DNA variants that affect gene activity mapped in human cells

More than 13,000 genetic variants that alter gene activity and may contribute to complex diseases have been identified.

Genetic variants are known to influence complex traits and diseases, but it has remained difficult to determine which DNA changes are responsible and how. Using data from UK and Japanese biobanks, US-based researchers conducted a large-scale analysis of specific regions of the genome, creating high-resolution maps of how hundreds of thousands of human genetic variants affect gene activity linked to traits such as blood pressure, cholesterol, and blood sugar regulation.

'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 Dr Ryan Tewhey, geneticist at the Jackson Laboratory, Maine, and coauthor of the study published in Nature. '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.'

Around 98 percent of the human genome consists of noncoding DNA, which does not encode proteins but often plays important regulatory roles in gene expression. Most disease-linked variants lie in these noncoding regions, making it difficult to identify which variants drive specific changes, especially as each often has a small effect and nearby variants are often inherited together.

The researchers synthesised and tested over 220,000 DNA sequences representing variants identified in genome-wide association studies of UK Biobank and BioBank Japan participants, using a technique called a massively parallel reporter assay that can analyse thousands of variants simultaneously. By performing the assay in five different cell types, they identified non-coding variants that alter gene regulation and explored how these changes may influence disease risk.

The study found over 13,000 genetic variants that can change how strongly genes are expressed. About 11 percent of nearby genetic variants were found to interact with each other, showing that combinations of changes, rather than single variants alone, often influence disease risk. For example, one pair of variants together altered the activity of a gene linked to cholesterol levels.

Although millions more variants remain to be tested, and further experiments are needed, this research represents an important step toward understanding how genetic changes influence complex traits and disease.

First author, Dr Layla Siraj, a resident in obstetrics and gynaecology at Columbia University said: 'By uncovering the patterns underlying how single-letter changes affect gene regulation, we can start mechanistically connecting genetic risk to the pathways therapies could target.'