Testing approach reveals new dementia risk genes

Science

A new UCLA-led study used a combination of new testing methods, allowing for mass screening of genetic variants in a single experiment, and has identified a number of new risk genes for Alzheimer's disease and an uncommon, related brain disorder called progressive supranuclear palsy (PSP).

A new, revised model has additionally been presented in the study that shows how common genetic variants collectively may raise the risk of disease by disrupting specific transcriptional programs across the genome.

“A new UCLA-led study used a combination of new testing methods, allowing for mass screening of genetic variants in a single experiment.“

Researchers typically have depended on genome-wide association studies (GWAS), in which they survey the genomes of a big group of people to classify genetic variants that grow the risk of the disease. This is done by testing for markers along the chromosome associated with a disease. However, it can be challenging to identify which are the functional variants that cause the disease as each chromosome, on average, has dozens of genetic markers in common that are co-inherited and therefore associated with the disease.

This study provides an appropriate solution for tackling this problem in modern biomedicine, identifying the causal variants and the genes they impact.

The authors ram massively parallel reporter assays to simultaneously test approximately five thousand seven hundred genetic variants in twenty-five chromosomes associated with Alzheimer's and nine associated with PSP, a neurological disease with a similar pathology to Alzheimer's.

The authors identified three hundred and twenty functional genetic variants from that test. They also ran a pooled CRISPR screen on forty-two of those variants in multiple cell types to authenticate the results.

Dr Dan Geschwind, the study's corresponding author, has stated, "We combined multiple advances that allow one to conduct high-throughput biology, in which instead of doing one experiment at a time, one does thousands of experiments in parallel in a kind of pooled format. This allows us to approach this challenge of how to move from thousands of genetic variants associated with a disease to identifying which are functional and which genes they impact."

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