Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study

Pichler, Irene; Del Greco M., Fabiola; Gögele, Martin; Lill, Christina M.; Bertram, Lars; Do, Chuong B.; Eriksson, Nicholas; Foroud, Tatiana; Myers, Richard H.; PD GWAS Consortium; Nalls, Michael; Keller, Margaux F.; International Parkinson's Disease Genomics Consortium; Wellcome Trust Case Control Consortium 2; Benyamin, Beben; Whitfield, John B.; Genetics of Iron Status Consortium; Pramstaller, Peter P.; Hicks, Andrew A.; Thompson, John R.; Minelli, Cosetta

doi:10.1371/journal.pmed.1001462

Cited by 173Parkinson's Disease Mechanisms and TreatmentsIron Metabolism and DisordersGenetic Associations and Epidemiology

Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study

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Pichler, Irene, Del Greco M., Fabiola, Gögele, Martin, Lill, Christina M., Bertram, Lars, Do, Chuong B., Eriksson, Nicholas, Foroud, Tatiana +13 more·2013·PLoS Medicine

DOI 10.1371/journal.pmed.1001462PMC PMC3672214

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Abstract

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 were not statistically significant after correcting for multiple testing in the current analysis.
“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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Background
Using multiple genetic variants as instrumental variables for modifiable risk factors
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BackgroundInfluential
The serine protease TMPRSS6 is required to sense iron deficiency
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MethodSelf-citation
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Method
Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury.
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Hereditary hemochromatosis: Effects of C282Y and H63D mutations on association with β <sub>2</sub> -microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells
Waheed, A., Parkkila, S., Zhou, X. Y., Tomatsu, S., Tsuchihashi, Z., Feder, J. N., Schatzman, R. C., Britton, R. S., Bacon, B. R., & Sly, W. S. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.23.12384 · Cited by 380 · cited 1× · see citing works
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Background
Meta-analysis of Parkinson disease: Identification of a novel locus, RIT2
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A Two-Stage Meta-Analysis Identifies Several New Loci for Parkinson's Disease
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Self-citation
Common variants in TMPRSS6 are associated with iron status and erythrocyte volume
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BackgroundInfluential
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Background
Neonatal Iron Deficiency Results in Irreversible Changes in Dopamine Function in Rats
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Background
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Self-citation
The University of Texas Southwestern Medical Center
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Result
In vitro and in vivo studies investigating possible antioxidant actions of nicotine: relevance to Parkinson's and Alzheimer's diseases.
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Background
THE CLEVELAND CLINIC FOUNDATION
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TMPRSS6 rs855791 modulates hepcidin transcription in vitro and serum hepcidin levels in normal individuals
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Background
Characterization of the Active Site Iron in Tyrosine Hydroxylase
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Background
Genetics of iron regulation and the possible role of iron in Parkinson's disease
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Result
TMPRSS6, but not TF, TFR2 or BMP2 variants are associated with increased risk of iron-deficiency anemia
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Background
Mutations in the hemochromatosis gene (HFE), Parkinson's disease and parkinsonism.
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Result
Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a Portuguese cohort
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Background
Fe and Cu do not differ in Parkinson's disease: a replication study plus meta-analysis.
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“heterogeneity across studies [6].”
Estimation of Bias in Nongenetic Observational Studies Using “Mendelian Triangulation”
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“using the Delta method [33,34].”
ANEMIA OR LOW HEMOGLOBIN LEVELS PRECEDING PARKINSON DISEASE: A CASE-CONTROL STUDY
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Background
Role of dietary iron restriction in a mouse model of Parkinson's disease
Levenson, C. W., Cutler, R. G., Ladenheim, B., Cadet, J. L., Hare, J., & Mattson, M. P. (2004) · Experimental Neurology · doi:10.1016/j.expneurol.2004.08.014 · Cited by 64 · cited 2× · see citing works
“A reduction in ferritin could decrease neuronal iron utilization by decreasing the pool of iron available for neuronal enzymes [47], thus leading to the accumulation of free iron in SN [1].”
