Whole-Genome Sequencing Reveals Rare Variants Tied To Alzheimer's Disease

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    Whole-genome sequencing (WGS) has uncovered rare genetic variants related to Alzheimer's disease (AD), researchers say.

    "Genome-wide association studies (GWAS) using only common single-nucleotide polymorphisms (SNPs) in screens for AD genes miss at least half of the genes involved with AD risk," Dr. Rudolph Tanzi of Massachusetts General Hospital in Boston told Reuters Health by email. "So, we decided to test all genomic variants in the human genome by carrying out GWAS using WGS datasets."

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    "Instead of only analyzing 500,000 to one million common variants, as is done in traditional GWAS . . . we were able to test over 60 million genomic variants for association with AD," he explained. "We observed that 75% of those genomic variants are rare - present in less than 1% of the population. We hypothesized that the 60% of genetic factors missed in standard GWAS for AD might be accounted for by these rare mutations. We found those rare mutations in 13 genes."

    "Surprisingly, those 13 genes were involved with neuronal networks and synapses, and not with innate immunity and neuroinflammation, which our and other's traditional AD GWAS landed on over the past decade," he noted. "By using WGS data, we found an entire new set of genes carrying rare mutations associated with AD and all pointed at problems with synapses' formation and maintenance."

    As reported in Alzheimer's and Dementia, Dr. Tanzi and colleagues identified the 13 rare variants by performing WGS analyses on the genomes of 2,247 individuals from 605 families with multiple members diagnosed with AD (discovery cohort). They also analyzed datasets from 1,669 unrelated individuals (replication cohort).

    Loci that yielded consistent rare-variant signals in both cohorts implicated these genes: FNBP1L, SEL1L, LINC00298, PRKCH, C15ORF41, C2CD3, KIF2A, APC, LHX9, NALCN, CTNNA2, SYTL3, and CLSTN2.

    Further analyses showed, as Dr. Tanzi noted, that these loci are involved in synaptic function, in contrast to more common AD-associated variants, which are involved in innate immunity and amyloid processing.

    "These loci have not been associated previously with AD, emphasizing the ability of WGS to identify AD-associated rare variants, particularly outside of the exome," the authors conclude.

    Dr. Tanzi said his team is now using CRISPR-CAS to insert the new rare variants into human neurons and observe how they contribute to AD neuropathology. Those experiments are being done with the team's "Alzheimer's in a Dish" model, in which human stem cells in a gel-like matrix create mini brain organoids that recreate AD neuropathology in a petri dish.

    "We can also use those models to rapidly screen all approved drugs and hundreds of natural products for the ability to prevent or reverse the neuropathological consequences," he said, "and proceed to consider such drugs and natural products for clinical trials aimed treating and preventing AD."

    Dr. David Knopman, professor of neurology at Mayo Clinic in Rochester, Minnesota, and a scientific advisor to the Alzheimer's Association, told Reuters Health by email, "Identification of particular genes takes advantage of the rich cell biological advances that have been made over the past few decades that link a particular gene to a particular cellular process or pathway."

    "The authors applied sophisticated genetic analysis that examined very rare genetic variants, something that has not been previously done with the statistical power available in this analysis," he noted. "While the results do not have any clinical relevance today, they strengthen an already compelling model of AD in which alterations in synaptic functions are at the heart of the disease."

    —Marilynn Larkin

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