Evidence for genetic causality between iron homeostasis and Parkinson's disease: A two-sample Mendelian randomization study.
Parkinson's disease (PD) is a degenerative disease of the central nervous system, and its specific etiology is still unclear. At present, it is believed that the main pathological basis is the reduction of dopamine concentration in the brain striatum. Although many previous studies have believed that iron as an important nutrient element participates in the occurrence and development of PD, whether there is a causal correlation between total iron binding capacity(TIBC), transferring saturation(TSAT), ferritin and serum iron in iron homeostasis indicators and PD, there has been a lack of effective genetic evidence.
We used Mendelian randomization (MR) as an analytical method to effectively evaluate the genetic association between exposure and outcome, based on the largest genome-wide association study (GWAS) data to date. By using randomly assigned genetic instrumental variables (SNPs, Single Nucleotide Polymorphisms) that are not affected by any causal relationship, we effectively evaluated the causal relationship between iron homeostasis indicators and PD while controlling for confounding factors.
By coordinated analysis of 86 SNPs associated with iron homeostasis markers and 12,858,066 SNPs associated with PD, a total of 56 SNPs were finally screened for genome-wide significance of iron homeostasis associated with PD. The results of inverse variance weighting(IVW) analysis suggested that iron（ β = - 0.524; 95%cl=-0.046 to -0.002; P=0.032) was considered to have a genetic causal relationship with PD. Cochran's Q, Egger intercept and MR-PRESSO global tests did not detect the existence of heterogeneity and pleiotropy (P>0.05). Mr Steiger directionality test further confirmed our estimation of the potential causal direction of iron and PD (P=0.001). In addition, TIBC (β=-0.142; 95%Cl=-0.197-0.481; P=0.414), TSAT (β=-0.316; 95%Cl=-0.861-0.229; P=0.255), and ferritin (β=-0.387; 95%Cl=-1.179-0.405; P=0.338) did not have genetic causal relationships with PD, and the results were not heterogeneous and pleiotropic (P>0.05). In addition, TIBC (β=-0.142; 95%Cl=-0.197-0.481; P=0.414), TSAT (β=-0.316; 95%Cl=-0.861-0.229; P=0.255), and ferritin (β=-0.101; 95%Cl=--0.987 to -0.405; P=0.823) did not have genetic causal relationships with PD, and the results were not heterogeneous and pleiotropic (P>0.05). TIBC (P=0.008), TSAT (P=0.000) and ferritin (P=0.013) were all consistent with the estimation of MR Steiger directivity test.
Our study found that among the four iron homeostasis markers, there was a genetic causal association between serum iron and PD, and the serum iron level was negatively correlated with the risk of PD. In addition, TIBC, TSAT, ferritin had no genetic causal relationship with PD.
Chen H
，Wang X
，Chang Z
，Zhang J
，Xie D
... -
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Iron status and obesity-related traits: A two-sample bidirectional Mendelian randomization study.
The association between iron status and obesity-related traits is well established by observational studies, but the causality is uncertain. In this study, we performed a two-sample bidirectional Mendelian randomization analysis to investigate the causal link between iron status and obesity-related traits.
The genetic instruments strongly associated with body mass index (BMI), waist-hip ratio (WHR), serum ferritin, serum iron, transferrin saturation (TSAT), and total iron-binding capacity (TIBC) were obtained through a series of screening processes from summary data of genome-wide association studies (GWAS) of European individuals. We used numerous MR analytical methods, such as inverse-variance weighting (IVW), MR-Egger, weighted median, and maximum likelihood to make the conclusions more robust and credible, and alternate methods, including the MR-Egger intercept test, Cochran's Q test, and leave-one-out analysis to evaluate the horizontal pleiotropy and heterogeneities. In addition, the MR-PRESSO and RadialMR methods were utilized to identify and remove outliers, eventually achieving reduced heterogeneity and horizontal pleiotropy.
The results of IVW analysis indicated that genetically predicted BMI was associated with increased levels of serum ferritin (β: 0.077, 95% CI: 0.038, 0.116, P=1.18E-04) and decreased levels of serum iron (β: -0.066, 95% CI: -0.106, -0.026, P=0.001) and TSAT (β: -0.080, 95% CI: -0.124, -0.037, P=3.08E-04), but not associated with the levels of TIBC. However, the genetically predicted WHR was not associated with iron status. Genetically predicted iron status were not associated with BMI and WHR.
In European individuals, BMI may be the causative factor of serum ferritin, serum iron, and TSAT, but the iron status does not cause changes in BMI or WHR.
Zhou Z
，Zhang H
，Chen K
，Liu C
... -
《Frontiers in Endocrinology》
Causal relationships between metabolic-associated fatty liver disease and iron status: Two-sample Mendelian randomization.
Dysregulated iron homeostasis plays an important role in the hepatic manifestation of metabolic-associated fatty liver disease (MAFLD). We investigated the causal effects of five iron metabolism markers, regular iron supplementation and MAFLD risk.
Genetic summary statistics were obtained from open genome-wide association study databases. Two-sample bidirectional Mendelian randomization analysis was performed to estimate the causal effect between iron status and MAFLD, including Mendelian randomization inverse-variance weighted, weighted median methods and Mendelian randomization-Egger regression. The Mendelian randomization-PRESSO outlier test, Cochran's Q test and Mendelian randomization-Egger regression were used to assess outliers, heterogeneity and pleiotropy respectively.
Mendelian randomization inverse-variance weighted results showed that the genetically predicted per standard deviation increase in liver iron (Data set 2: odds ratio 1.193, 95% confidence interval [CI] 1.074-1.326, p = .001) was associated with an increased MAFLD risk, consistent with the weighted median estimates and Mendelian randomization-Egger regression, although Data set 1 was not significant. Mendelian randomization inverse-variance weighted analysis showed that genetically predicted MAFLD was significantly associated with increased serum ferritin levels in both datasets (Dataset 1: β = .038, 95% CI = .014 to .062, p = .002; Dataset 2: β = .081, 95% CI = .025 to .136, p = .004), and a similar result was observed with the weighted median methods for Dataset 2 instead of Mendelian randomization-Egger regression.
This study uncovered genetically predicted causal associations between iron metabolism status and MAFLD. These findings underscore the need for improved guidelines for managing MAFLD risk by emphasizing hepatic iron levels as a risk factor and ferritin levels as a prognostic factor.
He H
，Liao S
，Zeng Y
，Liang L
，Chen J
，Tao C
... -
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ResearchGate
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