Background
The Cys282Tyr polymorphism in the HFE gene in Australian Parkinson's disease patients.
Buchanan, D., Silburn, P., Chalk, J., Couteur, D. L., & Mellick, G. (2002) · Neuroscience Letters · doi:10.1016/s0304-3940(02)00398-1 · Cited by 60 · cited 3× · see citing works
“our analysis for both rs1800562 [13–20] and rs1799945 [13– 17,19–21] (Tables 1 and S2).”
Method
Hereditary haemochromatosis mutation frequencies in the general population
Bradley, L., Johnson, D. D., Palomaki, G., Haddow, J., Robertson, N. H., & Ferrie, R. (1998) · Journal of Medical Screening · doi:10.1136/jms.5.1.34 · Cited by 58 · cited 1×
“The two variants in the HFE gene are responsible for most cases of hereditary hemochromatosis [59,60], and they are associated with iron overload when present in the homozygous (C282Y/C282Y) or compound heterozygous (C282Y/H63D) state.”
Background
DMT1 polymorphism and risk of Parkinson's disease.
He, Q., Du, T., Yu, X., Xie, A., Song, N., Kang, Q., Yu, J.-T., Tan, L., Xie, J.-X., & Jiang, H. (2011) · Neuroscience Letters · doi:10.1016/j.neulet.2011.07.001 · Cited by 57 · cited 1× · see citing works
“Among the many genes evaluated, which include FTL, FTH1, TF, TFRC, IREB2, LTF, CP, FXN, HFE [52], HPX, HAMP, HFE2 [53], and FTMT [54], only the G258S polymorphism in the TF gene showed a statistically significant association with PD [17], although the finding was not replicated in a subsequent study [55], and a haplot…”
Result
Screening for mutations of the HFE gene in Parkinson's disease patients with hyperechogenicity of the substantia nigra.
Akbas, N., Hochstrasser, H., Deplazes, J., Tomiuk, J., Bauer, P., Walter, U., Behnke, S., Riess, O., & Berg, D. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2006.07.070 · Cited by 48 · cited 2× · see citing works
“our analysis for both rs1800562 [13–20] and rs1799945 [13– 17,19–21] (Tables 1 and S2).”
Severity of bias of a simple estimator of the causal odds ratio in Mendelian randomization studies
Harbord, R. M., Didelez, V., Palmer, T., Meng, S., Sterne, J. A. C., & Sheehan, N. A. (2012) · Statistics in Medicine · doi:10.1002/sim.5659 · Cited by 46 · see citing works
Prevalence of haemochromatosis gene mutations in Parkinson’s disease
Aamodt, A., Stovner, L., Thorstensen, K., Lydersen, S., White, L., & Aasly, J. (2006) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2006.101352 · Cited by 40 · cited 1× · see citing works
“performing a per-genotype analysis based on an additive genetic model [19], or a per-allele analysis when genotype data were not available [20].”
Method
Blood donations, iron stores, and risk of Parkinson's disease
Logroscino, G., Chen, H., Wing, A., & Ascherio, A. (2006) · Movement Disorders · doi:10.1002/mds.20826 · Cited by 38 · cited 1× · see citing works
“A case-control study suggested an increased risk of PD in men who reported multiple recent blood donations and thus experienced depleted systemic iron stores [45], and another study showed an association of anemia experienced early in life with increased PD risk, with the authors hypothesizing that anemia could be a s…”
Background
Neuroprotection by the multitarget iron chelator M30 on age-related alterations in mice
Kupershmidt, L., Amit, T., Bar‐Am, O., Youdim, M. B. H., & Weinreb, O. (2012) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2012.03.001 · Cited by 38 · cited 1× · see citing works
“MAO inhibitors may have iron-chelating effects and thus reduce iron blood levels, which could lead to spurious epidemiological evidence of a difference in iron levels between PD cases and controls [42].”
Background
Mount Sinai School of Medicine.
