Researchers at Sidra Medicine, a member of Qatar Foundation, have created the Middle East’s first population-scale atlas showing how genetic variation regulates gene activity in blood and tracing its effects to clinical traits.
Published in Nature Genetics, the study, titled “A catalogue of transcriptome genetic regulation in a consanguineous Middle Eastern biobank”, provides a new resource to advance precision medicine and addresses a major gap in global genomics and advances precision medicine by enabling more precise genetic diagnosis and disease-risk prediction, while supporting the discovery of new biomarkers and therapeutic targets.
Led by Professor Younes Mokrab, principal investigator in Genome and Biomedicine Informatics and Director of the Neuroscience Research Programme, with Dr Haroon Naeem, staff scientist as First Author, the research team drew on data from nearly 2,000 Qatar Biobank participants, combining whole-genome sequencing, whole-blood transcriptomics and other information.
The team traced, across the entire genome, how variation at the DNA level influences gene regulation, and how these changes connect to health and diseases. Moving beyond conventional associations, advanced computational techniques were applied to uncover nearly 30,000 “causal” effects that control how the genome is transcribed — linking them to 20 clinical traits and disease pathways, including those related to metabolic function.
Professor Mokrab said: “The genome is the body’s genetic blueprint, while the blood transcriptome shows that blueprint in action. Using a population-level cohort from QBB, we brought these layers together with clinical information. Leveraging advanced analytics, we moved beyond genetic associations to uncover causal effects on gene regulation and health at a genome-wide scale.”
The study also revealed the less understood effect of consanguinity on gene activity. Consanguinity increases the chance of inheriting two copies of the same genetic variant, a phenomenon best known for its role in rare genetic diseases.
The researchers showed that inheriting two copies of certain regulatory variants can also lead to unusually high or low activity of specific genes, extending the biological impact of consanguinity beyond variants that directly alter proteins.
First author Dr Naeem said: “We leveraged the high levels of consanguinity in our study cohort to gain novel insights into the impact of inbreeding on gene regulation, revealing effects that extend beyond its established role in recessive genetic disease.”
The research represents a significant milestone in improving the interpretation of genomic test results and increasing the yield of genetic diagnosis through better annotation of non-coding variants. Also, it enables the development of ancestry-aware, functionally-informed polygenic scores for better assessment of risk to complex diseases and more successful clinical trials.
Professor Khalid Fakhro, chief research officer at Sidra Medicine, said: “Precision medicine relies heavily on population-matched reference databases, and this study builds exactly that for RNA data, to complement the extensive DNA resources we have built for Qatar and the Middle East over the years. Building such resources requires deep expertise and world-class core facilities, and creates a foundation for personalised healthcare for our populations.”
