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 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.
Laboratory of NeuroImaging, Department of Neurology, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90095, USA.
Neda
N
Jahanshad
Omid
O
Kohannim
Derrek P
DP
Hibar
Jason L
JL
Stein
Katie L
KL
McMahon
Greig I
GI
de Zubicaray
Sarah E
SE
Medland
Grant W
GW
Montgomery
John B
JB
Whitfield
Nicholas G
NG
Martin
Margaret J
MJ
Wright
Arthur W
AW
Toga
Paul M
PM
Thompson
D000328:Adult; D001921:Brain / Q000033:anatomy & histology*; D005260:Female; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D012016:Reference Values; D014168:Transferrin / Q000378:metabolism*
C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014168:Transferrin