TY - JOUR
T1 - Novel loci and biomedical consequences of iron homoeostasis variation
AU - Allara, Elias
AU - Bell, Steven
AU - Smith, Rebecca
AU - Keene, Spencer J.
AU - Gill, Dipender
AU - Gaziano, Liam
AU - Morselli Gysi, Deisy
AU - Wang, Feiyi
AU - Tragante, Vinicius
AU - Mason, Amy
AU - Karthikeyan, Savita
AU - Lumbers, R. Thomas
AU - Bonglack, Emmanuela
AU - Ouwehand, Willem
AU - Roberts, David J.
AU - Dowsett, Joseph
AU - Ostrowski, Sisse Rye
AU - Larsen, Margit Hørup
AU - Ullum, Henrik
AU - Pedersen, Ole Birger
AU - Brunak, Søren
AU - Banasik, Karina
AU - Erikstrup, Christian
AU - Westergaard, David
AU - Werge, Thomas
AU - Topholm Bruun, Mie
AU - Þorsteinsdóttir, Unnur
AU - Thørner, Lise Wegner
AU - Stefánsson, Hreinn
AU - Stefansson, Kari
AU - Schwinn, Michael
AU - Sørensen, Erik
AU - Rostgaard, Klaus
AU - Rohde, Palle Duun
AU - Rafnar, Þórunn
AU - Quinn, Liam James Elgaard
AU - Nyegaard, Mette
AU - Mikkelsen, Christina
AU - Mikkelsen, Susan
AU - Kjerulff, Bertram Dalskov
AU - Kaspersen, Kathrine
AU - Jensen, Bitten Aagaard
AU - Hindhede, Lotte
AU - Hansen, Thomas Folkmann
AU - Erikstrup, Christian
AU - Dinh, Khoa Manh
AU - Boldsen, Jens Kjærgaard
AU - Luo, Shuang
AU - Liu, Aoxing
AU - Chen, Hao
AU - FinnGen Consortium
AU - DBDS Genomic Consortium
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85211476953&partnerID=8YFLogxK
U2 - 10.1038/s42003-024-07115-3
DO - 10.1038/s42003-024-07115-3
M3 - Journal article
C2 - 39643614
AN - SCOPUS:85211476953
SN - 2399-3642
VL - 7
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 1631
ER -