A Multiomic Network Approach to Uncover Disease Modifying Mechanisms of Inborn Errors of Metabolism
For many inborn errors of metabolism (IEM) the understanding of disease mechanisms remains limited, in part explaining their unmet medical needs. The expressivity of IEM disease phenotypes is affected by disease-modifying factors, including rare and common polygenic variation. We hypothesize that we can identify these modulating pathways using molecular signatures of IEM in combination with multiomic data and gene regulatory networks generated from non-IEM animal and human populations. We tested this approach by identifying and subsequently validating glucocorticoid signaling as a candidate modifier of mitochondrial fatty acid oxidation disorders, and recapitulating complement signaling as a modifier of inflammation in Gaucher disease. Our work describes a novel approach that can overcome the rare disease-rare data dilemma and reveal new IEM pathophysiology and potential drug targets using multiomics data in seemingly healthy populations.
Authors
- Pablo Ranea‐Robles (ORCID: https://orcid.org/0000-0001-6478-3815)
- Johan Auwerx (ORCID: https://orcid.org/0000-0002-5065-5393)
- Aaron Bender
- Christiaan N. Levelt (ORCID: https://orcid.org/0000-0002-1813-6243)
- Johannes M. F. G. Aerts (ORCID: https://orcid.org/0000-0001-8168-2565)
- Mina Mirzaian (ORCID: https://orcid.org/0000-0001-9404-2903)
- J. Alexander Heimel (ORCID: https://orcid.org/0000-0002-5291-4184)
- Sander M. Houten (ORCID: https://orcid.org/0000-0002-6167-9147)
- Ronald J. A. Wanders (ORCID: https://orcid.org/0000-0001-7818-1452)
- Carmen Argmann (ORCID: https://orcid.org/0000-0002-1110-8012)
- Jun Zhu (ORCID: https://orcid.org/0000-0002-9176-6786)
- Evan G. Williams (ORCID: https://orcid.org/0000-0002-9746-376X)
Institutions
- Leiden University (NL)
- Netherlands Institute for Neuroscience (NL)
- Universidad de Granada (ES)
- University of Luxembourg (LU)
- Erasmus MC (NL)
- Emma Kinderziekenhuis (NL)
- Instituto de Investigación Biosanitaria de Granada (ES)
- Amsterdam University Medical Centers (NL)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Amsterdam (NL)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Journal of Inherited Metabolic Disease
- Published
- 2025-05-30
- DOI
- https://doi.org/10.1002/jimd.70045
- Primary Topic
- Metabolism and Genetic Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Leona M. and Harry B. Helmsley Charitable Trust
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health
- European Research Council
- National Institute of Diabetes and Digestive and Kidney Diseases