Primary Reference: Prokopenko, D. et al. Azheimer’s & Dementia, April 2, 2021.
Researchers say they have performed the first study using whole genome sequencing (WGS) to discover genetic markers for Alzheimer’s disease (AD). Further, they report that the study establishes new genetic links between AD and the function of synapses and the ability of neurons to reorganize the brain's neural network.
"This paper brings us to the next stage of disease-gene discovery by allowing us to look at the entire sequence of the human genome and assess the rare genomic variants, which we couldn't do before," says Dmitry Prokopenko, PhD, of MGH's McCance Center for Brain Health, who is lead author of the study.
The researchers performed WGS analyses on 2,247 individuals’ genomes from 605 families including multiple members diagnosed with AD. They also analyzed WGS datasets on 1,669 unrelated individuals. The study identified 13 previously unknown rare gene variants associated with AD. These gene variants were associated with functioning of synapses, development of neurons, and neuroplasticity.
Previously, genome-wide association studies (GWAS) were the main tool for identifying AD genes. But to date, common Alzheimer's-associated gene variants have accounted for less than half of the heritability of this disease.
The work was co-led by Rudolph Tanzi, PhD, vice chair of Neurology and director of the hospital's Genetics and Aging Research Unit. Tanzi says these less-common gene mutations may hold critical information about the biology of the disease. "Rare gene variants are the dark matter of the human genome," he says, and there are lots of them: Of the three billion pairs of nucleotide bases that form a complete set of DNA, each person has 50 to 60 million gene variants--and 77% are rare.”
Associations of Alzheimer's disease risk variants with gene espression, amyloidosis, tauopathy, and neurodegeneration. Schwartzenruber, J. et al. Nature Genetics, March, 2021. Genome-wide association studies have identified more than 30 Alzheimer's disease (AD) risk genes, although the mechanism underlying how these genes influence the disease are still unknown. These researchers evaluated the roles of the variants in top 30 non-APOE AD risk genes, based on whether these variants were associated with altered mRNA transcript levels, as well as brain amyloidosis, tauopathy, and neurodegeneration. Altogether, 27 variants were detected to be associated with the altered expression of 21 nearby genes in blood and brain regions.
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