Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 14, Pages E851-E859Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1105543109
Keywords
neuroimaging genetics; twin modeling; pathway analysis; tensor-based morphometry; voxel based analysis
Categories
Funding
- National Institute of Child Health and Human Development [R01 HD050735]
- National Health and Medical Research Council (NHMRC
- Australia) [486682, T15 LM07356]
- Achievement Rewards for College Scientists Foundation
- National Institute of Mental Health [1F31MH087061]
- Australian Research Council [FT0991634]
- NHMRC [389875]
- National Institutes of Health [R01 EB008432, R01 EB008281, R01 EB007813]
- Australian Research Council [FT0991634] Funding Source: Australian Research Council
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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.
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