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Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study
Open accessAbstract
BACKGROUND: Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date. METHODS AND FINDINGS: We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%-6%; p = 0.001) per 10 µg/dl increase in serum iron. CONCLUSIONS: Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made.
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“The previously described MR effects of iron status on risk of Parkinson’s disease and coronary artery disease (coronary atherosclerosis) were not statistically significant after correcting for multiple testing in our current analysis, although the directions of effect were consistent with previous work (S5 Table) [8,9].”
From Associations of genetically determined iron status across the phenome: A mendelian randomization study (2019) · cites this paper as [9]
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Nigrostriatal iron accumulation in the progression of Parkinson’s disease
López‐Aguirre, M., Balzano, T., Monje, M. H. G., Esteban-García, N., Martínez‐Fernández, R., del Rey, N. L., Ciorraga, M., Sánchez‐Ferro, Á., Trigo‐Damas, I., Blesa, J., et al. (2025) · npj Parkinson s Disease · doi:10.1038/s41531-025-00911-6 · Cited by 22
Ou, Y., Yang, Y., Shen, X., Ma, Y., Chen, S.-D., Dong, Q., Tan, L., & Yu, J. (2021) · Alzheimer s Research & Therapy · doi:10.1186/s13195-021-00782-y · Cited by 33
Analysis of Mitochondrial haemoglobin in Parkinson's disease brain
Shephard, F., Greville‐Heygate, O., Liddell, S., Emes, R. D., & Chakrabarti, L. (2016) · Mitochondrion · doi:10.1016/j.mito.2016.05.001 · Cited by 28
“Since the majority of iron in the body is haemoglobin derived there may be also some connection with observations that serum and brain iron levels change in Parkinson's disease (Pichler et al., 2013).”
M endelian R andomization — the K ey to U nderstanding A spects of P arkinson's D isease C ausation?
Noyce, A. J., & Nalls, M. A. (2015) · Movement Disorders · doi:10.1002/mds.26492 · Cited by 21
“Separately, a group reported observations relating to serum iron and PD, using data from PD GWAS.23 Three genetic variants were used as instrumental variables (HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791) and were associated with serum iron levels (accounting for 1.7%, 0.9%, and 1.7% of iron total variance, res…”
MethodInfluentialSelf-citationPatton, S. M., Wang, Q., Hulgan, T., Connor, J. R., Jia, P., Zhao, Z., Letendre, S. L., Ellis, R. J., Bush, W. S., Samuels, D. C., et al. (2017) · Fluids and Barriers of the CNS · doi:10.1186/s12987-017-0058-1 · Cited by 24
Fulfilling the promise of Mendelian randomizationPreprint
Pickrell, J. K. (2015) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/018150 · Cited by 22
“For example, this approach has recently been used to argue that alcohol consumption increases risk of heart disease [16], and that increasing serum iron levels decreases risk of Parkinson’s disease [27].”
Jallow, M. W., Cerami, C., Clark, T. G., Prentice, A. M., & Campino, S. G. (2020) · PLoS ONE · doi:10.1371/journal.pone.0235141 · Cited by 26
Probabilistic modeling of short survivability in patients with brain metastasis from lung cancer
Makond, B., Wang, K., & Wang, K.-M. (2015) · Computer Methods and Programs in Biomedicine · doi:10.1016/j.cmpb.2015.02.005 · Cited by 23
Huang, L., Ou, Y., Yang, Y., Wang, Z.-T., Tan, L., & Yu, J. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02553-9 · Cited by 28
“If F-statistics are greater than 10, the instrument strength is sufficient for MR analysis [17].”