Stagnaro-Green, A., & Smith, L. G. (2000) · Academic medicine : journal of the Association of American Medical Colleges · doi:10.1097/00001888-200009001-00070 · Cited by 30
HFE gene mutations in a population of Italian Parkinson's disease patients.
Biasiotto, G., Goldwurm, S., Finazzi, D., Tunesi, S., Zecchinelli, A., Sironi, F., Pezzoli, G., & Arosio, P. (2008) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2007.10.011 · Cited by 28 · cited 1× · see citing works
“performing a per-genotype analysis based on an additive genetic model [19], or a per-allele analysis when genotype data were not available [20].”
Method
Genetic predisposition to Parkinson's disease: CYP2D6 and HFE in the Faroe Islands
Halling, J., Petersen, M. S., Grandjean, P., Weihe, P., & Brøsen, K. (2008) · Pharmacogenetics & Genomics · doi:10.1097/fpc.0b013e3282f5106e · Cited by 28 · cited 2×
“our analysis for both rs1800562 [13–20] and rs1799945 [13– 17,19–21] (Tables 1 and S2).”
Substantia nigra echogenicity in Parkinson’s disease: relation to serum iron and C-reactive protein
Walter, U., Witt, R., Wolters, A., Wittstock, M., & Benecke, R. (2011) · Journal of neural transmission · doi:10.1007/s00702-011-0664-z · Cited by 17 · cited 1× · see citing works
“A recent study showed a negative correlation between SN echogenicity, a marker for increased SN iron content [43], and serum iron levels in PD patients [44].”
Background
Association study between four polymorphisms in the HFE, TF and TFR genes and Parkinson’s disease in Southern Italy
Greco, V., Marco, E. V. D., Rocca, F., Annesi, F., Civitelli, D., Provenzano, G., Tarantino, P., Scornaienchi, V., Pucci, F., Salsone, M., et al. (2011) · Neurological Sciences · doi:10.1007/s10072-011-0504-9 · Cited by 16 · cited 2× · see citing works
“our analysis for both rs1800562 [13–20] and rs1799945 [13– 17,19–21] (Tables 1 and S2).”
Sequence Variations in Mitochondrial Ferritin: Distribution in Healthy Controls and Different Types of Patients
Castiglioni, E., Finazzi, D., Goldwurm, S., Levi, S., Pezzoli, G., Garavaglia, B., Nardocci, N., Malcovati, L., della Porta, M. D., Gallì, A., et al. (2010) · Genetic Testing and Molecular Biomarkers · doi:10.1089/gtmb.2010.0076 · Cited by 16 · cited 2× · see citing works
“Among the many genes evaluated, which include FTL, FTH1, TF, TFRC, IREB2, LTF, CP, FXN, HFE [52], HPX, HAMP, HFE2 [53], and FTMT [54], only the G258S polymorphism in the TF gene showed a statistically significant association with PD [17], although the finding was not replicated in a subsequent study [55], and a haplot…”
Result
Analysis of Nucleotide Variations in Genes of Iron Management in Patients of Parkinson's Disease and Other Movement Disorders
Castiglioni, E., Finazzi, D., Goldwurm, S., Pezzoli, G., Forni, G., Girelli, D., Maccarinelli, F., Poli, M., Ferrari, M., Cremonesi, L., et al. (2010) · Parkinson's Disease · doi:10.4061/2011/827693 · Cited by 12 · cited 2× · see citing works
“Among the many genes evaluated, which include FTL, FTH1, TF, TFRC, IREB2, LTF, CP, FXN, HFE [52], HPX, HAMP, HFE2 [53], and FTMT [54], only the G258S polymorphism in the TF gene showed a statistically significant association with PD [17], although the finding was not replicated in a subsequent study [55], and a haplot…”
Result
Association study of the G258S transferrin gene polymorphism and Parkinson's disease in the Spanish population
Ezquerra, M., Campdelacreu, J., Muñóz, E., & Tolosa, E. (2005) · Journal of Neurology · doi:10.1007/s00415-005-0695-1 · Cited by 11 · cited 1× · see citing works
