Translating genetic changes into future health impact
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Large-scale research has mapped how thousands of inherited genetic variants play a role in developing chronic conditions, including hypertension and dermatitis, uncovering new connections between genes and health.
In this new study, published today (4 March) in Nature Genetics, an international team from the Wellcome Sanger Institute, University of Cambridge, AstraZeneca, and other collaborators, analysed gene activity and integrated this with other molecular and health data from the same individuals. This allowed them to identify how genetic variation can affect biological pathways and influence the risk of developing certain conditions.
The study’s findings, along with the analysed data are freely accessible via the open-access INTERVAL RNA-seq portal. This resource is available to scientists worldwide, supporting efforts to better understand and treat chronic health conditions.
Genome-wide association studies (GWAS) analyse large collections of DNA to find genetic changes that are associated with certain traits or health conditions.1 Research from GWAS has shown that most genetic variants associated with chronic health conditions are found in non-protein coding regions of the genome. While these regions do not encode proteins, they play a crucial role in regulating gene activity. This makes it more challenging to understand how these variants influence protein function and contribute to disease risk.
To investigate this, the team analysed blood samples from over 4,700 healthy participants in the INTERVAL study,2 which collected comprehensive genetic, biochemical, and lifestyle data from UK blood donors. Using RNA sequencing, they measured gene activity and examined how genetic variants influence these activity levels.
In addition, to create a more complete picture of the biological mechanisms at play, the team combined gene activity data with the protein, metabolite, and lipid information from the same people. This multi-omic approach is crucial in order to uncover how genetic variation impacts cellular function and to begin to understand its role in the development of various health conditions.
The researchers identified tens of thousands of instances where genetic variants influenced gene expression levels and the location of gene splicing.3 This helps clarify where genetic variants disrupt biological processes, linking GWAS findings to specific mechanisms and identifying potential therapeutic targets that could inform the discovery of novel medicines.
Using advanced statistical methods, 222 genomic sites were identified where genetic variants impacted regulatory pathways. This led to the identification of genes that could be potential therapeutic targets, such as WARS1 for hypertension, IL7R for dermatitis, and IFNAR2 for COVID-19. These findings pave the way for developing personalised treatments tailored to an individual’s genetic profile.
“This research gives us a clearer picture of how changes to non-protein coding regions of a gene impact biological pathways. Our research shows the full cascade of effects that genetic changes can have, illuminating each possible pathway to show how these changes can eventually lead to disease. By making this data resource freely available, we are providing a valuable tool for researchers around the world to explore the genetic roots of complex diseases and find new treatment strategies.”
Dr Alex Tokolyi, co-first author at the Wellcome Sanger Institute
“By combining gene regulatory data with protein, metabolite, and lipid levels from the same individuals, we created an intricate map of how genetic variants can affect how a cell functions. This approach starts to fill in the gaps in our knowledge and helps to explain how genetic variants might impact disease mechanisms. Understanding which pathways are involved in health conditions could help future researchers find new ways to treat those that have a genetic component. The answers to many of our health questions could be hidden in our non-protein coding DNA, and this study means we are one step closer to finding these.”
Dr Elodie Persyn, co-first author at the University of Cambridge
“Our genes play a role in how likely we are to get certain conditions and how we react to infections, such as COVID-19. Our large-scale multi-omics approach would not have been possible without all the previous efforts that have given us crucial data, from genome-wide association studies as well as all the volunteers who participated in the INTERVAL study. Thanks to the efforts of all those involved, we have created a resource that scientists worldwide can use to investigate new ways to understand and treat disease.”
Dr Emma Davenport, co-senior author at the Wellcome Sanger Institute
More information
The INTERVAL RNA-seq portal provides open access to these valuable data, supporting global research efforts in understanding and treating complex diseases. For more information, visit https://IntervalRNA.org.uk
Footnotes
- Uffelmann, Q.Q. Huang, N.S Munung, et al. (2021) Genome-wide association studies. Nat Rev Methods Primers. DOI: 10.1038/s43586-021-00056-9
- The INTERVAL trial was a randomised trial of 50,000 participants assessing how often blood donors can safely give whole blood funded by the National Institute for Health and Care Research (NIHR), and NHS Blood and Transplant England. These participants also consented to be part of a bio-resource enabling a broad range of health-related research. For more information on the INTERVAL study, please access: https://www.sanger.ac.uk/collaboration/interval/
- Gene splicing is a post-transcriptional modification that allows one gene to code for multiple proteins. It is an essential and highly regulated gene expression mechanism whereby some sequences are removed and others are preserved and then joined together. More information: https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/gene-splicing
Publication:
Tokolyi, E. Persyn, A. P. Nath, et al. (2025) The contribution of genetic determinants of blood gene expression and splicing to molecular phenotypes and health outcomes. Nature Genetics. DOI: 10.1038/s41588-025-02096-3
Funding:
This research was funded in part by Wellcome, among others. A full acknowledgement list can be found in the publication.