MethodMerrill, J. E., Boyle, H. K., Barnett, N. P., & Carey, K. B. (2017) · Addictive Behaviors · doi:10.1016/j.addbeh.2017.10.003 · Cited by 27
Smartphone technology and its applications in urology: a review of the literature
Tapiero, S., Yoon, R., Jefferson, F. A., Sung, J., Limfueco, L., Cottone, C., Lu, S., Patel, R., Landman, J., & Clayman, R. (2019) · World journal of urology · doi:10.1007/s00345-019-02960-y · Cited by 21
Boal, A. L., Abroms, L., Simmens, S., Graham, A. L., & Carpenter, K. (2016) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntv249 · Cited by 21
Morbidity, risk of cancer and mortality in 3645 HFE mutations carriers
Hagström, H., Ndegwa, N., Jalmeus, M., Ekstedt, M., Posserud, I., Rorsman, F., Nyhlin, N., Klintman, D., Werner, M., Marschall, H., et al. (2021) · Liver International · doi:10.1111/liv.14792 · Cited by 23
Shen, X., Yang, H., Zhang, D., & Jiang, H. F. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00939 · Cited by 21
Xia, J.-J., Xu, H.-M., Jiang, H., & Xie, J.-X. (2015) · Neuroscience Letters · doi:10.1016/j.neulet.2015.04.010 · Cited by 20
Fouad, G. I., El‐Sayed, S. A. M., Mabrouk, M., Ahmed, K. A., & Beherei, H. H. (2022) · Neurotoxicity Research · doi:10.1007/s12640-022-00555-x · Cited by 23
““Fe” plays an essential role in the synthesis of neurotransmitters and acts as a cofactor of tyrosine hydroxylase; thus, the decreased Fe content in CIS-brains is linked to the malfunctioning of neuronal enzymes by contributing to a reduced Fe storage in neurons (Pichler et al. 2013).”
BackgroundAssociation between sex, systemic iron variation and probability of Parkinson's disease
Mariani, S., Ventriglia, M., Simonelli, I., Bucossi, S., Siotto, M., Donno, S., Vernieri, F., & Squitti, R. (2016) · International Journal of Neuroscience · doi:10.3109/00207454.2015.1020113 · Cited by 19
What have we learned from genome-wide association studies (GWAS) in Parkinson's disease?
Fernández‐Santiago, R., & Sharma, M. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101648 · Cited by 26
“For example, one of the earlier studies using PD GWAS showed a causal relationship between increased iron levels in serum and reduced PD risk (Pichler et al., 2013).”
ResultA novel treatment strategy to prevent Parkinson’s disease: focus on iron regulatory protein 1 (IRP1)
Berry, T. M., & Moustafa, A. A. (2021) · International Journal of Neuroscience · doi:10.1080/00207454.2021.1885403 · Cited by 17
“A meta-analysis of 32 studies indicates that serum/plasma iron levels are significantly reduced in PD [36] A Mendelian randomization study indicates that increased levels of iron in serum are associated with decreased risks of developing PD with a relative risk reduction for PD of 3% per 10 mg/dl increase in serum iro…”
BackgroundAteudjieu, J., Stoll, B., Nguefack‐Tsague, G., Tchangou, C., & Genton, B. (2014) · Vaccine · doi:10.1016/j.vaccine.2014.08.012 · Cited by 15
Risky behaviors and Parkinson disease
Grover, S., Del, G. M. F., Kasten, M., Klein, C., Lill, C. M., & König, I. R. (2019) · Neurology · doi:10.1212/wnl.0000000000008245 · Cited by 48
“For example, a recent MR study reported a significant causal association with a lifelong PD risk reduction of 3% per 10-μg/dL increase in serum iron levels.(12) Most recently, another study further reported a risk reduction of 18% with a lifetime exposure of 5-kg/m(2) higher body mass index.”
BackgroundMethodSelf-citationThe causal association between iron status and the risk of autism: A Mendelian randomization study
Chen, L., Guo, X.-Z., Hou, C.-X., Tang, P., Zhang, X., Chong, L. T., & Li, R. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.957600 · Cited by 15
Takeuchi, H., & Kawashima, R. (2022) · Nutrients · doi:10.3390/nu14214671 · Cited by 15
“However, a Mendelian randomization study suggested that serum iron may protect against PD [10], and anemia due to low iron is associated with increased lifetime risk of PD [11,12].”
BackgroundPang, P.-F., Zhang, S.-R., Fan, X., & Zhang, S. (2024) · Cell Biology International · doi:10.1002/cbin.12118 · Cited by 14
“In addition, the features of ferroptosis, such as GSH depletion, was observed in the substantia nigra of PD patients (Pichler et al., 2013).”
BackgroundWang, T., Cheng, J., & Wang, Y. (2022) · Genes & Nutrition · doi:10.1186/s12263-022-00708-9 · Cited by 19
“Previous MR studies have shown that increased iron status reduces the risk of coronary artery-related diseases [47] and Parkinson’s syndrome [48] and increases the risk of type 2 diabetes Fig.”
