Polygenic architecture of a novel MRI endophenotype: the “hemochromatosis brain”

Abstract Iron is a mineral crucial for cellular processes but can be neurotoxic when imbalanced. Cumulative evidence suggests motor circuitry is particularly vulnerable to neurotoxic effects of iron, as both peripheral and central iron levels have been associated with movement disorders such as Parkinson’s Disease (PD) 1–7 . However, clinical trials to reduce iron levels among movement disorder patients have shown both therapeutic and pathological effects 8,9 , indicating an incomplete understanding of iron dysregulation and its consequences in the human brain. In this study, we drew upon the archetypal brain pattern observed in C282Y homozygous individuals 10 who exhibit excessive absorption of dietary iron and risk of hemochromatosis 11 . The score we generated to summarize the continuum of the iron dysregulation in vulnerable brain regions from Magnetic Resonance Imaging exhibited a U-shape relationship with PD risk. Compared to individuals in the fourth quartile of scores, those in the lowest quartile of scores had an over 3-fold risk for developing PD (OR=3.19, Z=5.61, p=2.06x10 -8 ), in addition to C282Y homozygotes having an over 2-fold risk for developing PD (OR=2.40, Z=3.34, p=8.41x10 -4 ). Genome wide associations implicated genes involved in iron homeostasis: TF (rs6794370, p=2.43x10 -81 ); HFE (rs1800562, p=6.93x10 -75 ); and TMPRSS6 (rs2413450, p=2.52x10 -50 ). We found these associations colocalized with gene expression of glial cells and variation in scores appeared to be driven by the peripheral iron levels. Our findings highlight the pivotal role of glial cells in balancing iron in motor circuitry, with iron depletion and overload both appearing to be related to PD risk. Disruptions in peripheral iron levels may upset the glial cells’balance, causing problems with central iron homeostasis and, in turn, motor function. We envision this is an initial step toward a more personalized approach in designing iron related therapy for movement disorders, providing iron supplement or iron chelation based on a more comprehensive understanding of brain iron dysregulation.