Advances in genetic technologies have enabled researchers to find regions of the genome that are linked to disease, but it has sometimes been difficult to identify the exact changes within those regions that can lead to various health problems. But in a new study, scientists have developed a genomic map of small changes in the sequence of the genome. With that data, they learned more about how specific variants can work in cells to affect health characteristics like blood pressure or blood sugar levels, and the likelihood that some disease may develop. The findings have been reported in Nature.
In this work, the researchers utilized data from 220,000 genetic variants that have been found before in five types of cells. They created a method that assessed the impact of these variants, one at a time. This work may help improve the prediction of disease risk, or the creation of new therapies.
"For nearly two decades, genetic studies have identified where in the genome we need to look for disease risk, but not which specific DNA changes are responsible," said senior study author Ryan Tewhey, a geneticist and associate professor at The Jackson Laboratory (JAX). "Our study helps close this gap by working at the scale needed to confidently pinpoint the specific DNA changes that matter across thousands of regions all at once, rather than one by one."
Many studies have found genetic variants that can influence the risk of some health condition, like heart disease. But many of these variants arise in areas that lay outside of protein-coding regions. Instead, they often occur in regulatory sequences that help control the activity of protein-coding genes. Millions of variants like this have been found, but what is less clear is what the impact of the variants may be.
To address this knowledge gap, the investigators engineered a type of massively parallel reporter assay to test the effects of variants in different cell types, like blood, brain, or liver cells. Bits of DNA were matched with a molecular tag that could report on whether a variant led to an increase, or decrease in gene activity, or had no effect.
More than 13,000 single-base pair variants were identified that can affect the expression of a gene. Many variants act independently, but the influence of about 11% changed when another variant was nearby. This means the risk of some disorders can depend on variant combinations, not just individual variants.
While some of these findings must be confirmed with additional data, the work shows how new insights into the impact of genetic variants could advance personalized medicine and the study of individual disorders.
"These findings do more than explain known disease associations. They provide training data to build predictive models of the effects of variants we haven't yet studied or that remain undiscovered," Tewhey added.
Sources: The Jackson Laboratory, Nature
