Editors' ChoiceHuman Genetics

Ironing Out Parkinson’s Disease

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Science Translational Medicine  31 Jul 2013:
Vol. 5, Issue 196, pp. 196ec127
DOI: 10.1126/scitranslmed.3007047

Testing the hypothesis that an intermediate trait—iron concentration—causes a clinical endpoint such as Parkinson’s disease (PD) is a challenging problem. A randomized clinical trial is the standard strategy for determining causality but is not always feasible. An analogous experiment can be performed by using natural genetic variation in humans. This approach—called Mendelian Randomization (MR)—capitalizes on the fact that alleles segregating at meiosis assort randomly, in effect serving as a way to randomize patients to subgroups before they are exposed to any additional risk factors. This randomization allows for an assessment of causality, minimizing the issues of confounding and reverse causality that haunt standard observational epidemiology. The new report by Pichler and colleagues uses the MR approach to clarify the role for serum iron in the risk of PD.

Before this study, the role of iron in the causation of or protection against PD was not clear. In patients with Parkinson’s, higher concentrations of iron had been observed in the substantia nigra and globus pallidus, parts of the brain that are central to the regulation of voluntary movement. However, the observational epidemiological studies correlating iron with PD risk were underpowered, generating heterogeneous risk assessments and leaving the precise role of iron uninterpretable.

To close this gap in knowledge, the authors took advantage of three genetic variants whose alleles are strongly and reproducibly correlated with serum iron concentration in Europeans, based on large-scale genetic studies. The authors collected data on the association of these variants with PD, from over 20,000 PD cases and 88,000 controls. After applying MR analysis to these data, they found a causal and statistically significant effect, with a 3% reduction in the risk of PD for every 10 µg/ml increase in serum iron concentration.

The authors emphasize that additional studies are necessary to confirm this initial finding, as well as to understand the mechanism for the effect of iron on PD risk, which was not addressed here. However, this study does provide evidence supporting the hypothesis that dietary or pharmacological interventions may be able to balance serum iron concentration with iron storage, as a strategy to decrease the risk of PD over a lifetime.

I. Pichler et al., Serum iron levels and the risk of Parkinson disease: A mendelian randomization study. PLoS Med. 10, e1001462 (2013). [Full Text]

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