Parkinson's disease (PD) is a movement disorder and the second most common degenerative disease of the central nervous system worldwide after Alzheimer's disease. PD was first described and documented by James Parkinson in 1817, and its main symptomatic manifestations include resting tremor, bradykinesia, myotonia, and postural balance disorders, as well as a number of nonmotor symptoms including olfactory dysfunction, autonomic dysfunction, psychiatric disorders, sleep disorders, and cognitive disorders [1], [2]. The exact etiology of Parkinson's disease is unknown, and studies have reported that smoking, alcohol consumption, vitamin D exposure, insecticide use, and uric acid levels may be potential risk factors [3]. Its main pathological basis is the reduction in the dopamine concentration in the striatum and the presence of discovered neuroleptic vesicles [4], [5], [6].

In recent years, many scholars have conducted various and in-depth studies on the pathological mechanisms of PD, including mutations of genes, dysfunctions of mitochondria, damage to the ubiquitinproteasome system, activation of the oxidative stress enzyme signaling pathway, accumulation of misfolded proteins in the autophagy-lysosomal system, the endoplasmic reticulum stress response, the inflammatory response, etc. [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], which are believed to be important factors leading to the death of dopamine neurons in the brain.

As one of the essential elements, iron participates in many important biological processes in the human body and plays an important role in mitochondrial respiration, redox homeostasis, ATP metabolism, immune regulation, and DNA and hormone synthesis [17], [18]. To maintain sufficient iron content, the cell maintains the stability of iron content by coordinating multiple genes so that they work together to restrict intracellular iron metabolism in the organism [19], [20], [21], so called iron homeostasis. In recent years, with the introduction of the concept of iron homeostasis, the number of studies in this field has increased annually. It is believed that iron homeostasis is involved in the development of many diseases, and similar to the role of iron, it is associated with the inflammatory response and immune regulation [22], [23]. In particular, changes in iron levels are considered to be associated with a variety of central nervous system disease pathologies, including PD, Alzheimer's disease, multiple sclerosis, stroke, etc. [24], [25], [26], [27]. Studies have shown that Parkinson's disease patients have higher iron concentrations in the substantia nigra [28], [29], which may be one of the main reasons for the induced oxidative stress in the cells, affecting mitochondrial function, and causing apoptosis of neuronal cells and ferroptosis [30], [31].

The Mendelian randomization (MR) analysis method, proposed in recent years, is an effective means for evaluating biological information. The MR analysis method is based on Mendel's first and second laws of inheritance and genetic fixity, i.e., when meiotic gametes are formed, alleles from the parents are randomly assigned to the offspring, and the relationship between genes and outcomes is not affected by common confounders such as the postnatal environment, socioeconomic characteristics, and behavioral habits. The causal time series derived from this method is rational, which is the basis upon which MR theory can be established [32]. This approach provides a valid assessment of the causal relationship between exposures and outcomes by using randomly assigned genetic instrumental variables (IVs), i.e., single nucleotide polymorphisms (SNPs), that are not subject to any causality and by controlling for confounding factors [33], [34].

A review of the literature revealed that the association between iron and PD has been studied by many experts and scholars; however, genetic studies conducted in this area are scarce. Earlier studies suggested that iron-related gene variants may be associated with the development of PD [35]. A recent study showed that rs602201 and rs198440 had a stimulatory effect on nigral iron deposition in PD patients, revealing the possible role of iron in the pathogenesis of PD from a genetic perspective [36]. However, the exact genetic causal link between iron and PD is still unclear, especially in the context of the "iron homeostasis" theory that was recently proposed. Therefore, in the present study, we attempted to elucidate the genetic association between iron homeostasis and PD using two-sample MR analysis with genome-wide association summary data.