Abstract
Iron is essential for both humans and pathogens, yet its genetic regulation remains understudied in African populations. Here, we report genome-wide association studies of six iron-related biomarkers in 3928 children from five sites across Africa, with replication in 2868 African American adults and investigate associations with severe malaria and bacteremia. We identify previously unreported loci at genome-wide significance, for transferrin at GTF3C5, and for hepcidin at CHCHD7/SDR16C5. Variants tagging the DUP4 haplotype, encoding the Dantu blood group (rs552439837) are associated with soluble transferrin receptor levels. Variants at GTF3C5 (rs2905094) and DUP4 confer protection against severe malaria and bacteremia. The CHCHD7/SDR16C5 variant (rs73596248) increases hepcidin levels and is associated with reduced risk of Klebsiella pneumoniae and Staphylococcus aureus bacteremia. Polygenic risk scores derived from European data show limited transferability to African populations. In this work, we demonstrate new genetic insights into iron regulation and highlight iron’s role in host-pathogen interactions.
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Data availability
Summary statistics for the genome-wide association tests of imputed data for iron biomarkers in continental African populations reported in this study have been deposited in the Harvard Dataverse at https://doi.org/10.7910/DVN/ZGGN2F. The supplementary data generated in this study are provided in the Supplementary Information and Supplementary Data files. The European GWAS meta-analysis summary level data for serum ferritin, serum iron, total iron-binding capacity, and transferrin saturation used in this study are available from NTNU Open Research Data (https://doi.org/10.18710/S9TJEL), while those for hepcidin and soluble transferrin receptors were obtained from the NHGRI-EBI GWAS Catalogue (hepcidin: accession number GCST90451683; soluble transferrin receptor: accession number GCST90451684). Source data are provided with this paper.
Code availability
All analyses used preassigned code defined within software packages that are publicly available as described in Methods. Any other requests for clarifications may be sought from the corresponding authors.
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Acknowledgements
We thank all study participants who contributed to this study and staff involved with consent, sample and data collection and preparation. This work was funded by Wellcome (Grant numbers [224317 to JMM], [226014 to SHA], [202800 to TNW], [103951 to AOE], [106289 to AJM], [311117 to JJG], and [064693, 079110, 095778 to AME]) and with core awards to the KEMRI-Wellcome Trust Research Programme (203077, 227131), The Wellcome Centre for Human Genetics (090532, 203141) and the Wellcome Sanger Institute (098051, 206194). GDS & GH works within the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00032/1). This work was also supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (grant number: 2024-I2M-2-001-1). The Jackson Heart Study (JHS) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I) and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute on Minority Health and Health Disparities (NIMHD). The authors also wish to thank the staff and participants of the JHS. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. This project was supported in part by the Intramural Research Program of the National Human Genome Research Institute of the National Institutes of Health (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). The contributions of the NIH author(s) are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. JJG was funded by a National Institute for Health and Care Research Clinical Lectureship. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This study was published with the permission of the Director of KEMRI.
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JMM, AJM, GDS, AME, TNW, AA, and SHA conceptualized and designed the methods for the research project; JMM performed the analyses; JMM, AJM, GB, AYC, AWM, RMM, KMA, RM, JJG, ELW, FMN, LMR, LE, ARB, SBS, SAM, AVSH, AMP, PB, GH, GDS, MSS, AME, TNW, and SHA were involved in resources generation, data curation, and analytical support. JMM, AJM, AME, GDS, TNW, AA, and SHA were responsible for funding acquisition. JMM and SHA wrote the manuscript and all co-authors reviewed the manuscript.
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Muriuki, J.M., Mentzer, A.J., Band, G. et al. African-specific genetic loci determine iron status and risk of severe malaria and bacteremia in African children. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71567-w
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DOI: https://doi.org/10.1038/s41467-026-71567-w
