Every three months, the HDR UK Impact Committee considers dozens of articles and selects the most impactful examples, ranked against core pillars of the HDR UK ethos: research quality, team science, scale, open science, patient and public involvement, patient impact and diversity.

In May 2025, the committee chose ‘The contribution of genetic determinants of blood gene expression and splicing to molecular phenotypes and health outcomes’, as their winning publication in the Empower category.

Overview

In their paper, published in Nature Genetics, researchers 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.

The challenge

Much research into the way genes work has historically focused on their ‘protein-coding’ processes. These are sets of genetic instructions within each cell’s nucleus that directly bring about the creation (synthesis) of proteins – molecules which perform essential roles for all living organisms. By contrast, ‘nonprotein-coding/non-coding’ processes have largely been overlooked, as they are more challenging to elucidate. Non-coding processes can disrupt healthy gene regulation (where genes are turned on and off). But little is known about how these non-coding genetic mechanisms work – restricting our ability to tackle the problems they can cause for human health.

Solution

To address this knowledge gap, the authors applied a data analysis process called molecular quantitative trait loci (QTL) mapping. This process can identify the biological mechanisms through which nonprotein-coding genetic variants affect disease risk. Usually applied to a singular functional area of a gene, the researchers hypothesized that a broader, ‘multi-omic’ biological analysis approach (using data from multiple ‘omes’ – genome, transcriptome, proteome, etc. in the same people) should be used for QTL mapping in this context. This broader approach is important if we are to understand the molecular chain of events by which genes bring about cellular functions, and their role in the development of various health conditions.

The authors used the INTERVAL study’s large bioresource, including approximately 50,000 blood donors with extensive multidimensional ‘omics’ profiling. By integrating gene activity data with other molecular and health data in over 4,700 donors, the team uncovered how these variants contribute to disease mechanisms. Based on their analyses, they developed an open-access portal to allow for further investigation in the future, into the molecular QTLs data they had compiled (https://IntervalRNA.org.uk).

Impact

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.

By making this data resource freely available, the team provided a valuable tool for researchers around the world to explore the genetic roots of complex diseases, and find new treatment strategies.

The Impact Committee found the paper to be: “strong and high quality, with a translational impact.”

Dr Dirk Paul, one of the study’s co-authors, added:

“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.”