“Among the many genes evaluated, which include FTL, FTH1, TF, TFRC, IREB2, LTF, CP, FXN, HFE [52], HPX, HAMP, HFE2 [53], and FTMT [54], only the G258S polymorphism in the TF gene showed a statistically significant association with PD [17], although the finding was not replicated in a subsequent study [55], and a haplot…”
Result

Flagged first, then by citations

12 of the 81 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

[5]Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, et al (1997) Alpha-synuclein in Lewy bodies. Nature 388: 839– 840. 9278044
[35]Pierce BL, Ahsan H, Vanderweele TJ (2011) Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol 40: 740– 752. 20813862 PMC3147064
[66]Fleiss JL (1993) The statistical basis of meta-analysis. Stat Methods Med Res 2: 121– 145. 8261254

Sorted by citations

Mendelian randomization: genetic anchors for causal inference in epidemiological studies
Davey Smith, G., & Hemani, G. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu328 · Cited by 4,677 · see citing works
“Biomarkers CRP Coronary heart disease Observational association between CRP and coronary heart disease is a result of confounding and/or reverse causation (18) Serum iron Parkinson’s disease Higher serum iron levels lower the risk of Parkinson’s disease (19) Uric acid Coronary heart disease Observational association b…”
Background
The role of iron in brain ageing and neurodegenerative disorders
Ward, R. J., Zucca, F. A., Duyn, J. H., Crichton, R. R., & Zecca, L. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70117-6 · Cited by 1,819 · see citing works
Detection and interpretation of shared genetic influences on 42 human traits
Pickrell, J. K., Berisa, T., Liu, J. Z., Ségurel, L., Tung, J. Y., & Hinds, D. A. (2016) · Nature Genetics · doi:10.1038/ng.3570 · Cited by 1,151 · see citing works
Mendelian randomization studies: a review of the approaches used and the quality of reporting
Boef, A. G. C., Dekkers, O. M., & le Cessie, S. (2015) · International Journal of Epidemiology · doi:10.1093/ije/dyv071 · Cited by 610 · see citing works
“One of the reviewed MR studies mentioned that the Wald-type estimator used to estimate an odds ratio was an approximate method.(169) The properties and limitations of these IV methods used to estimate a causal odds ratio deserve more attention in the Mendelian randomization studies in which they are used.”
Method
Iron neurochemistry in Alzheimer's disease and Parkinson's disease: targets for therapeutics
Belaidi, A. A., & Bush, A. I. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13425 · Cited by 580 · see citing works
“have been also proposed as a possible marker for PD in a large Mendelian randomization study (Pichler et al. 2013).”
Background
Mendelian Randomization: New Applications in the Coming Age of Hypothesis-Free Causality
Evans, D. M., & Smith, G. D. (2015) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-090314-050016 · Cited by 524 · see citing works
“Given its potential, two-sample MR has, until recently, been underutilized in the literature to date, with only a handful of studies taking advantage of the approach (91).”
Background
Ferroptosis and Its Role in Diverse Brain Diseases
Weiland, A., Wang, Y., Wu, W., Lan, X., Han, X., Li, Q., & Wang, J. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1403-3 · Cited by 469 · see citing works
Neurotoxicity Linked to Dysfunctional Metal Ion Homeostasis and Xenobiotic Metal Exposure: Redox Signaling and Oxidative Stress
Garza-Lombó, C., Posadas, Y., Quintanar, L., Gonsebatt, M. E., & Franco, R. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7272 · Cited by 254 · see citing works
“Previous findings have also suggested a link between Fe deficiency and predisposition to PD, while Fe overload seems to be protective (157, 190, 271).”
