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In addition, epigenetic studies in West African populations are particularly sparse, despite the high and rising burden of type 2 diabetes in these populations. Hence, we aimed to identify CpGs causally associated with type 2 diabetes among West Africans by leveraging Mendelian randomisation (MR) analysis and longitudinal data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We used the Illumina EPIC DNA methylation array to profile the methylation of DNA extracted from white blood cells collected from 879 Ghanaian\u00a0individuals (the Research on Obesity and Diabetes among African Migrants [RODAM] study) and 332 Nigerian\u00a0individuals (the Africa America Diabetes Mellitus [AADM] study) who were not on glucose-lowering medication. We carried forwards CpGs identified in EWAS for type 2 diabetes and meta-analysed EWAS for HbA\n                      <jats:sub>1c<\/jats:sub>\n                      and homeostatic model assessment estimates of insulin sensitivity (HOMA-S) as exposures to two-sample MR analysis. Independent\n                      <jats:italic>cis<\/jats:italic>\n                      methylation quantitative trait loci (meQTLs) were calculated using methylation data from blood and primary hepatocytes and subsequently used as instrumental variables (SNP\u2013exposure associations). Genome-wide association analyses for type 2 diabetes on 4120 participants from the AADM study were used to derive the SNP\u2013outcome associations. Longitudinal trait data (\n                      <jats:italic>n<\/jats:italic>\n                      =138) and RNA-seq data (\n                      <jats:italic>n<\/jats:italic>\n                      =77 blood, 49 adipose, 55 muscle) available for a subset of Nigerians were used for follow-up analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified 28 CpGs associated with type 2 diabetes, 26 with HbA\n                      <jats:sub>1c<\/jats:sub>\n                      and three with HOMA-S (total CpGs: 57), of which 49 had meQTLs in blood (AADM study data) and four had meQTLs in primary hepatocytes from African American\u00a0individuals. MR analysis provided evidence for causality for cg00036588 and cg16759041 in type 2 diabetes using blood and hepatocyte meQTLs, respectively. Longitudinal analyses showed an association between baseline methylation of these CpGs with HbA\n                      <jats:sub>1c<\/jats:sub>\n                      at follow-up. RNA-seq data revealed a\n                      <jats:italic>cis<\/jats:italic>\n                      correlation of cg00036588 with\n                      <jats:italic>FAM83C<\/jats:italic>\n                      (false discovery rate [FDR]=3.3 \u00d7 10\n                      <jats:sup>\u20134<\/jats:sup>\n                      ) and\n                      <jats:italic>EIF6<\/jats:italic>\n                      (FDR=0.13) in skeletal muscle.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>Our study identified two epigenetic markers as likely to be causal for type 2 diabetes in West African populations. In addition to enhancing our understanding of disease mechanisms, these CpGs with evidence of causal associations could be prioritised as potential biomarkers for early detection of disease or as drug development targets.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06716-3","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T21:51:16Z","timestamp":1777067476000},"page":"1882-1897","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Causal relationship between epigenetic markers and type 2 diabetes in West African\u00a0populations: a Mendelian randomisation analysis"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3032-405X","authenticated-orcid":false,"given":"Karlijn A. 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The authors are very grateful to Dr Erik Beune (Department of Public Health, Academic Medical Center, Amsterdam, the Netherlands) who with great dedication and an eye for detail coordinated the RODAM study. This work used the computational resources of the NIH HPC Biowulf cluster (\n                      \n                      ). The contributions of the NIH authors are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The datasets analysed during the current study are not publicly available due to the informed consent obtained not granting permission for deposition in an open-access repository of research data. Qualified investigators may request access to the data as part of a collaboration, in accordance with the project\u2019s institutional review board approval and the participants\u2019 signed informed consent. Requests can be directed to the Principal Investigator of the AADM study, Dr Charles Rotimi (rotimic@mail.nih.gov) and\/or the Principal Investigator of the RODAM study, Professor Charles Agyemang (c.o.agyemang@amsterdamumc.nl).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"The analysis code is available at\n                      \n                      .","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Code availability"}},{"value":"This research was supported in part by the Intramural Research Program of the NIH through the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is also supported by the National Institute of Diabetes and Digestive and Kidney Diseases and the Office of the Director at the NIH (Z01HG200362). KACM is additionally supported by the NIH Pathway to Independence Award (K99\/R00) DK131018. Support for participant recruitment and initial genetic studies of the AADM study was provided by NIH grant no. 3T37TW00041-03S2 from the Office of Research on Minority Health. The RODAM study was funded by the European Commission under the Seventh Framework Programme (grant no. 278901).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"APD, AAA and CNR contributed to the conception, design and\/or data acquisition of the AADM study. KACM, ELL, PH, EO-D and CA contributed to the conception, design and\/or data acquisition of the RODAM study. KACM, AAA and CNR designed the analyses presented in this manuscript. KACM and ELL performed the data analysis. KACM drafted the manuscript with input from all authors. All authors contributed to the interpretation of the data, critically revised the manuscript for important intellectual content and approved the final version for publication. KACM and CNR are responsible for the integrity of the work as a whole.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}