Genome Analysis Reveals 13 New Alzheimer’s-linked Gene Variants
Using a genetic approach that can “read” the entire human genetic signature, researchers have identified 13 gene variants — or mutations — associated with Alzheimer’s disease risk whose functions are related to neuronal or nerve cell development and connections.
Moreover, the scientists said their study establishes new genetic links to neuroplasticity, or the brain’s ability to change and reorganize over time.
This discovery of Alzheimer’s-linked rare gene variants underscores the potential of whole-genome analysis to detect rare disease-related genetic variants that result from mutations in a gene’s DNA sequence, according to researchers.
The study, “Whole‐genome sequencing reveals new Alzheimer’s disease-associated rare variants in loci related to synaptic function and neuronal development,” was published in Alzheimer’s & Dementia.
Genome-wide association studies consist of scanning the genome — one’s genetic signature — to identify specific genetic variations (or markers) that are associated with a disease. The approach previously has been used to identify several genetic variants that are linked to the risk of developing Alzheimer’s.
However, rare genetic variants — which can hold crucial information on the biology of a disease — frequently go undetected in standard genome analysis, the scientists said.
“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,” Dmitry Prokopenko, PhD, the study’s lead author and an instructor of neurology at Mass General Hospital, in Boston, said in a press release.
“Rare gene variants are the dark matter of the human genome,” said Rudolph Tanzi, PhD, vice-chair of neurology and director of the genetics and aging research unit at Mass General. Tanzi, the study’s corresponding author, has pioneered research on the genetic origins of Alzheimer’s.
The researchers noted that “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.”
Now, the team attempted to detect rare Alzheimer’s disease-related gene variants using what they termed rigorous deep whole-genome sequencing. This technique consists of sequencing the entire genome of an organism at a single time.
Genomic data were analyzed from a group of 2,247 individuals from 605 families, of which multiple members had Alzheimer’s disease. The newly identified variants were then validated in 1,669 unrelated individuals.
The analysis detected a total of 13 new candidate gene variants associated with Alzheimer’s disease risk: FNBP1L, SEL1L, LINC00298, PRKCH, C15ORF41, C2CD3, KIF2A, APC, LHX9, NALCN, CTNNA2, SYTL3, and CLSTN2.
Analysis of the variants’ functions revealed an emphasis on roles in neuroplasticity, synaptic function, and neuronal development. Of note, synapses are the junctions between two nerve cells that allow them to communicate.
Four genes — APC, CTNNA2, KIF2A, and NALCN — were all primarily expressed in brain tissue, while PRKCH expression was significantly reduced in the temporal cortex (a brain region associated with memory and some aspects of language) of patients with Alzheimer’s. Gene expression is the process by which information in a gene is synthesized to create a protein.
Additionally, FNBP1L and KIF2A were both found to interact with known Alzheimer’s-related genes.
“With this study, we believe we have created a new template for going beyond standard GWAS [genome-wide association studies] and association of disease with common genome variants, in which you miss much of the genetic landscape of the disease,” Tanzi said.
The study was limited by the availability of samples from families with multiple affected individuals and by the fact that 80% of the participants were of European descent, limiting the ability to generalize the study’s results.
“Our study highlights several novel promising routes of AD [Alzheimer’s disease] research and provides new potential targets for therapeutic interventions aimed at the early treatment or prevention of AD,” the researchers concluded.
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