Background
In defence of ferroptosis
Alves, F. M., Lane, D. J. R., Nguyen, T. P. M., Bush, A. I., & Ayton, S. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02088-5 · Cited by 197 · see citing works
Physiology and pathophysiology of iron in hemoglobin-associated diseases
Coates, T. D. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.03.039 · Cited by 181 · see citing works
Why should neuroscientists worry about iron? The emerging role of ferroptosis in the pathophysiology of neuroprogressive diseases
Morris, G., Berk, M., Carvalho, A. F., Maes, M. H. J., Walker, A. J., & Puri, B. K. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.12.036 · Cited by 154 · see citing works
Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice
Matak, P., Matak, A., Moustafa, S. M., Aryal, D. K., Benner, E. J., Wetsel, W. C., & Andrews, N. C. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1519473113 · Cited by 133 · see citing works
Iron and Oxidative Stress in Parkinson’s Disease: An Observational Study of Injury Biomarkers
Medeiros, M. S., Schumacher-Schuh, A., Cardoso, A. M., Bochi, G. V., Baldissarelli, J., Kegler, A., Santana, D., Chaves, C. M. M. B. S., Schetinger, M. R. C., Moresco, R. N., et al. (2016) · PLOS ONE · doi:10.1371/journal.pone.0146129 · Cited by 131 · see citing works
“Previous studies suggest that altered iron homeostasis may be involved with PD pathogenesis, where lower levels of serum iron were found in individuals who developed the disease [3, 4].”
BackgroundInfluential
Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis
Nüesch, E., Dale, C. E., Palmer, T., White, J., Keating, B. J., van Iperen, E. P. A., Goel, A., Padmanabhan, S., Asselbergs, F. W., EPIC-Netherland Investigators, et al. (2015) · International Journal of Epidemiology · doi:10.1093/ije/dyv074 · Cited by 126 · see citing works
A mobile health intervention promoting healthy gestational weight gain for women entering pregnancy at a high body mass index: the txt4two pilot randomised controlled trial
Willcox, J. C., Wilkinson, S. A., Lappas, M., Ball, K., Crawford, D. A., McCarthy, E. A., Fjeldsoe, B. S., Whittaker, R., Maddison, R., & Campbell, K. J. (2017) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/1471-0528.14552 · Cited by 119 · see citing works
Genetic Support of A Causal Relationship Between Iron Status and Type 2 Diabetes: A Mendelian Randomization Study
Wang, X.-H., Fang, X.-X., Zheng, W.-R., Zhou, J., Song, Z.-J., Xu, M.-Q., Min, J.-X., & Wang, F.-D. (2021) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/clinem/dgab454 · Cited by 116 · see citing works
Meta-analyses of Blood Homocysteine Levels for Gender and Genetic Association Studies of the MTHFR C677T Polymorphism in Schizophrenia
Nishi, A., Numata, S., Tajima, A., Kinoshita, M., Kikuchi, K., Shimodera, S., Tomotake, M., Ohi, K., Hashimoto, R., Imoto, I., et al. (2014) · Schizophrenia Bulletin · doi:10.1093/schbul/sbt154 · Cited by 100 · see citing works
Acceptability and feasibility of using established geosocial and sexual networking mobile applications to promote HIV and STD testing among men who have sex with men.
Sun, C. J., Stowers, J., Miller, C., Bachmann, L. H., & Rhodes, S. D. (2015) · AIDS and Behavior · doi:10.1007/s10461-014-0942-5 · Cited by 102 · see citing works
Detection and interpretation of shared genetic influences on 40 human traitsPreprint
Pickrell, J. K., Berisa, T., Ségurel, L., Tung, J. Y., & Hinds, D. A. (2015) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/019885 · Cited by 23 · see citing works
“Mendelian randomization has been used to provide evidence for (or against) a causal role for various clinical variables in disease etiology [De Silva et al., 2011; Granell et al., 2014; Holmes et al., 2014; Lim et al., 2014; Panoutsopoulou et al., 2013; Pichler et al., 2013; Voight et al., 2012].”
Emerging Therapeutic Strategies for Parkinson’s Disease and Future Prospects: A 2021 Update
Gouda, N. A., Elkamhawy, A., & Cho, J. (2022) · Biomedicines · doi:10.3390/biomedicines10020371 · Cited by 110 · see citing works
Is early-life iron exposure critical in neurodegeneration?
