Hemochromatosis Neural Archetype Reveals Iron Disruption in Motor Circuits

Abstract Our understanding of brain iron regulation and its disruption in disease is currently lacking. We previously found that motor circuitry is susceptible to the cumulative neurotoxic effects of excessive iron, leading to the manifestation of Parkinson’s disease. However, beyond a few well-known genes involved in peripheral iron metabolism, the underlying molecular mechanisms regulating central iron levels remain unclear. To bridge this gap, we generated scores in neurotypical individuals based on the archetypal brain iron accumulation observed in magnetic resonance imaging scans of individuals who exhibit excessive absorption of dietary iron and hemochromatosis risk. Genome-wide analysis, using common-variant SNP-array and rare-variant exome data, demonstrated this archetypal brain iron accumulation pattern is highly heritable, revealing both known and novel loci associated with iron homeostasis, and causally driven by peripheral iron levels. Our score predicted abnormalities in gait and revealed a U-shape relationship with PD risk - identifying a group of individuals with a 3-fold increased risk for this disorder. Taken together these results establish a hormetic relationship between brain iron and PD risk, in which central iron levels are strongly determined by genetics via peripheral iron. We believe this framework combining forward and reverse genetics represents a powerful new study design to understand genomic drivers underlying high dimensional phenotypes.