Abstract
Background
While genetic studies have identified hundreds of loci associated with adiposity, the phenotypic expression of this individual genetic risk is not fixed but dependent on environmental circumstances. Socioeconomic Position (SEP), which includes education, income, and area-level deprivation, serves as an important environmental modulator of genetic liability. However, the literature on Gene-Environment (G×E) interactions remains fragmented, particularly regarding how these evolve across the life course.
Provide a comprehensive overview of available literature on how SEP factors relate to the effects of polygenic risk scores (PRS), genetic susceptibility, and epigenetic mechanisms in obesity
Methods
Following PRISMA guidelines, we searched five databases for human studies examining SEP, genetic or epigenetic markers, life course, and adiposity-related outcomes. In total, we synthesized 98 studies (79 genetic, 21 epigenetic, including two papers contributing to both domains) and assessed risk of bias using QUIPS
Results
Lower SEP, particularly lower educational attainment and greater area-level deprivation, was often associated with stronger genetic susceptibility to obesity, although findings differed by SEP component, life stage, PRS construction, outcome definition, ancestry, and analytical framework. Among the 29 studies formally testing genetic susceptibility-by-SEP interactions, PRS-size patterns were descriptive rather than indicating a clear hierarchy: large PRS produced the greatest number of formal interaction findings, while medium PRS showed a high proportion of significant findings in fewer and less comparable studies. Epigenetic analyses identified DNA methylation at stress-related and metabolic loci as a potential pathway linking socioeconomic disadvantage to obesity, though tissue specificity and causal direction remain limiting factors.
Conclusion
Lower educational attainment and socioeconomic deprivation appear to amplify genetic susceptibility to obesity, although evidence remains heterogeneous in PRS construction, SEP operationalization, outcome definition, ancestry, and analytical framework. Emerging evidence suggests educational attainment and early-life socioeconomic conditions may represent modifiable contexts influencing genetic obesity risk across the life course
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Subjects
- Genetics
- Obesity
- Risk factors
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Acknowledgements
The authors thank the OBCT consortium and all colleagues who contributed to discussions relevant to this work
Funding
JU and RM disclose support for the research of this work from the European Union’s Horizon Europe Research and Innovation Programme under grant agreement No. 101080250: the OBCT project. The views and opinions expressed are those of the author(s) only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them. The funders had no role in the design, data collection, data analysis, interpretation, writing, or reporting of this study. All other authors declare no relevant funding. ER is financially supported by the Dutch Research Council and the Dutch Ministry of Education, Culture and Science (NWO gravitation grant number 024.005.010): research project “Stress in Action”: www.stress-in-action.nl.
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Division of Pediatric Endocrinology, Department of Pediatrics, Erasmus University Medical Center-Sophia Children’s Hospital, Rotterdam, The Netherlands
J. van Uhm, R. E. H. Meeusen & E. L. T. van den Akker
Obesity Center CGG, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
J. van Uhm, R. E. H. Meeusen, E. F. C. van Rossum & E. L. T. van den Akker
Division of Endocrinology, Erasmus MC, Department of Internal Medicine, University Medical Center Rotterdam, Rotterdam, The Netherlands
J. van Uhm, R. E. H. Meeusen & E. F. C. van Rossum
Department of Human Genetics, Amsterdam UMC, Amsterdam, The Netherlands
P. R. Jansen & M. M. van Haelst
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JU, RM, PJ, EA, ER, and MH contributed to the study design. JU and RM performed the literature screening and data extraction. JU and PJ conducted the data synthesis. JU wrote the original draft of the manuscript, with writing contributions from PJ. Critical feedback and revisions were provided by EA, ER, and MH. All authors read and approved the final manuscript
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ER receives royalties from publisher Ambo Anthos for a book for lay and professional audiences: FAT, the secret organ (Dutch: VET Belangrijk, 2019; VET Belangrijk 2.0, 2026) and reports speaker fees from academic and/or medical education organizations, including Dutch Obesity Academy, Medische Scholing (medical education), Medscape/WebMD, Radcliffe CVRM, Bohn Stafleu van Loghum, and Prevents (most payments to the institution), and was involved in clinical trials funded by Rhythm Pharmaceuticals investigating setmelanotide in rare genetic obesity disorders (payments to institution; not related to this article).
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van Uhm, J., Meeusen, R.E.H., Jansen, P.R. et al. Socioeconomic position, genetic susceptibility, and epigenetic profiles in obesity across the life course: a systematic review.
Int J Obes (2026). https://doi.org/10.1038/s41366-026-02181-5
Received:12 January 2026
Revised:25 June 2026
Accepted:20 July 2026
Published:03 August 2026
Version of record:03 August 2026
DOI
:https://doi.org/10.1038/s41366-026-02181-5
