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. 2025 Oct 8.
doi: 10.1007/s00125-025-06549-6. Online ahead of print.

DNA methylation of genes involved in lipid metabolism drives adiponectin levels and metabolic disease

Lucy Sinke  1 , Thomas Delerue  2 , Rory Wilson  2 , Xueling Lu  3   4 , Yujing Xia  5 , Ricardo Costeira  5 , M Kamal Nasr  6   7 , Marian Beekman  1 , Lude Franke  8 , Alexandra Zhernakova  8 , Jingyuan Fu  8   9 , Christian Gieger  2   10 , Christian Herder  11   12   13 , Wolfgang Koenig  10   14   15 , Annette Peters  2   10   16 , José M Ordovas  17 , Marcus Dörr  7   18 , Hans J Grabe  6   19 , Matthias Nauck  7   20 , Jordana T Bell  5 , Alexander Teumer  6   7   21 , Harold Snieder  3 , Melanie Waldenberger  2   10 , P Eline Slagboom  1 , Bastiaan T Heijmans  22
Affiliations

DNA methylation of genes involved in lipid metabolism drives adiponectin levels and metabolic disease

Lucy Sinke et al. Diabetologia. .

Abstract

Aims/hypothesis: Despite playing critical roles in the pathophysiology of type 2 diabetes and other metabolic disorders, the molecular mechanisms underlying circulating adipokine levels remain poorly understood. By identifying genomic regions involved in the regulation of adipokine levels and adipokine-mediated disease risk, we can improve our understanding of type 2 diabetes pathogenesis and inter-individual differences in metabolic risk.

Methods: We conducted an epigenome-wide meta-analysis of associations between serum adiponectin (n=2791) and leptin (n=3661) and leukocyte DNA methylation at over 400,000 CpG sites across five European cohorts. The resulting methylation signatures were followed up using functional genomics, integrative analyses and causal inference methods.

Results: Our findings revealed robust associations with adiponectin at 73 CpGs and leptin at 211 CpGs. Many of the identified sites were also associated with risk factors for the metabolic syndrome and located in enhancers close to relevant transcription factor binding sites. Integrative analyses additionally linked 35 of the adiponectin-associated CpGs to the expression of 46 genes, and 100 of the leptin-associated CpGs to the expression of 151 genes, with implicated genes enriched for lipid transport (e.g. ABCG1), metabolism (e.g. CPT1A) and biosynthesis (e.g. DHCR24). Bidirectional two-sample Mendelian randomisation further identified two specific CpG sites as plausible drivers of both adiponectin levels and metabolic health: one annotated to ADIPOQ, the gene encoding adiponectin; and another linked to the expression of SREBF1, an established modifier of type 2 diabetes risk known to exert its effects via adiponectin.

Conclusions/interpretation: Taken together, these large-scale and integrative analyses uncovered links between adipokines and widespread, yet functionally specific, differences in regulation of genes with a central role in type 2 diabetes and its risk factors.

Keywords: Adiponectin; Causal inference; Epigenomics; Leptin; Lipid metabolism; Meta-analysis; Metabolic health; Type 2 diabetes.

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Conflict of interest statement

