A new UCLA-led study has identified multiple risk genes for Alzheimer’s disease and a rare brain disorder related to it, called progressive supranuclear palsy (PSP), using a combination of new analysis methods that allow massive screening of genetic variants in a single experiment.
The study, published in the scientific journal Science, also presents a new revised model showing how common genetic variants, although individually having very little impact on disease, collectively may increase disease risk by altering specific transcriptional programs in the whole genome.
Typically, researchers have turned to genome-wide association studies (GWAS), in which they examine the genomes of a large group of people to identify genetic variants that increase the risk of disease. To do this, they look for markers along the chromosome, or loci, associated with a disease.
Each locus has on average dozens – and sometimes hundreds or thousands – of genetic markers in common that are consistent and therefore associated with the disease, making it difficult to identify which functional variants actually cause the disease.
Identifying causal variants and the genes they influence is a major challenge in modern genetics and biomedicine. This study provides an effective roadmap to address this problem.
For this study, the authors carried out one of the first known uses of high-throughput tests to study neurodegenerative diseases. The authors conducted massively parallel reporter assays (MPRA) to simultaneously analyze 5,706 genetic variants at 25 loci associated with Alzheimer’s and nine loci associated with PSP, a much rarer neurological disease than Alzheimer’s but with similar pathology.
From that test, the authors were able to confidently identify 320 genetic variants that were functional. To validate the results, they performed a pooled CRISPR screen of 42 such high-confidence variants across multiple cell types.
"We combine several advances that allow you to do high-throughput biology, where instead of doing one experiment at a time, you do thousands of experiments in parallel in a kind of pooled format. This allows us to address the challenge of how to go from thousands of genetic variants associated with a disease to identify which ones are functional and which genes they affect."explains Dr. Dan Geschwind, corresponding author of the study.
Their data provided evidence implicating several new risk genes for Alzheimer’s, including C4A, PVRL2 and APOC1, and other new risk genes for PSP (PLEKHM1 and KANSL1). The authors were also able to validate several previously identified risk loci. The next steps will be to study how the newly identified risk genes interact in model cells and systems.
The authors were also able to demonstrate in PSP at least one mechanism in which multiple disease-associated loci act additively to alter a core set of transcription factors, which essentially turn genes on and off, and are known to work together in specific cell types.
According to Geschwind, this indicated that a common genetic variation located throughout the genome affected specific regulatory networks in particular cell types. This finding, she said, identifies potential new drug targets and suggests that instead of targeting a gene, targeting a network of genes might be an effective approach. "We are entering a new stage of therapies: it is beginning to be plausible to think about addressing the networks"emphasizes the researcher.