Causal Associations Between Iron Levels in Subcortical Brain Regions and Psychiatric Disorders: a Mendelian Randomization Study

Overview

Journal Transl Psychiatry

Date 2025 Jan 22

PMID 39843424

Authors

Wei Du

Biqiu Tang

Senhao Liu

Wenjing Zhang

Su Lui

Affiliations

Soon will be listed here.

Abstract

Despite observational studies linking brain iron levels to psychiatric disorders, the exact causal relationship remains poorly understood. This study aims to examine the relationship between iron levels in specific subcortical brain regions and the risk of psychiatric disorders. Utilizing two-sample Mendelian randomization (MR) analysis, this study investigates the causal associations between iron level changes in 16 subcortical nuclei and eight major psychiatric disorders, including schizophrenia (SCZ), major depressive disorder (MDD), autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder, bipolar disorder, anxiety disorders, obsessive-compulsive disorder, and insomnia. The genetic instrumental variables linked to iron levels and psychiatric disorders were derived from the genome-wide association studies data of the UK Biobank Brain Imaging and Psychiatric Genomics Consortium. Bidirectional causal estimation was primarily obtained using the inverse variance weighting (IVW) method. Iron levels in the left substantia nigra showed a negative association with the risk of MDD (OR = 0.94, 95% CI = 0.91-0.97, p < 0.001) and trends with risk of SCZ (OR = 0.90, 95% CI = 0.82-0.98, p = 0.020). Conversely, iron levels in the left putamen were positively associated with the risk of ASD (OR = 1.11, 95% CI = 1.04-1.19, p = 0.002). Additionally, several bidirectional trends were observed between subcortical iron levels and the risk for psychiatric disorders. Lower iron levels in the left substantia nigra may increase the risk of MDD, and potentially increase the risk of SCZ, indicating a potential shared pathogenic mechanism. Higher iron levels in the left putamen may lead to the development of ASD. The observed bidirectional trends between subcortical iron levels and psychiatric disorders, indicate the importance of the underlying biomechanical interactions between brain iron regulation and these disorders.

References

Burgess S, Thompson S . Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017; 32(5):377-389. PMC: 5506233. DOI: 10.1007/s10654-017-0255-x. View

Shibukawa S, Kan H, Honda S, Wada M, Tarumi R, Tsugawa S . Alterations in subcortical magnetic susceptibility and disease-specific relationship with brain volume in major depressive disorder and schizophrenia. Transl Psychiatry. 2024; 14(1):164. PMC: 10965930. DOI: 10.1038/s41398-024-02862-7. View

Kritikos M, Clouston S, Huang C, Pellecchia A, Mejia-Santiago S, Carr M . Cortical complexity in world trade center responders with chronic posttraumatic stress disorder. Transl Psychiatry. 2021; 11(1):597. PMC: 8611009. DOI: 10.1038/s41398-021-01719-7. View

Davey Smith G, Hemani G . Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet. 2014; 23(R1):R89-98. PMC: 4170722. DOI: 10.1093/hmg/ddu328. View

Demontis D, Walters G, Athanasiadis G, Walters R, Therrien K, Nielsen T . Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains. Nat Genet. 2023; 55(2):198-208. PMC: 10914347. DOI: 10.1038/s41588-022-01285-8. View

Ward R, Zucca F, Duyn J, Crichton R, Zecca L . The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 2014; 13(10):1045-60. PMC: 5672917. DOI: 10.1016/S1474-4422(14)70117-6. View

Kuchcinski G, Munsch F, Lopes R, Bigourdan A, Su J, Sagnier S . Thalamic alterations remote to infarct appear as focal iron accumulation and impact clinical outcome. Brain. 2017; 140(7):1932-1946. PMC: 6248443. DOI: 10.1093/brain/awx114. View

Yao S, Zhong Y, Xu Y, Qin J, Zhang N, Zhu X . Quantitative Susceptibility Mapping Reveals an Association between Brain Iron Load and Depression Severity. Front Hum Neurosci. 2017; 11:442. PMC: 5581806. DOI: 10.3389/fnhum.2017.00442. View

Deistung A, Schweser F, Reichenbach J . Overview of quantitative susceptibility mapping. NMR Biomed. 2016; 30(4). DOI: 10.1002/nbm.3569. View

10.

Yao S, Zhang M, Dong S, Wang J, Zhang K, Guo J . Bidirectional two-sample Mendelian randomization analysis identifies causal associations between relative carbohydrate intake and depression. Nat Hum Behav. 2022; 6(11):1569-1576. DOI: 10.1038/s41562-022-01412-9. View

11.

Davies N, Holmes M, Davey Smith G . Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018; 362:k601. PMC: 6041728. DOI: 10.1136/bmj.k601. View

12.

McCutcheon R, Abi-Dargham A, Howes O . Schizophrenia, Dopamine and the Striatum: From Biology to Symptoms. Trends Neurosci. 2019; 42(3):205-220. PMC: 6401206. DOI: 10.1016/j.tins.2018.12.004. View

13.

Tran P, Fretham S, Wobken J, Miller B, Georgieff M . Gestational-neonatal iron deficiency suppresses and iron treatment reactivates IGF signaling in developing rat hippocampus. Am J Physiol Endocrinol Metab. 2011; 302(3):E316-24. PMC: 3287363. DOI: 10.1152/ajpendo.00369.2011. View

14.

Grove J, Ripke S, Als T, Mattheisen M, Walters R, Won H . Identification of common genetic risk variants for autism spectrum disorder. Nat Genet. 2019; 51(3):431-444. PMC: 6454898. DOI: 10.1038/s41588-019-0344-8. View

15.

Chen Q, Chen Y, Zhang Y, Wang F, Yu H, Zhang C . Iron deposition in Parkinson's disease by quantitative susceptibility mapping. BMC Neurosci. 2019; 20(1):23. PMC: 6532252. DOI: 10.1186/s12868-019-0505-9. View

16.

Wu H, Luan Y, Wang H, Zhang P, Liu S, Wang P . Selenium inhibits ferroptosis and ameliorates autistic-like behaviors of BTBR mice by regulating the Nrf2/GPx4 pathway. Brain Res Bull. 2022; 183:38-48. DOI: 10.1016/j.brainresbull.2022.02.018. View

17.

Erikson K, Jones B, Hess E, Zhang Q, Beard J . Iron deficiency decreases dopamine D1 and D2 receptors in rat brain. Pharmacol Biochem Behav. 2001; 69(3-4):409-18. DOI: 10.1016/s0091-3057(01)00563-9. View

18.

Rasooly D, Patel C . Conducting a Reproducible Mendelian Randomization Analysis Using the R Analytic Statistical Environment. Curr Protoc Hum Genet. 2019; 101(1):e82. PMC: 6424604. DOI: 10.1002/cphg.82. View

19.

Xu M, Guo Y, Cheng J, Xue K, Yang M, Song X . Brain iron assessment in patients with First-episode schizophrenia using quantitative susceptibility mapping. Neuroimage Clin. 2021; 31:102736. PMC: 8254125. DOI: 10.1016/j.nicl.2021.102736. View

20.

Trubetskoy V, Pardinas A, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli T . Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 2022; 604(7906):502-508. PMC: 9392466. DOI: 10.1038/s41586-022-04434-5. View