In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 14 ( 2012-04-03)
Abstract:
Iron is vital for brain function, and here we discovered poorer brain integrity in those with lower levels of iron available for transport to the brain. This is especially remarkable, as the people we studied were all in good health, and with access to a healthy diet. We found brain pathways whose structure is controlled by the same gene that affects transferrin levels, revealing inherited developmental properties. We can now see the effects of this common gene on the brain, revealing how iron pathways affect brain pathways. Our study reveals connections between transferrin levels, iron-related genes, and brain integrity as it changes throughout our lives. Our analysis had three major findings. First, serum transferrin levels, measured during adolescence, were associated with differences in brain structure and fiber integrity in adulthood (approximately 9 y after blood was drawn). Second, overlapping sets of genes mediated these associations with white matter integrity. This was evident from the cross-twin cross-trait correlations between transferrin levels and white matter integrity. Third, we found that a very commonly carried genetic variant—the well known HFE H63D polymorphism—influences white matter microstructure in the external capsule, a key neural pathway. This points to a direct link between genomic variation and brain structure via the iron transport pathway. After discovering a common genetic basis for transferrin levels and brain fiber integrity, we used a family-based genetic association test to further investigate (second question mark in Fig. P1 ) how the brain is affected by specific variants in the transferrin gene, TF , on chromosome 3 and in the HFE gene on chromosome 6. Together, these genes explain a remarkable 40% of the genetic variance in serum transferrin levels ( 5 ). Genetic factors explain a large proportion of the variance in serum transferrin levels ( 3 ). As such, if transferrin is associated with brain differences, we might expect that some of the same genes might influence brain structure and iron availability. To understand such shared genetic contributions to brain variations and transferrin, we used a twin design. Cross-twin cross-trait designs can discover overlapping (i.e., pleiotropic) genetic influences on very different biological traits, such as fiber integrity and IQ ( 4 ). We further hypothesized that volumes of iron-rich brain regions might also be lower in people with high serum transferrin levels. In people with low iron levels, more transferrin is produced by the liver—this is thought to be a compensatory reaction, to make more iron available to the body, including the brain. By measuring brain volumes regionally, we predicted that we might find insufficiently developed (i.e., smaller) brain structures in those with higher transferrin levels. Iron deficiency alters dopamine metabolism in the caudate and putamen ( 2 ), so we predicted that people with high transferrin (and lower brain iron) might have lower volumes for dopamine-containing structures, involved in learning and motor control. We note these hypotheses relating brain structure to transferrin levels in Fig. P1 as the first arrow marked with a question mark. We studied healthy individuals with serum measures taken during the teenage years (age 12–16 y); their brains were imaged later, as young adults (age 20–30 y); iron overload is unlikely in this young population. We instead expected that iron levels toward the lower end of the normal range might lead to a poorer developmental phenotype in the brain. Most of the brain's iron is found in cells called oligodendrocytes, and iron is critical to allow these cells to produce myelin, a fatty insulation that speeds up brain impulses ( 1 ). Our primary hypothesis was that people with lower iron levels during adolescence might have poorer white matter integrity later in life. To assess brain integrity in adulthood, we used the widely accepted method of assessment of fractional anisotropy, measured from the diffusion tensor imaging scans. This measures the coherence of fibers in the brain: lower fractional anisotropy can be a sign of less mature or poorer myelination. Iron levels in the human body are critical for healthy brain development, but too much iron can promote brain degeneration. We set out to investigate whether brain structure in healthy adults depends on the level of transferrin, a protein that transports iron to the brain. With brain MRI, we scanned 615 young adult twins and their siblings. We also scanned 574 of them with a type of MRI called diffusion tensor imaging. This type of scan assesses the integrity of fibers and connections that transmit information in the brain. We were particularly interested to see if iron availability to the developing brain in adolescence would affect brain integrity later in life. This work reveals how iron levels in the body can affect the structure of the living brain. Iron is critical for healthy brain function. Iron-deficient children often have cognitive problems, but too much iron can promote brain degeneration in old age. Clearly, iron transport to the brain must be carefully regulated. Here we discovered that levels of the iron transport protein, transferrin, affect the overall structure of the human brain, i.e., its fiber integrity and the volumes of different brain regions. These changes are genetically influenced; we discovered one gene that affects brain integrity and iron availability.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1105543109
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2012
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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