimer's disease risk, researchers led by the University of Pennsylvania's Gerard Schellenberg conducted a three-stage case-control study drawing on data from more than 85,000 people.

As they reported today in Nature Genetics, they linked rare coding variants in three genes to Alzheimer's disease. These genes, the researchers noted, are expressed in microglia and suggest a role for microglial-mediated innate immunity in late-onset Alzheimer's disease.

"It's been known for decades that microglia — a first-line-of-defense cell we are born with — surround amyloid plaque deposits associated with Alzheimer's," Schellenberg said in a statement. "These multiple gene 'hits' all originating from microglia are the clearest demonstration that these cells are part of Alzheimer's pathology and, more importantly, provide clear protein targets where we can start to intervene with drugs."

For the first stage of their three-stage study, the researchers genotyped 16,097 late-onset Alzheimer's disease cases and 18,077 controls using the Illumina HumanExome microarray. In this stage, they identified 43 candidate variants, after excluding known risk loci. These candidate variants were then tested in a separate cohort of 14,041 Alzheimer's disease cases and 21,921 controls that underwent de novo genotyping and imputation. Variants from that stage were then carried forward for examination in a set of 6,652 cases and 8,345 controls.

Through this tiered analysis, Schellenberg and his colleagues uncovered four rare coding variants with genome-wide significant association signals for late-onset Alzheimer's disease: a missense variant in PLCG2, a missense variant in ABI3, and two independent variants in TREM2, one of which was previously known.

The PLCG2 variant, they noted, appears to be protective. PLCG2 encodes a transmembrane signaling protein — PLCγ2 — that hydrolyzes PIP2 into IP3 and DAG to set off a signaling cascade. ABI3, meanwhile, has a role in innate immune response, and TREM2 forms an immune-receptor signaling complex with DAP12.

PLCG2, ABI3, and TREM2 are each highly expressed in microglia cells, the researchers added.

In a protein-protein interaction network analysis, they also found that these three genes interact with other variants linked to Alzheimer's disease. The researchers built a 56-gene interaction network based on common and rare variants associated with Alzheimer's disease, and found that this network was enriched for genes involved in immune response.

This indicated to the researchers that the microglia-mediated innate immune response contributes directly to the development of late-onset Alzheimer's disease, rather than being a consequence of neurodegeneration.

Additionally, Schellenberg and his colleagues suggested that PLCγ2 — the protein encoded by PLCG2 — could represent a drug target.

"Since prevention is a key goal of therapy, influencing microglial cells before onset of cognitive changes needs to be explored," Schellenberg added.