Brain structure in healthy adults is related to serum transferrin and the H63D polymorphism in the HFE gene

Control of iron homeostasis is essential for healthy central nervous system function: iron deficiency is associated with cognitive impairment, yet iron overload is thought to promote neurodegenerative diseases. Specific genetic markers have been previously identified that influence levels of transfe...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-04, Vol.109 (14), p.E851-E859
Main Authors: Jahanshad, Neda, Kohannim, Omid, Hibar, Derrek P, Stein, Jason L, McMahon, Katie L, de Zubicaray, Greig I, Medland, Sarah E, Montgomery, Grant W, Whitfield, John B, Martin, Nicholas G, Wright, Margaret J, Toga, Arthur W, Thompson, Paul M
Format: Article
Language:English
Subjects:
Adult
Biological Sciences
brain
Brain - anatomy & histology
Brain research
Female
Genes
Genetic markers
genetic polymorphism
Glycoproteins
Hemochromatosis Protein
Histocompatibility Antigens Class I - genetics
Homeostasis
Humans
Iron
magnetic resonance imaging
Male
Membrane Proteins - genetics
microstructure
PNAS Plus
Polymorphism
Polymorphism, Genetic
Reference Values
Social Sciences
transferrin
Transferrin - metabolism
twins
young adults
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Summary:Control of iron homeostasis is essential for healthy central nervous system function: iron deficiency is associated with cognitive impairment, yet iron overload is thought to promote neurodegenerative diseases. Specific genetic markers have been previously identified that influence levels of transferrin, the protein that transports iron throughout the body, in the blood and brain. Here, we discovered that transferrin levels are related to detectable differences in the macro- and microstructure of the living brain. We collected brain MRI scans from 615 healthy young adult twins and siblings, of whom 574 were also scanned with diffusion tensor imaging at 4 Tesla. Fiber integrity was assessed by using the diffusion tensor imaging-based measure of fractional anisotropy. In bivariate genetic models based on monozygotic and dizygotic twins, we discovered that partially overlapping additive genetic factors influenced transferrin levels and brain microstructure. We also examined common variants in genes associated with transferrin levels, TF and HFE, and found that a commonly carried polymorphism (H63D at rs1799945) in the hemochromatotic HFE gene was associated with white matter fiber integrity. This gene has a well documented association with iron overload. Our statistical maps reveal previously unknown influences of the same gene on brain microstructure and transferrin levels. This discovery may shed light on the neural mechanisms by which iron affects cognition, neurodevelopment, and neurodegeneration.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1105543109