In a new study, researchers from the Faculty of Medicine at the University of Freiburg and the University Medical Centre Greifswald have discovered how rare genetic variants can strongly influence human metabolism and contribute to metabolic diseases. The study, published in Nature Genetics on 2 January 2025, combines genome analyses with comprehensive measurements of metabolic products in blood plasma and urine. The researchers identified 192 significant links between individual genes and metabolites, many of which were previously unknown. These results were 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 these findings, we can better understand metabolic diseases and explore new treatment options,” says CIBSS member Prof. Dr. Anna Köttgen, co-leader of the study and Director of the Institute of Genetic Epidemiology at the Freiburg University Medical Centre. Among others, the study was carried out within the framework of the Collaborative Research Centres 1453 ‘NephGen’ and SFB 1597 ‘Small Data’ at the University of Freiburg, funded by the German Research Foundation.

Rare gene variants analysed in a virtual whole-body model

As part of the study, tissue from more than 4,700 participants in the German Chronic Kidney Disease (GCKD) study was genetically analysed. 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 analysed. 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, Tenure Track Professor of Systems Medicine at the University Medical Centre Greifswald.

Small changes with serious consequences

One of the newly discovered genes plays an important role in sulphate metabolism. A disruption of this metabolism due to a mutation in the gene can be associated with an increased risk of musculoskeletal diseases – such as growth disorders and an increased risk of bone fractures. “We were also able to validate and expand the links 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 Centre. In this way, 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 utilisation of certain amino acids. “These findings open up new possibilities for research into diagnostic markers for a variety of metabolic disorders,” says Köttgen.

Original Publication

Nora Scherer, Daniel Fässler, Oleg Borisov, Yurong Cheng, Pascal Schlosser, Matthias Wuttke, Stefan Haug, Yong Li, Fabian Telkämper, Suraj Patil, Heike Meiselbach, Casper Wong, Urs Berger, Peggy Sekula, Anselm Hoppmann, Ulla T. Schultheiss, Sahar Mozaffari, Yannan Xi, Robert Graham, Miriam Schmidts, Michael Köttgen, Peter J. Oefner, Felix Knauf, Kai-Uwe Eckardt, Sarah C. Grünert, Karol Estrada, Ines Thiele, Johannes Hertel & Anna Köttgen (2025). Coupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits. In: Nature Genetics. DOI: 10.1038/s41588-024-01965-7.

CIBSS-Profile of Prof. Dr. Anna Köttgen

Original Press Release by the University Medical Centre Freiburg