Novel loci and biomedical consequences of iron homoeostasis variation

E Allara; S Bell; R Smith; SJ Keene; D Gill; L Gaziano; D Morselli Gysi; F Wang; V Tragante; A Mason; S Karthikeyan; RT Lumbers; E Bonglack; W Ouwehand; DJ Roberts; J Dowsett; SR Ostrowski; MH Larsen; H Ullum; OB Pedersen; S Brunak; K Banasik; J Erikstrup C; DBDS Genomic Consortium; Mitchell; Christian Fuchsberger; Cristian Pattaro; Peter P. Pramstaller; D Girelli; M Arvas; J Toivonen; S Molnos; A Peters; O Polasek; I Rudan; C Hayward; C McDonnell; N Pirastu; JF Wilson; K van den Hurk; F Quee; L Ferrucci; S Bandinelli; T Tanaka; G Girotto; MP Concas; A Pecori; N Verweij; P van der Harst; YJ van de Vegte; LA Kiemeney; FC Sweep; TE Galesloot; P Sulem; D Gudbjartsson; L Ferkingstad E; FinnGen Consortium; Djousse; K Cho; M Inouye; S Burgess; B Benyamin; K Oexle; D Swinkels; K Stefansson; M Magnusson; A Ganna; M Gaziano; K Ivey; J Danesh; A Pereira; AM Wood; AS Butterworth; E Di Angelantonio

doi:10.1038/s42003-024-07115-3

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Novel loci and biomedical consequences of iron homoeostasis variation

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Novel loci and biomedical consequences of iron homoeostasis variation

E Allara, S Bell, R Smith, SJ Keene, D Gill, L Gaziano, D Morselli Gysi, F Wang, V Tragante, A Mason, …

Communications Biology, Vol.7, 1631

06/12/2024

DOI: https://doi.org/10.1038/s42003-024-07115-3

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https://hdl.handle.net/10863/48377

Abstract

Computational Genomics

CHRIS study

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.

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Title: Novel loci and biomedical consequences of iron homoeostasis variation
Creators: E Allara - University of Cambridge
S Bell - University of Cambridge
R Smith - University of Cambridge
SJ Keene - University of Cambridge
D Gill - Imperial College London
L Gaziano - University of Cambridge
D Morselli Gysi
F Wang - Institute for Molecular Medicine Finland
V Tragante - deCODE Genetics
A Mason - University of Cambridge
S Karthikeyan - University of Cambridge
RT Lumbers - University College London
E Bonglack - University of Cambridge
W Ouwehand - NHS Blood and Transplant
DJ Roberts - Churchill Hospital
J Dowsett - Copenhagen University Hospital
SR Ostrowski - Copenhagen University Hospital
MH Larsen - Copenhagen University Hospital
H Ullum - Statens Serum Institut
OB Pedersen - University of Copenhagen
S Brunak - Novo Nordisk Foundation
K Banasik - Novo Nordisk Foundation
J Erikstrup C; DBDS Genomic Consortium; Mitchell
Christian Fuchsberger - Institute for Biomedicine
Cristian Pattaro - Institute for Biomedicine
Peter P. Pramstaller - Institute for Biomedicine
D Girelli - University of Verona
M Arvas - Finnish Red Cross
J Toivonen - Finnish Red Cross
S Molnos
A Peters - Helmholtz Zentrum München
O Polasek - University of Split
I Rudan
C Hayward - Medical Research Council
C McDonnell - University of Edinburgh
N Pirastu - University of Edinburgh
JF Wilson - Institute of Genetics
K van den Hurk - Sanquin
F Quee - Sanquin
L Ferrucci - National Institute on Aging
S Bandinelli - Azienda Sanitaria di Firenze
T Tanaka - National Institute on Aging
G Girotto - IRCCS Materno Infantile Burlo Garofolo
MP Concas - IRCCS Materno Infantile Burlo Garofolo
A Pecori - IRCCS Materno Infantile Burlo Garofolo
N Verweij - University Medical Center Groningen
P van der Harst - University Medical Center Groningen
YJ van de Vegte - University Medical Center Groningen
LA Kiemeney - Radboud University Nijmegen
FC Sweep
TE Galesloot - Radboud University Nijmegen
P Sulem - deCODE Genetics
D Gudbjartsson
L Ferkingstad E; FinnGen Consortium; Djousse
K Cho - Harvard University
M Inouye - Baker Heart and Diabetes Institute
S Burgess - Medical Research Council
B Benyamin - South Australian Health and Medical Research Institute
K Oexle - Technical University of Munich
D Swinkels - Sanquin
K Stefansson
M Magnusson - deCODE Genetics
A Ganna - Institute for Molecular Medicine Finland
M Gaziano - Harvard University
K Ivey - Harvard University
J Danesh - Wellcome Sanger Institute
A Pereira - Harvard University
AM Wood
AS Butterworth - University of Cambridge
E Di Angelantonio - Human Technopole
Publication Details: Communications Biology, Vol.7, 1631
EISSN: 2399-3642
Series / Volume: 7
Publisher: Nature Research
Identifiers: (EURAC)30570676
991007084577701241
Web of Science ID: 001385774900001
Copyright: CC BY 4.0
Academic Unit: Institute for Biomedicine
Language: English
Resource Type: Journal article
Description coverage: none
Description audience: Scientific
Local Fields: Scientific
Author Names String: Allara E, Bell S, Smith R, Keene SJ, Gill D, Gaziano L, Morselli Gysi D, Wang F, Tragante V, Mason A, Karthikeyan S, Lumbers RT, Bonglack E, Ouwehand W, Roberts DJ, Dowsett J, Ostrowski SR, Larsen MH, Ullum H, Pedersen OB, Brunak S, Banasik K, Erikstrup C; DBDS Genomic Consortium; Mitchell J, Fuchsberger C, Pattaro C, Pramstaller PP, Girelli D, Arvas M, Toivonen J, Molnos S, Peters A, Polasek O, Rudan I, Hayward C, McDonnell C, Pirastu N, Wilson JF, van den Hurk K, Quee F, Ferrucci L, Bandinelli S, Tanaka T, Girotto G, Concas MP, Pecori A, Verweij N, van der Harst P, van de Vegte YJ, Kiemeney LA, Sweep FC, Galesloot TE, Sulem P, Gudbjartsson D, Ferkingstad E; FinnGen Consortium; Djousse L, Cho K, Inouye M, Burgess S, Benyamin B, Oexle K, Swinkels D, Stefansson K, Magnusson M, Ganna A, Gaziano M, Ivey K, Danesh J, Pereira A, Wood AM, Butterworth AS, Di Angelantonio E

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