| Title: | Hemochromatosis neural archetype reveals iron disruption in motor circuits |
| Journal: | Science Advances |
| Published: | 22 Nov 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39576859/ |
| DOI: | https://doi.org/10.1126/sciadv.adp4431 |
Publication 14269
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Abstract
Our understanding of brain iron regulation and its disruption in disease is limited. Excess iron affects motor circuitry, contributing to Parkinson's disease (PD) risk. The molecular mechanisms regulating central iron levels, beyond a few well-known genes controlling peripheral iron, remain unclear. We generated scores based on the archetypal brain iron accumulation observed in magnetic resonance imaging scans of individuals with excessive dietary iron absorption and hemochromatosis risk. Genome-wide analysis revealed that this score is highly heritable, identifying loci associated with iron homeostasis, and driven by peripheral iron levels. Our score predicted gait abnormalities and showed a U-shaped relationship with PD risk, identifying individuals with threefold increased risk. These results establish a hormetic relationship between brain iron and PD risk, where central iron levels are strongly determined by genetics via peripheral iron. This framework combining forward and reverse genetics is a powerful study design to understand genomic drivers underlying high dimensional phenotypes.</p>
11 Keywords
- Brain
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Hemochromatosis
- Humans
- Iron
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Parkinson Disease
15 Authors
- Robert Loughnan
- Jonathan Ahern
- Mary Boyle
- Terry L. Jernigan
- Donald J. Hagler
- John R. Iversen
- Oleksandr Frei
- Diana M. Smith
- Ole Andreassen
- Noah Zaitlen
- Leo Sugrue
- Wesley K. Thompson
- Anders Dale
- Andrew J. Schork
- Chun Chieh Fan
1 Application
| Application ID | Title |
|---|---|
| 27412 | Boosting the power of GWAS using novel statistical tools |
Enabling scientific discoveries that improve human health