Scientists have uncovered how specific genetic changes function inside cells to influence disease risk and a wide range of human health traits. By closely examining regions of DNA already linked to disease, the team produced high-resolution maps showing how individual DNA variants behave. This approach helps identify the exact changes that shape complex traits such as blood pressure, cholesterol levels, and blood sugar. Rather than broadly associating regions of the genome with disease, the study focuses on pinpointing the precise genetic differences that have real biological effects.
The research, published in Nature and led by teams from The Jackson Laboratory, the Broad Institute, and Yale University, addresses a long-standing challenge in human genetics. For many years, scientists have known that certain stretches of DNA are connected to disease, but these regions often contain many possible variants. This made it difficult to determine which specific changes were actually responsible. Testing each variant individually was slow and labour-intensive, limiting progress in understanding how genetic risk truly works.
To overcome this, the researchers used a large-scale experimental approach capable of analysing thousands of DNA variants at once. In total, they examined more than 220,000 previously identified genetic changes across five different cell types. This allowed them to clarify about 20 per cent of the targeted regions in the genome. By doing so, they revealed new insights into how these variants influence gene activity, offering a clearer picture of how genetic differences contribute to health outcomes and disease risk.
The study identified over 13,000 single-letter DNA changes that affect how strongly genes are expressed. While many of these variants act independently, the researchers found that about 11 per cent behave differently when combined with nearby variants. This suggests that some genetic effects are not simply additive but depend on specific combinations of changes working together. In some cases, these combinations were linked to lower levels of LDL cholesterol, while others appeared to influence genes related to blood pressure or developmental processes.
Another important finding highlights the value of studying genetic variation across diverse populations. The researchers identified a DNA variant linked to long-term blood sugar control that had been discovered mainly in people of European ancestry. Based on its biological behaviour, they predicted that similar variants in people of African ancestry would show comparable effects. Follow-up analysis confirmed this, demonstrating how understanding genetic mechanisms can improve equity in research and ensure that findings are relevant across different populations.
Although the study provides detailed insights into how many DNA variants regulate gene activity, it is only one step towards fully understanding disease. The human body contains many different tissues and cell types, and gene regulation can vary widely between them. Many genetic variants also remain untested. Even so, the findings offer valuable data that can strengthen future research, improve genetic risk prediction, and support the development of targeted therapies. By moving from broad associations to precise biological understanding, this work helps bridge a critical gap in human genetics.
More information: Layla Siraj et al, Functional dissection of complex trait variants at single-nucleotide resolution, Nature. DOI: 10.1038/s41586-026-10121-6
Journal information: Nature Provided by Jackson Laboratory