Hare, D. J., Arora, M., Jenkins, N. L., Finkelstein, D. I., Doble, P., & Bush, A. I. (2015) · Nature Reviews Neurology · doi:10.1038/nrneurol.2015.100 · Cited by 100 · see citing works
Biological and Clinical Implications of Comorbidities in Parkinson’s Disease
Santiago, J. A., Bottero, V., & Potashkin, J. A. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00394 · Cited by 95 · see citing works
“It has been documented that PD patients exhibit lower serum iron levels (Savica et al., 2009; Pichler et al., 2013; Medeiros et al., 2016).”
Background
Meta‐Analysis of Copper and Iron in Parkinson's Disease Brain and Biofluids
Genoud, S., Senior, A. M., Hare, D. J., & Double, K. L. (2019) · Movement Disorders · doi:10.1002/mds.27947 · Cited by 92 · see citing works
“Nevertheless, like the discovery of markedly reduced dopamine levels that motivated the first trials of dopamine replacement therapy in the early 1960s, our findings provide strong empirical evidence of specific changes in the primary region of neurodegeneration in PD, supporting the rationale of current clinical tria…”
BackgroundInfluential
Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson’s disease
Ayton, S., Lei, P., Adlard, P. A., Volitakis, I., Cherny, R. A., Bush, A. I., & Finkelstein, D. I. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-27 · Cited by 79 · see citing works
Red blood cell indices and anaemia as causative factors for cognitive function deficits and for Alzheimer’s disease
Winchester, L., Powell, J., Lovestone, S., & Nevado-Holgado, A. (2018) · Genome Medicine · doi:10.1186/s13073-018-0556-z · Cited by 76 · see citing works
Ferroptosis: An emerging therapeutic target in stroke
Liu, Y., Fang, Y., Zhang, Z., Luo, Y., Zhang, A., Lenahan, C., & Chen, S. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15351 · Cited by 83 · see citing works
“Inhibitors of ferroptosis, such as ferrostatins, are also protective in models of such neurological diseases (Ahmad et al., 2014; Fang, Gao, et al., 2020; Pichler et al., 2013; Tuo et al., 2017).”
Background
Genetic comorbidities in Parkinson's disease
Nalls, M. A., Saad, M., Noyce, A. J., Keller, M. F., Schrag, A. E., Bestwick, J., Traynor, B. J., Gibbs, J. R., Hernandez, D. G., Cookson, M., et al. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt465 · Cited by 72 · see citing works
Self-citation
Lactoferrin protects against iron dysregulation, oxidative stress, and apoptosis in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced Parkinson’s disease in mice
Liu, H., Wu, H., Zhu, N., Xu, Z., Wang, Y., Qu, Y., & Wang, J. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14857 · Cited by 72 · see citing works
Parkinson’s Disease: The Mitochondria-Iron Link
Muñoz, Y., Carrasco, C. M., Campos, J., Aguirre, P., & Núñez, M. T. (2016) · Parkinson s Disease · doi:10.1155/2016/7049108 · Cited by 73 · see citing works
Associations of genetically determined iron status across the phenome: A mendelian randomization study
Gill, D., Benyamin, B., Moore, L. S. P., Monori, G., Zhou, A., Koskeridis, F., Evangelou, E., Laffan, M., Walker, A. P., Tsilidis, K. K., et al. (2019) · PLOS Medicine · doi:10.1371/journal.pmed.1002833 · Cited by 63 · see citing works
Self-citation
Homocysteine and Alzheimer’s Disease: Evidence for a Causal Link from Mendelian Randomization
Hu, Q., Teng, W.-H., Li, J.-J., Hao, F.-F., & Wang, N.-D. (2016) · Journal of Alzheimer's Disease · doi:10.3233/jad-150977 · Cited by 62 · see citing works
Regional siderosis: a new challenge for iron chelation therapy
Cabantchik, Z. I., Münnich, A., Youdim, M. B. H., & Devos, D. (2013) · Frontiers in Pharmacology · doi:10.3389/fphar.2013.00167 · Cited by 67 · see citing works
“…serum iron levels have recently been suggested by genome-wide meta-analysis (GWAS) to be correlated with a decreased risk of developing PD (Pichler et al., 2013), although, as we referred earlier, a direct role of the implicated genes (HFE and TMPRSS) in brain iron metabolism in general…”
BackgroundMethodInfluential
Brain iron concentrations in regions of interest and relation with serum iron levels in Parkinson disease
Costa‐Mallen, P., Gatenby, C., Friend, S., Maravilla, K. R., Hu, S., Cain, K. C., Agarwal, P., & Anzai, Y. (2017) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2017.04.035 · Cited by 61 · see citing works
“Interestingly, genetic variants of iron-related proteins that are associated with higher levels of serum iron seem to protect from the risk of developing PD [34].”
