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Background: Differences in cortical morphology have been reported in individuals with Parkinson's disease (PD). However, the pathophysiological mechanism of transcriptomic vulnerability in local brain regions remains unclear. Objective: This study aimed to characterize the morphometric changes of brain regions in early drug‐naive PD patients and uncover the brain‐wide gene expression correlates. Methods: The morphometric similarity (MS) network analysis was used to quantify the interregional structural similarity from multiple magnetic resonance imaging anatomical indices measured in each brain region of 170 early drug‐naive PD patients and 123 controls. Then, we applied partial least squares regression to determine the relationship between regional changes in MS and spatial transcriptional signatures from the Allen Human Brain Atlas dataset, and identified the specific genes related to MS differences in PD. We further investigated the biological processes by which the PD‐related genes were enriched and the cellular characterization of these genes. Results: Our results showed that MS was mainly decreased in cingulate, frontal, and temporal cortical areas and increased in parietal and occipital cortical areas in early drug‐naive PD patients. In addition, genes whose expression patterns were associated with regional MS changes in PD were involved in astrocytes, excitatory, and inhibitory neurons and were functionally enriched in neuron‐specific biological processes related to trans‐synaptic signaling and nervous system development. Conclusions: These findings advance our understanding of the microscale genetic and cellular mechanisms driving macroscale morphological abnormalities in early drug‐naive PD patients and provide potential targets for future therapeutic trials. [ABSTRACT FROM AUTHOR]