The causal relationship between genetic prediction of iron homeostasis and Parkinson's disease: a two-sample Mendelian randomization study

Abstract

Abstract Background The specific etiology of Parkinson's disease (PD), a degenerative disease of the central nervous system, is still unclear, and it is currently believed that its main pathological basis is a decrease in dopamine concentration in the striatum of the brain.Although many previous studies have suggested that iron, as an important nutrient, is involved in the development of PD, there has been a lack of validated genetic evidence on whether there is a causal association between iron homeostasis indices (ferritin, serum iron, TIBC, and TSAT) and PD. Methods We used Mendelian randomization (MR) as an analytical method to efficiently assess the genetic association of exposure and outcome, based on the largest genome-wide association study (GWAS) data so far, for the causal association between iron homeostasis indicators and Parkinson's disease, controlling for confounders, by using genetic instrumental variables, that is, single-nucleotide polymorphisms (SNPs), which are randomly assigned and are not subject to any causative effect. Results 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 Parkinson's disease.The results of the IVW analysis suggested that total iron binding capacity ( β= -0.142; 95%Cl = -0.197 to 0.481; P = 0.4138421 ), transferrin saturation ( β= -0.316 ; 95%Cl = -0.861 to 0.229; P = 0.2553290 ), ferritin ( β= -0.387 ; 95%Cl = -1.179 to 0.405; P = 0.33783807 ) were not genetically causally associated with PD, serum iron ( β= -0.524; 95%Cl = -0.046 to -0.002; P = 0.03191512 ) was considered to have genetic causality with PD. Cochran's Q test for MR-IVW suggested that TIBC ( P = 0.1618872), TSAT ( P = 0.7099448), ferritin ( P = 0.09768154), serum iron ( P = 0.8557510) were not heterogeneous with the results of Mr analysis of PD. MR-PRESSO global test showed that TIBC ( P = 0.404), TSAT ( P = 0.759), ferritin ( P = 0.113), serum iron ( P = 0.87 ) were not detected the presence of horizontal pleiotropy. Conclusion Our study found that of the four iron homeostasis markers, TIBC, TSAT, and ferritin were not genetically causally associated with PD, whereas there was a genetically causal association between serum iron and PD, and the increase of serum iron level may reduce the risk of PD.