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Alzheimer's Genome-Wide Meta-Analysis Uncovers Nine Novel Disease Loci

NEW YORK (GenomeWeb) – An international team of researchers has linked nine novel loci to Alzheimer's disease risk in a large genome-wide association study.

Alzheimer's disease affects about 35 million people worldwide. While previous research has implicated variants in APP, PSEN1, and PSEN2 in the familial form of the disease and APOE in late-onset Alzheimer's disease, these variants don't fully account for disease heritability, which is estimated to be between 60 percent and 80 percent.

In their GWAS of nearly 72,000 clinically diagnosed Alzheimer's disease patients and Alzheimer's disease-by-proxy cases and more than 380,000 controls, the researchers uncovered 29 loci linked to disease risk. Through subsequent functional analyses, they traced most of these SNPs to intronic or intergenic regions, but also noted their influence on genes involved in immune-related tissues and lipid-related processes.

"We anticipate that functional interpretation strategies and follow-up experiments will result in a comprehensive understanding of late-onset AD etiology, which will serve as a solid foundation for improvement of AD therapy," the researchers, led by Vrije Universiteit Amsterdam's Danielle Posthuma, wrote in their paper, which appeared in Nature Genetics today.

In the first part of their three-phase GWAS, the researchers identified 18 independent loci linked to Alzheimer's disease in a cohort of nearly 80,000 individuals. The second phase, meanwhile, uncovered 13 independent loci linked to the disease, eight of which overlapped with ones identified in the first phase. This cohort of more than 376,000 individuals included both cases that were clinically diagnosed and people with a parent who had had Alzheimer's disease.

In the third step, a meta-analysis of those cohorts, the researchers homed in on 29 loci linked to disease, including 15 of the loci identified in phase one, all the loci from phase two, and nine loci that did not reach significance in the earlier phases.

Nine of these loci were novel, and the researchers were able to clearly replicate four of them.

They traced most of the SNPs they identified to intronic or intergenic regions or areas of active transcription. Additionally, they used three different gene-mapping approaches to link the variants to genes: positional gene mapping implicated 99 genes, while expression quantitative trait locus gene mapping matched cis-eQTL SNPs to 168 genes, and chromatin interaction mapping linked SNPs to 21 genes.

These genes, the researchers noted, were often active in immune-related tissues or in lipid-related processes. In particular, they reported that the CLU/PTK2B locus on chromosome 8 — which has previously been linked to disease as two distinct loci — again appeared to be two loci in their data. However, chromatin interaction data suggested that the two loci might physically interact in the spleen and liver, two immune-related tissues.

A gene ontology analysis uncovered four gene sets associated with Alzheimer's disease risk, including those implicated in protein lipid complexes, regulation of amyloid precursor protein catabolic processes, high-density lipoprotein particles, and protein lipid complex assembly.

Another eight genes, meanwhile, were implicated through eQTL interactions in the hippocampus, a brain region that is affected early on in Alzheimer's development.

The researchers also performed genome-wide gene-based association analysis using Multi-Marker Analysis of GenoMic Annotation (MAGMA), which linked 97 genes with Alzheimer's disease.

Overall, the researchers noted that 16 genes were implicated through all four methods, suggesting that they might be of interest for further analyses.

They added that their findings underscore the role of the immune system in the disease, noting that they "strengthen the hypothesis that AD pathogenesis involves an interplay between inflammation and lipids, as lipid changes might harm immune responses of microglia and astrocytes, and vascular health of the brain."