Novel loci and biomedical consequences of iron homoeostasis variation

Elias Allara*, Steven Bell, Rebecca Smith, Spencer J. Keene, Dipender Gill, Liam Gaziano, Deisy Morselli Gysi, Feiyi Wang, Vinicius Tragante, Amy Mason, Savita Karthikeyan, R. Thomas Lumbers, Emmanuela Bonglack, Willem Ouwehand, David J. Roberts, Joseph Dowsett, Sisse Rye Ostrowski, Margit Hørup Larsen, Henrik Ullum, Ole Birger PedersenSøren Brunak, Karina Banasik, Christian Erikstrup, David Westergaard, Thomas Werge, Mie Topholm Bruun, Unnur Þorsteinsdóttir, Lise Wegner Thørner, Hreinn Stefánsson, Kari Stefansson, Erik Sørensen, Michael Schwinn, Klaus Rostgaard, Palle Duun Rohde, Þórunn Rafnar, Liam James Elgaard Quinn, Mette Nyegaard, Janna Nissen, Christina Mikkelsen, Mette Kongstad, Andrew Joseph Schork, Jakob Hjorth von Stemann, Henrik Hjalgrim, Thomas Folkmann Hansen, Maria Didriksen, Lea Arregui Nordahl Christoffersen, Alfonso Buil Demur, Jakob Bay, DBDS Genomic Consortium, FinnGen Consortium

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Iron homoeostasis is tightly regulated, with hepcidin and soluble transferrin receptor (sTfR) playing significant roles. However, the genetic determinants of these traits and the biomedical consequences of iron homoeostasis variation are unclear. In a meta-analysis of 12 cohorts involving 91,675 participants, we found 43 genomic loci associated with either hepcidin or sTfR concentration, of which 15 previously unreported. Mapping to putative genes indicated involvement in iron-trait expression, erythropoiesis, immune response and cellular trafficking. Mendelian randomisation of 292 disease outcomes in 1,492,717 participants revealed associations of iron-related loci and iron status with selected health outcomes across multiple domains. These associations were largely driven by HFE, which was associated with the largest iron variation. Our findings enhance understanding of iron homoeostasis and its biomedical consequences, suggesting that lifelong exposure to higher iron levels is likely associated with lower risk of anaemia-related disorders and higher risk of genitourinary, musculoskeletal, infectious and neoplastic diseases.

Original languageEnglish
Article number1631
JournalCommunications Biology
Volume7
Issue number1
Number of pages17
ISSN2399-3642
DOIs
Publication statusPublished - 2024

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