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Study identifies new links between genes and metabolites / Publication in Nature Genetics

In a new study, researchers from the Faculty of Medicine at the University of Freiburg and the University Medical Center Greifswald have discovered how rare genetic variants can strongly influence human metabolism and contribute to metabolic diseases. The study, published in the journal Nature Genetics on January 2, 2025, combines genome analyses with comprehensive measurements of metabolic products in blood plasma and urine. The researchersidentified 192 significant links between individual genes and metabolites, many of which were previously unknown. These results were then integrated into comprehensive digital models of human metabolism, allowing important conclusions to be drawn about the possible development of diseases.

"Our study provides new insights into which genes play a role in certain metabolic pathways and how genetic variations can lead to health problems. With this understanding, we can better understand metabolic diseases and explore new treatment options," says Prof. Dr. Anna Köttgen, co-leader of the study and Director of the Institute of Genetic Epidemiology at the Freiburg University Medical Center. Köttgen is also a member of the Cluster of Excellence CIBSS - Center for Integrative Biological Signalling Studies at the University of Freiburg. The study was carried out within the framework of the Collaborative Research Centers 1453 "NephGen" and SFB 1597 "Small Data" at the University of Freiburg, which are funded by the German Research Foundation.

Rare gene variants analyzed in a virtual whole-body model

As part of the study, tissue from more than 4,700 participantsin the German Chronic Kidney Disease (GCKD) study wasgenetically analyzed. In contrast to previous studies, which focus on frequently occurring gene variants, the influence of rare genetic variants on a total of 2,690 different metabolites in blood plasma and urine was analyzed. The researchers identified 192 links between genes and metabolites. "The ability to map important metabolic processes with computer-assisted, digital replicas of the human body allows us to better understand the effects of genetic variants on human metabolism," says co-study leader Prof. Dr. Johannes Hertel, W1 Tenure Track Professor of Systems Medicine at the University Medical Center Greifswald.

Small changes with serious consequences

One of the newly discovered genes plays an important role in sulphate metabolism. If this is disrupted due to a mutation in the gene, this can be associated with an increased risk of musculoskeletal diseases, for example growth disorders and an increased risk of bone fractures. "We were also able to validate and supplement the relationships between already known connections between genes and metabolic processes," says Nora Scherer, first author of the study from the Institute of Genetic Epidemiology at the Freiburg University Medical Center. For example, the research team gained new insights into the role of a gene that has already been linked to the metabolic disorder Hartnup syndrome, which inhibits the absorption and utilization of certain amino acids. "These findings open up new possibilities for research into diagnostic markers for a variety of metabolic disorders," says Köttgen. 

Original study title: Coupling metabolomics and exome sequencing reveals graded effects of rare damaging 1 heterozygous variants on gene function and human traits
DOI: 10.1038/s41588-024-01965-7
Link to the study: https://www.nature.com/articles/s41588-024-01965-7