Background
Iron Metabolism Disturbance in a French Cohort of ALS Patients
Veyrat-Durebex, C., Corcia, P., Mucha, A., Benzimra, S., Mallet, C., Gendrot, C., Moreau, C., Devos, D., Piver, E., Pagès, J., et al. (2014) · BioMed Research International · doi:10.1155/2014/485723 · Cited by 59 · see citing works
Evaluation of an association between plasma total homocysteine and schizophrenia by a Mendelian randomization analysis
Numata, S., Kinoshita, M., Tajima, A., Nishi, A., Imoto, I., & Ohmori, T. (2015) · BMC Medical Genetics · doi:10.1186/s12881-015-0197-7 · Cited by 55 · see citing works
“We calculated a Mendelian randomization estimate of the effect of the plasma total homocysteine levels on the risk of schizophrenia (OR scz/hcy) as log OR scz/hcy = (log OR scz/per T-allele)/ beta hcy/per T-allele, as in previous studies [4, 21].”
Result
Feasibility and Acceptability of a Culturally- and Linguistically-Adapted Smoking Cessation Text Messaging Intervention for Latino Smokers
Cartujano‐Barrera, F., Cox, L. S., Arana‐Chicas, E., Ramírez, M., Perales‐Puchalt, J., Valera, P. A., Díaz, F. J., Catley, D., Ellerbeck, E. F., & Cupertino, A. P. (2020) · Frontiers in Public Health · doi:10.3389/fpubh.2020.00269 · Cited by 54 · see citing works
Modeling and predicting the occurrence of brain metastasis from lung cancer by Bayesian network: A case study of Taiwan
Wang, K., Makond, B., & Wang, K.-M. (2014) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2014.02.002 · Cited by 51 · see citing works
Elemental fingerprint as a cerebrospinal fluid biomarker for the diagnosis of Parkinson's disease
Maass, F., Michalke, B., Leha, A., Boerger, M., Zerr, I., Koch, J. C., Tönges, L., Bähr, M., & Lingor, P. (2018) · Journal of Neurochemistry · doi:10.1111/jnc.14316 · Cited by 51 · see citing works
“Alterations in blood iron levels seem to modulate the risk of developing PD as was shown in a Mendelian randomization study (Pichler et al. 2013).”
Background
A significant causal association between C-reactive protein levels and schizophrenia
Inoshita, M., Numata, S., Tajima, A., Kinoshita, M., Umehara, H., Nakataki, M., Ikeda, M., Maruyama, S., Yamamori, H., Kanazawa, T., et al. (2016) · Scientific Reports · doi:10.1038/srep26105 · Cited by 42 · see citing works
Retracted
Epistemology of causal inference in pharmacology
Landes, J., Osimani, B., & Poellinger, R. (2017) · European Journal for Philosophy of Science · doi:10.1007/s13194-017-0169-1 · Cited by 67 · see citing works
A Multidimensional Investigation of the Effects of Publication Retraction on Scholarly Impact
Shuai, X., Rollins, J., Moulinier, I., Custis, T., Edmunds, M., & Schilder, F. (2017) · Journal of the Association for Information Science and Technology · doi:10.1002/asi.23826 · Cited by 48 · see citing works
Dynamics of Nigral Iron Accumulation in Parkinson's Disease: From Diagnosis to Late Stage
Du, G., Wang, E., Sica, C. T., Chen, H., Jesus, S. D., Lewis, M. M., Kong, L., Connor, J. R., Mailman, R. B., & Huang, X. (2022) · Movement Disorders · doi:10.1002/mds.29062 · Cited by 51 · see citing works
Lower hemoglobin levels in patients with parkinson's disease are associated with disease severity and iron metabolism.
