AbstractBackgroundWe previously identified a significant association between Aquaporin‐4 (AQP4) and Parkinson's disease (PD).ObjectivesTo identify whether AQP4 single‐nucleotide polymorphism (SNP) rs162009 affects regional brain activity and clinical phenotypes of PD.MethodsLow‐frequency fluctuation amplitude (ALFF) was used to evaluate spontaneous brain activity, regional homogeneity (ReHo) was used to evaluate the pace of activity of adjacent voxel regions, and degree centrality (DC) was used to describe the functional connection strength between a voxel and the whole brain. Disease severity and PD stage were assessed with the Movement Disorder Society‐sponsored revision of the Unified Parkinson's Disease Rating Scale and Hoehn and Yahr scales, and the Montreal Cognitive Assessment (MoCA) was used to assess the participants' cognitive function.ResultsIn patients with PD, AQP4 SNP rs162009 was associated with a significant higher ALFF in the right caudate head and the left occipital gyrus, a significant lower ReHo in the right inferior frontal gyrus, a different DC in the right frontal gyrus, the left calcarine, and the right inferior temporal gyrus. A significant positive correlation between ALFF in the right caudate head and MoCA in rs162009_A carriers was found. A significant negative correlation between the DC at the left calcarine and MDS‐UPDRS and MDS‐UPDRS III in rs162009_A noncarriers was found.ConclusionsOur study further revealed the effect of AQP4 SNP rs162009 on brain activity in PD, indicating that AQP4 may play an important role in PD neuropathophysiology.