AbstractBackgroundDysfunction of iron metabolism, especially in substantia nigra (SN), is widely acknowledged in Parkinson's disease (PD), but the genetic influence on iron deposition remains largely unknown. Thus, in this study, we aimed to investigate potential genetic impacts on iron deposition in PD.MethodsSeventy‐four subjects, including 38 patients with PD and 36 age‐matched normal controls, participated in this study. Imaging genetic association analysis was used to identify the specific influence of single nucleotide polymorphism (SNP) on iron‐related quantitative traits (QT). Genetic effects on iron deposition at the disease level, SNP level, and their interactive effect were highlighted.ResultsFour strong SNP–QT associations were detected: rs602201‐susceptibility of bilateral SN, rs198440‐susceptibility of left SN, and rs7895403‐susceptibility of left caudate head. Detailed analyses showed that: (1) significant iron deposition was exclusively found in bilateral SN in PD; (2) altered polymorphisms of the A allele/A− genotype of rs602201 and G allele/G− genotype of rs198440 and rs7895403 were more frequently observed in PD; (3) for rs602201, among all subjects, A− genotype carriers showed significantly increased iron content than TT genotype in bilateral SN; for rs198440 and rs7895403, G− carriers showed increased iron content than AA genotype in left SN and left caudate head, respectively; and (4) rs602201 exhibited significant SNP‐by‐disease interaction in bilateral SN.ConclusionsThis study shows that rs602201 and rs198440 have a stimulative impact on nigral iron deposition in PD, which provides improved understanding of iron‐related pathogenesis in PD, and specifically, that vulnerability to iron deposition in SN is genetic‐based.