Deng, Q.-Y., Zhou, X., Chen, J., Pan, M.-Q., Gao, H., Zhou, J., Wang, D.-M., Chen, Q., Zhang, X.-M., Wang, Q., et al. (2017) · Brain Research · doi:10.1016/j.brainres.2016.11.007 · Cited by 48 · see citing works
Newly Diagnosed Anemia Increases Risk of Parkinson’s disease: A Population-Based Cohort Study
Hong, C., Huang, Y. H., Liu, H. Y., Chiou, H., Chan, L., & Chien, L. (2016) · Scientific Reports · doi:10.1038/srep29651 · Cited by 48 · see citing works
Quality assessment of a sample of mobile app-based health behavior change interventions using a tool based on the National Institute of Health and Care Excellence behavior change guidance.
Mcmillan, B., Hickey, E., Patel, M., & Mitchell, C. (2016) · Patient Education and Counseling · doi:10.1016/j.pec.2015.10.023 · Cited by 43 · see citing works
When do information seekers trust scientific information? Insights from recipients’ evaluations of online video lectures
König, L., & Jucks, R. (2019) · International Journal of Educational Technology in Higher Education · doi:10.1186/s41239-019-0132-7 · Cited by 57 · see citing works
Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT
Moksnes, M. R., Graham, S. E., Wu, K.-H., Hansen, A. F., Taliun, S. A. G., Zhou, W., Thorstensen, K., Fritsche, L. G., Gill, D., Mason, A. M., et al. (2022) · Communications Biology · doi:10.1038/s42003-022-03529-z · Cited by 40 · see citing works
Using Mendelian Randomization to Study the Role of Iron in Health and Disease
Zeitoun, T., & El‐Sohemy, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241713458 · Cited by 42 · see citing works
“Distinctively, 2-sample Mendelian randomization research on iron and Parkinson’s disease (PD) shows a protective effect from iron on PD, with a 3% relative reduction in PD risk [67].”
Background
Anemia and Red Blood Cell Indices Predict HIV-Associated Neurocognitive Impairment in the Highly Active Antiretroviral Therapy Era.
Kallianpur, A., Wang, Q., Jia, P., Hulgan, T., Zhao, Z.-M., Letendre, S., Ellis, R. J., Heaton, R., Franklin, D., Barnholtz-Sloan, J., et al. (2016) · Journal of Infectious Diseases · doi:10.1093/infdis/jiv754 · Cited by 38 · see citing works
Mendelian randomisation analysis of red cell distribution width in pulmonary arterial hypertension
Ulrich, A., Wharton, J., Thayer, T., Świetlik, E., Assad, T., Desai, A., Gräf, S., Harbaum, L., Humbert, M., Morrell, N., et al. (2019) · European Respiratory Journal · doi:10.1183/13993003.01486-2019 · Cited by 36 · see citing works
Bayesian averaging over Decision Tree models for trauma severity scoring
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Beyond the Single SNP: Emerging Developments in Mendelian Randomization in the “Omics” Era
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Background
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Micronutrients and Risk of Parkinson’s Disease
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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: Pichler, Irene
Gögele, Martin
Lill, Christina M.
Bertram, Lars
Foroud, Tatiana
Myers, Richard H.
Keller, Margaux F.
Benyamin, Beben
Whitfield, John B.
Pramstaller, Peter P.
Hicks, Andrew A.
Minelli, Cosetta
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
DOI: 10.1371/journal.pmed.1001462
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
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
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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 › 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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Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study

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