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Whole Genome Sequencing Reveals 13 New Gene Variants in Alzheimer’s Disease

In a genome-wide association study (GWAS), the genomes of many individuals are scanned in search of common gene variants that occur more frequently in people who have a given disease, such as Alzheimer’s disease (AD). However, common Alzheimer’s-associated gene variants have accounted for less than half of the heritability of AD. A standard GWAS misses the rare gene variants (those occurring in less than 1% of the population).

Now researchers at Massachusetts General Hospital (MGH), the Harvard T. H. Chan School of Public Health, and Beth Israel Deaconess Medical Center, report they have used whole genome sequencing (WGS) to discover rare genomic variants associated with AD, and have identified 13 variants.

Their findings are published in the journal Alzheimer’s & Dementia in a paper titled, “Whole‐genome sequencing reveals new Alzheimer’s disease–associated rare variants in loci related to synaptic function and neuronal development.”

The researchers performed WGS analyses on the genomes of 2,247 individuals from 605 families that included multiple members who have been 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. The gene variants were also found to be associated with functioning of synapses, development of neurons, and neuroplasticity.

Identifying less-common gene mutations that increase the risk for AD is important because they may hold critical information about the biology of the disease, explained Rudolph Tanzi, PhD, director of the genetics and aging research unit at MGH. “Rare gene variants are the dark matter of the human genome,” he said.

The next 30 AD gene variants that were discovered are primarily linked to chronic inflammation in the brain. “It was always kind of surprising that whole-genome screens had not identified Alzheimer’s genes that are directly involved with synapses and neuroplasticity,” said Tanzi.

“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,” added Dmitry Prokopenko, PhD, of MGH’s McCance Center for Brain Health, and lead author of the study.

“With this study, we believe we have created a new template for going beyond standard GWAS and association of disease with common genome variants, in which you miss much of the genetic landscape of the disease,” asserted Tanzi.

Their findings could help pave a path for the development of new therapies for Alzheimer’s disease and lead to more WGS in other neurological conditions.

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