BackgroundNo Genetic Overlap Between Circulating Iron Levels and Alzheimer’s Disease
Lupton, M. K., Benyamin, B., Proitsi, P., Nyholt, D. R., Ferreira, M. A. R., Montgomery, G. W., Heath, A. C., Madden, P. A. F., Medland, S. E., Gordon, S. D., et al. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170027 · Cited by 14
“Previously three iron level influencing genetic variants (HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791) have been shown to be associated with PD risk [22].”
BackgroundMethodResultInfluentialSelf-citationMicronutrients and Risk of Parkinson’s Disease
Sherzai, A. Z., Tagliati, M., Park, K., Pezeshkian, S., & Sherzai, D. (2016) · Gerontology and Geriatric Medicine · doi:10.1177/2333721416644286 · Cited by 18
“The alteration of iron metabolism in the brain has been observed and extensively studied in multiple neurodegenerative diseases and PD in particular (Dusek, Jankovic, & Le, 2012; Pichler et al., 2013; SianHülsmann, Mandel, Youdim, & Riederer, 2011).”
BackgroundIron status and mental disorders: A Mendelian randomization study
Qiu, J., Lian, F., & Fang, X. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.1084860 · Cited by 13
“One previous MR study indicated that increased serum iron levels are causally associated with a decreased risk of developing PD (26).”
BackgroundAssociation between Anemia and Risk of Parkinson Disease
Wang, Y., Huang, A. P., Yuan, S., Huang, C.-Y., Wu, C.-C., Poly, T. N., Atique, S., & Kung, W. (2021) · Behavioural Neurology · doi:10.1155/2021/8360627 · Cited by 12
“Increased serum iron levels are related to decreased risk of PD, and high dietary iron intake reduces PD risk [18, 19].”
BackgroundKim, J. H., Oh, J. K., Wee, J. H., Min, C., Yoo, D. M., & Choi, H. G. (2021) · Brain Sciences · doi:10.3390/brainsci11050623 · Cited by 14
“Some clinical and epidemiological studies have shown that raised serum iron levels are related to decreased PD risk and that abundant dietary iron intake reduces PD risk [30,31].”
BackgroundYe, D., Zhu, Z., Huang, H., Sun, X., Liu, B., Xu, X., He, Z., Li, S., Wen, C., & Mao, Y. (2021) · Journal of Nutrition · doi:10.1093/jn/nxab015 · Cited by 11
Peter, E. L., Nagendrappa, P. B., Kaligirwa, A., Ogwang, P. E., & Sesaazi, D. C. (2020) · Phytotherapy Research · doi:10.1002/ptr.6853 · Cited by 14
Kim, Y., Stahl, M. C., Huang, X., & Connor, J. R. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15107 · Cited by 14
“Furthermore, in a mendelian randomization modeling study where the effect of multiple iron-related genes on Parkinson's disease was investigated, increased iron levels as determined by genotype of iron-related genes was found to decrease the risk for Parkinson's disease (Pichler et al., 2013).”
BackgroundKrimsky, S., & Schwab, T. (2017) · PLoS ONE · doi:10.1371/journal.pone.0172317 · Cited by 16
Metadata
- Authors
- Pichler, I., Del Greco M., F., Gögele, M., Lill, C. M., Bertram, L., Do, C. B., Eriksson, N., Foroud, T., Myers, R. H., PD GWAS Consortium, Nalls, M., Keller, M. F., International Parkinson's Disease Genomics Consortium, Wellcome Trust Case Control Consortium 2, Benyamin, B., Whitfield, J. B., Genetics of Iron Status Consortium, Pramstaller, P. P., Hicks, A. A., Thompson, J. R., & Minelli, C.
