The polymorphism of ERK and PTPRR in MDD is rarely reported. The present study investigated the association between the polymorphism of ERK/PTPRR and MDD at resting-state brain function using genomic imaging. It indicated that the amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) in functional magnetic resonance imaging (fMRI) changed significantly in various brain regions of MDD patients. The T/G allele of ERK-rs1267842 and G/C allele of PTPRR-rs1513105 showed abnormal ALFF and ReHo changes in cortex including superior frontal gyrus and middle temporal gyrus. The development of MDD may be related with the polymorphism of ERK-rs12678428 and PTPRR-rs1513105.