Department of Cognitive Science, University of California, San Diego, La Jolla.
Population Neuroscience and Genetics, University of California, San Diego, La Jolla.
JAMA Neurol. 2022 Sep 1;79(9):919-928. doi: 10.1001/jamaneurol.2022.2030.
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.
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.
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.
遗传性血色素沉着症（HH）是一种常染色体隐性遗传疾病，导致铁过载。先前研究的相互矛盾的结果导致一些人认为大脑免受 HH 中铁的毒性影响。
在比以前的同类研究更大的样本中，测试 HH 最强遗传风险变异对脑内对铁沉积敏感的全脑测量值和运动障碍发生率的相关性。
设计、地点和参与者：这项横断面回顾性研究纳入了英国生物银行的参与者，这是一个基于人群的样本。从 2006 年 1 月至 2021 年 5 月收集了基因型、健康记录和神经影像学数据。数据分析于 2021 年 1 月至 2022 年 4 月进行。测试的疾病包括运动障碍（国际疾病分类，第十次修订版[ICD-10]，代码 G20-G26）、步态和移动异常（ICD-10 代码 R26）和其他神经系统疾病（ICD-10 代码 G90-G99）。
p.C282Y 纯合子，这是 HH 最大的已知遗传风险因素。
脑磁共振成像扫描的 T2 加权和 T2*信号强度，对铁沉积敏感的测量值，以及神经障碍的临床诊断。
总队列包括 488288 人（264719 名女性；年龄 49-87 岁，主要为北欧血统），其中 2889 人为 p.C282Y 纯合子。神经影像学分析包括 836 人：165 名 p.C282Y 纯合子（99 名女性）和 671 名匹配的对照者（399 名女性）。由于同意书被撤回，共有 206 人被排除在分析之外。神经影像学分析表明，p.C282Y 纯合子与皮质下运动结构（基底节、丘脑、红核和小脑）中的 T2 加权和 T2*信号强度降低有关（Cohen d >1），这与大量铁沉积有关。在整个英国生物银行（2889 名 p.C282Y 纯合子，485399 名对照者）中，我们发现男性纯合子运动障碍的患病率显著增加（OR，1.80；95%CI，1.28-2.55；P =.001），但女性个体没有（OR，1.09；95%CI，0.70-1.73；P =.69）。在 31 名患有运动障碍的 p.C282Y 男性纯合子中，仅有 10 人同时患有 HH。
这些发现表明 p.C282Y 纯合子的皮质下运动回路中铁沉积增加，并证实了男性纯合子与运动障碍的关联增加。HH 的早期治疗可有效防止肝和心脏中铁过载的不良后果。我们的工作表明，对高危个体进行 p.C282Y 纯合子筛查也有可能减少脑内铁的积累，并降低该突变纯合子男性个体运动障碍的风险。
