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

Pichler, Irene; Greco, Fabiola Del; Lill, Christina M.; Bertram, Lars; Chuong, B.; Eriksson, Nicholas; Foroud, Tatiana; Myers, Richard H.; Nalls, Michael A.; Keller, Margaux F.; Benyamin, Beben; Whitfield, John B.; Pramstaller, Peter P.; Hicks, Andrew A.; Thompson, John R.; Minelli, Cosetta

doi:10.1371/journal.pmed.1001462

Cited by 128 publications

(122 citation statements)

References 67 publications

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“…Our current results for AD are in contrast to previous evidence of a causal association of increased peripheral iron measures with a decreased risk of PD [22]. The authors hypothesized that low peripheral iron may decrease neuronal iron storage though a reduction in ferritin, resulting in free iron accumulation in the brain.…”

Section: Discussioncontrasting

confidence: 99%

“…Controlling for APOE genotype did not significantly affect the results, and no significant association was identified in separate APOE ε4 carrier and non-carrier groups (data not shown). Previously three iron level influencing genetic variants (HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791) have been shown to be associated with PD risk [22]. There was no association of these SNPs with AD status in our dataset and no interaction identified with APOE ε4 status (Supplementary Table 2).…”

Section: Gps Analysismentioning

confidence: 64%

“…Finally, all datasets were combined in a mega analysis also controlling for study. In addition, we separately assessed the effect of the three iron level influencing variants that have previously been shown to associate with PD risk [22]. We tested for an association with the following SNPs: HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791 using logistic regression under an additive model and then combined the three variants in a GPS.…”

Section: Gps Association Analysismentioning

confidence: 99%

“…MR was recently used to test for an effect of serum iron on Parkinson's disease (PD) risk, using three genetic variants influencing iron levels (HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791) [22]. The combined MR estimate showed a statistically significant protective effect of increased serum iron in PD, suggesting that over the course of a life time, alteration in tissue iron homeostasis reflected by a decrease in serum iron levels is on the causal pathway in the pathogenesis of PD.…”

Section: Introductionmentioning

confidence: 99%

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No Genetic Overlap Between Circulating Iron Levels and Alzheimer’s Disease

Lupton

Benyamin

Proitsi

et al. 2017

JAD

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Abstract. Iron deposition in the brain is a prominent feature of Alzheimer's disease (AD). Recently, peripheral iron measures have also been shown to be associated with AD status. However, it is not known whether these associations are causal: do elevated or depleted iron levels throughout life have an effect on AD risk? We evaluate the effects of peripheral iron on AD risk using a genetic profile score approach by testing whether variants affecting iron, transferrin, or ferritin levels selected from GWAS meta-analysis of approximately 24,000 individuals are also associated with AD risk in an independent case-control 1 Data used in the preparation of this article were obtained from the Genetic and Environmental Risk for Alzheimer's disease (GERAD1) Consortium. As such, the investigators within the GERAD1 consortia contributed to the design and implementation of GERAD1 and/or provided data but did not participate in analysis or writing of this report (except those who are named authors). Membership of the GERAD1 Consortium is provided in the Acknowledgments section.2 Data used in preparing this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators may be found at: http://adni.loni.usc.edu/wpcontent/uploads/how to apply/ADNI Acknowledgement List.pdf * Correspondence to: Michelle K. Lupton, PhD, QIMR

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Section: Discussioncontrasting

confidence: 99%

Section: Gps Analysismentioning

confidence: 64%

Section: Gps Association Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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No Genetic Overlap Between Circulating Iron Levels and Alzheimer’s Disease

Lupton

Benyamin

Proitsi

et al. 2017

JAD

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“…Starting from well‐established observed associations where the direction of the effect is not clear, or from inconclusive results, this principle has already been applied to explore the causality of a number of parameters on PD, thereby showing, for example, that increased iron levels are causally linked to a decreased risk of PD,8 or that a higher body mass index is causally linked to a lower risk of PD 9. If the assumptions underlying MR are tested rigorously, finding evidence for causality through MR improves the understanding of PD and possibly opens new therapeutic avenues that can then be tested in RCTs, considering that the MR causal effect estimate may not correspond to the effect of a proposed intervention modifying the risk factor, given that it refers to the lifetime modification in the general population.…”

mentioning

confidence: 99%