- Affiliations
- Eurac Research (IT)
- Imperial College London (GB)
- Johannes Gutenberg University Mainz (DE)
- Max Planck Institute for Molecular Genetics (DE)
- 23andMe (United States) (US)
- Indiana University School of Medicine (US)
- Boston University (US)
- National Institutes of Health (US)
- The University of Queensland (AU)
- QIMR Berghofer Medical Research Institute (AU)
- Ospedale di Bolzano (IT)
- University of Leicester (GB)
- Corresponding author
- Pichler, Irene
- Minelli, Cosetta
- ORCID
- Venue
- PLoS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-06-04
- Volume
- 10
- Issue
- 6
- Pages
- e1001462
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- PMC
- PMC3672214
- OpenAlex
- W2169823945
- Cited by
- 173
- References
- 81
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 11 · 2023: 9 · 2022: 14 · 2021: 27 · 2020: 13 · 2019: 16 · 2018: 10 · 2017: 14 · 2016: 18 · 2015: 17 · 2014: 15 · 2013: 2
- FWCI
- 11.01
- Type
- journal article
- Language
- en
- Update notices
- correction (2013-06-10)
- Open access
- gold
- doi.org
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- Research Portal (King's College London) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- VU Research Portal (publishedVersion, other-oa)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- ePrints Soton (University of Southampton) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Max Planck Digital Library (submittedVersion, other-oa)
- Figshare (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion, cc-by)
- Site cant be reached (submittedVersion, cc-by)
- Pure Amsterdam UMC (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Open Research (University of Surrey) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- U.S. Department of Defense (W81XWH, Z01-AG000949-02, Z01-ES101986, W81XWH0920128)
- U.S. Department of Health and Human Services (W81XWH-09-2-0128, Z01-ES101986, RR024992, Z01‐AG000949‐02)
- Michael J. Fox Foundation for Parkinson's Research (Z01-ES101986, W81XWH-09-2-0128, Z01-AG000949-02)
- Susan G. Komen for the Cure
- American Association for the Advancement of Science
- Biogen
- American Parkinson Disease Association
- Cure Alzheimer's Fund
- University of Rochester
- University of Dundee
- Queen Mary University of London
- South London and Maudsley NHS Foundation Trust
- Prize4Life
- London School of Hygiene and Tropical Medicine
- National Alliance for Research on Schizophrenia and Depression
- Wellcome Trust (WT089698, 083948/Z/07/Z, WTCCC2, 090532, WTCCC1, NS057105, 083948, WT089698/Z/09/Z)
- University Hospitals Birmingham NHS Foundation Trust
- National Institute for Health and Care Research (NF-SI-0507-10376)
- Parkinson's UK (F-1202, G0909, J-0901, J‐0804)
- Imperial College London
- King's College London
- University College London
- University of Oxford
- European Commission (230596)
- Cardiff University
- University of Aberdeen
- Trinity College Dublin
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Universiteit Leiden
- Radboud Universiteit
- Vrije Universiteit Amsterdam
- Bundesministerium für Bildung und Forschung (01GR0468, 01GS08134, 01EW0908)
- Centre National de la Recherche Scientifique
- Leids Universitair Medisch Centrum
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- Tartu Ülikool
- Hersenstichting
- Moorfields Eye Hospital NHS Foundation Trust
- Provincia autonoma di Bolzano - Alto Adige
- National Institutes of Health (1z01es101986-03, 5r44hg006981-03, W81XWH, UL1TR000448, W81XWH-09-2-0128, Z01‐AG000949‐02, Z01-ES101986, RR024992, NS057105, Z01-AG000949)
- EMD Serono
- Fidelity Biosciences
- Medical Research Council (MR/K01417X/1, G0700943, WT089698)
- Cambridge Institute for Medical Research, University of Cambridge
- Erasmus Universitair Medisch Centrum Rotterdam
- Diamantina Institute, University of Queensland
- National Institute on Aging (Z01‐ES101986, W81XWH-09-2-0128, K24AG000949, Z01AG000949)
- National Human Genome Research Institute (R44-HG006981)
- National Institute of Neurological Disorders and Stroke (P30NS057105, NS057105, R01NS076843, P50NS071674)
- National Institute of Environmental Health Sciences (Z01-ES 101986)
- National Center for Research Resources (RR-024992, UL1RR024992)
- NIH Clinical Center
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Parkinson's disease, serum iron, iron levels, disease risk, HFE gene, TMPRSS6, genetic instruments, causal effects, protective effect, biomarkers
- MeSH terms
- Humans, Iron, Parkinson Disease, Risk Factors, Genetic Predisposition to Disease, Genetic Association Studies, Mendelian Randomization Analysis
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