Acknowledgements: The authors thank the staff, participants and related contributing research centres for all cohorts involved in this study. We are additionally grateful to P. S. DeVries (Human Genetics Center, University of Texas Health Science Center at Houston, USA) for his support with the SHIP-TREND EWAS pipeline. Data availability: Summary statistics and other data underlying these findings are available in the ESM. Regarding individual-level data from the cohorts involved, the informed consents given by KORA study participants does not cover data posting in public databases. However, data are available upon request from KORA Project Application Self-Service Tool ( https://helmholtz-muenchen.managed-otrs.com/external/Data ). Requests for data can be submitted online and are subject to approval by the KORA Board. The data of the SHIP study cannot be made publicly available due to the informed consent of the study participants but it can be accessed through a data application form available at https://transfer.ship-med.uni-greifswald.de/ for researchers who meet the criteria for access to confidential data. The HumanMethylation450 BeadChip data from the LLD and LLS are available as part of the BIOS Consortium in the European Genome-phenome Archive (EGA), under the accession code EGAD00010000887 ( https://ega-archive.org/datasets/EGAD00010000887 ). Additional -omic and phenotype data are available upon request via the BBMRI-NL BIOS consortium. All data can be requested by bona fide researchers from the respective cohorts. Information about the individual studies analysed in this manuscript can be found in ESM Methods. Correspondence and requests for materials should be addressed to the corresponding author. All other data used in this study are publicly available: EWAS summary statistics can be downloaded from the EWAS Catalogue [19] and EWAS atlas [20], PBMC reference epigenome data are available from ROADMAP [21], TFBS data are available within the HOMER software [22], full mQTL summary statistics can be requested from GoDMC [35], adiponectin [36] and leptin [37] GWAS summary statistics are available from the GWAS database, LD proxies and matrices can be accessed using LDlink [38], variances in methylation and expression were calculated from data generated by the BIOS (a full list of investigators is available from https://ega-archive.org/datasets/EGAD00010000887 ), libraries for GSEA were downloaded directly from Enrichr ( https://maayanlab.cloud/Enrichr/ ), and SGBS adipocyte data are available from GEO (GSE119593 for expression data, GSE119539 for DNAm data). All the software and programs used to conduct these analyses are freely available. Code availability: Custom code for the respective analyses is available at https://github.com/nebulyra/adipo_ewas . Funding: The work of LS was supported by the Joint Programming Initiative ‘a Healthy Diet for a Healthy Life’ (JPI-HDHL) DIMENSION project [ZonMW project number: 529051021]. Funding for the BIOS consortium was provided by the Netherlands Organization for Scientific Research (NWO 184.021.007 and 184.033.111), made available as a Rainbow Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). KORA F4: The KORA research platform (KORA, Cooperative Health Research in the Region of Augsburg) was initiated and financed by the Helmholtz Munich – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. This work was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the EU Joint Programming Initiative ‘A Healthy Diet for a Healthy Life’ (DIMENSION; grant no. 01EA1902A). The German Diabetes Center is supported by the Ministry of Culture and Science of the state of North Rhine-Westphalia (Düsseldorf, Germany) and the German Federal Ministry of Health (Berlin, Germany). This study was supported in part by a grant from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD). Leiden Longevity Study: The LLS was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE01014 and IGE05007), the Centre for Medical Systems Biology, and the National Institute for Healthy Ageing (grant 05040202 and 05060810), in the framework of the Netherlands Genomics Initiative / Netherlands Organization for Scientific Research, and the VOILA Consortium (ZonMW 457001001). TwinsUK: TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd. and the National Institute for Health Research (NIHR), Clinical Research Network (CRN) and Biomedical Research Centre based on Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. LifeLines DEEP: The Lifelines Biobank initiative has been made possible by a subsidy from the Dutch Ministry of Health, Welfare and Sport; the Dutch Ministry of Economic Affairs, the University Medical Centre Groningen (UMCG, the Netherlands); the University of Groningen and the Northern Provinces of the Netherlands. JF is supported by the ERC Consolidator grant (grant agreement no. 101001678), NWO-VICI grant VI.C.202.022 and the Ammodo Science Award 2023 for Biomedical Sciences from Stichting Ammodo. SHIP-TREND: SHIP (The Study of Health in Pomerania) is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grant no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). DNAm data have been supported by the DZHK (grant 81X3400104). AT has been funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – 542489987. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. Authors’ relationships and activities: HJG has received travel grants and speaker’s honoraria from Neuraxpharm, Servier, Indorsia and Janssen Cilag. CH is Reviews Editor at Diabetologia. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: LS conceived and designed the study, performed data preprocessing and quality control, undertook cohort-specific and main analyses, interpreted results and drafted the manuscript. BTH conceived and designed the study, supervised conduct of the study, iteratively critically revised the manuscript and provided critical intellectual contributions and interpretations of results. TD and RW (KORA F4), XL (LLD), YX and RC (TwinsUK) and MKN (SHIP-TREND) performed cohort-specific analyses, provided summary statistics for the meta-analyses, and provided critical intellectual contributions and interpretations of results; JMO provided critical intellectual contributions and interpretations of results. LF, AZ, JF and HS (LLD), CG, CH, WK, AP and MW (KORA F4), MD, HJG, MN and AT (SHIP-TREND), JTB (TwinsUK), and MB and PS (LLS) provided data, phenotype acquisition and harmonisation for these analyses, and provided critical intellectual contributions and interpretation of results. All authors reviewed the manuscript critically for important intellectual content and approved the final version prior to submission. BTH is responsible for the integrity of the work as a whole.

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