To what extent does genetic risk for hemochromatosis affect the brain and contribute to risk for neurological disorders?
In this cross-sectional study that included 836 participants, we found that individuals at high genetic risk for developing hemochromatosis had magnetic resonance imaging scans indicating substantial iron deposition localized to motor circuits of the brain. Further analysis of data for 488 288 individuals revealed that male individuals with high genetic risk for hemochromatosis (but not female individuals) were at 1.80-fold increased risk for developing a movement disorder, with the majority of these individuals not having a concurrent diagnosis for hemochromatosis.
Genetic risk for hemochromatosis is associated with abnormal iron deposition in motor circuits and increased risk of movement disorders, regardless of formal diagnosis of hemochromatosis, and treatment for hemochromatosis that reduces iron overload may prove beneficial for male individuals at genetic risk for hemochromatosis who have movement disorders.
Hereditary hemochromatosis (HH) is an autosomal recessive genetic disorder that leads to iron overload. Conflicting results from previous research has led some to believe the brain is spared the toxic effects of iron in HH.
To test the association of the strongest genetic risk variant for HH on brainwide measures sensitive to iron deposition and the rates of movement disorders in a substantially larger sample than previous studies of its kind.
Design, Setting, and Participants
This cross-sectional retrospective study included participants from the UK Biobank, a population-based sample. Genotype, health record, and neuroimaging data were collected from January 2006 to May 2021. Data analysis was conducted from January 2021 to April 2022. Disorders tested included movement disorders (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10], codes G20-G26), abnormalities of gait and mobility (ICD-10 codes R26), and other disorders of the nervous system (ICD-10 codes G90-G99).
Homozygosity for p.C282Y, the largest known genetic risk factor for HH.
Main Outcomes and Measures
T2-weighted and T2* signal intensity from brain magnetic resonance imaging scans, measures sensitive to iron deposition, and clinical diagnosis of neurological disorders.
The total cohort consisted of 488 288 individuals (264 719 female; ages 49-87 years, largely northern European ancestry), 2889 of whom were p.C282Y homozygotes. The neuroimaging analysis consisted of 836 individuals: 165 p.C282Y homozygotes (99 female) and 671 matched controls (399 female). A total of 206 individuals were excluded from analysis due to withdrawal of consent. Neuroimaging analysis showed that p.C282Y homozygosity was associated with decreased T2-weighted and T2* signal intensity in subcortical motor structures (basal ganglia, thalamus, red nucleus, and cerebellum; Cohen d >1) consistent with substantial iron deposition. Across the whole UK Biobank (2889 p.C282Y homozygotes, 485 399 controls), we found a significantly increased prevalence for movement disorders in male homozygotes (OR, 1.80; 95% CI, 1.28-2.55; P = .001) but not female individuals (OR, 1.09; 95% CI, 0.70-1.73; P = .69). Among the 31 p.C282Y male homozygotes with a movement disorder, only 10 had a concurrent HH diagnosis.
Conclusions and Relevance
These findings indicate increased iron deposition in subcortical motor circuits in p.C282Y homozygotes and confirm an increased association with movement disorders in male homozygotes. Early treatment in HH effectively prevents the negative consequences of iron overload in the liver and heart. Our work suggests that screening for p.C282Y homozygosity in high-risk individuals also has the potential to reduce brain iron accumulation and to reduce the risk of movement disorders among male individuals who are homozygous for this mutation.
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Loughnan R, Ahern J, Tompkins C, et al. Association of Genetic Variant Linked to Hemochromatosis With Brain Magnetic Resonance Imaging Measures of Iron and Movement Disorders. JAMA Neurol. 2022;79(9):919–928. doi:10.1001/jamaneurol.2022.2030
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