New dementia risk genes identified through novel testing approach

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

The study, published today in the journal Science, also presents a revised, new model showing how common genetic variants, while individually having a very small impact on disease, collectively may raise the risk of disease by disrupting specific transcriptional programs across the genome.

Typically, researchers have relied on genome-wide association studies (GWAS) in which they survey the genomes of a large group of people to identify genetic variants that increase risk for the disease. This is done by testing for markers along the chromosome, or loci, associated with a disease. Each locus on average has dozens — and sometimes hundreds or thousands — of genetic markers in common that are co-inherited and therefore associated with the disease, making it difficult to identify which are actually the functional variants that cause disease.

Identifying the causal variants and the genes they impact is a major challenge in modern genetics and biomedicine. This study provides an efficient roadmap for tackling this problem.

For this this study, the authors conducted one of the first known uses of high-throughput testing to study neurodegenerative disease. The authors ran massively parallel reporter assays (MPRAs) to simultaneously test 5,706 genetic variants in 25 loci associated with Alzheimer’s and nine loci associated with PSP, a neurological disease that is much rarer than Alzheimer’s but has a similar pathology.

From that test, the authors with high confidence were able to identify 320 genetic variants that were functional. To validate the results, they ran a pooled CRISPR screen on 42 of those high-confidence variants in multiple cell types.

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