Genetic mechanisms underlying gray matter atrophy in Parkinson’s disease: a combined transcriptome and neuroimaging study

Abstract Extensive research has shown prominent gray matter atrophy in patients with Parkinson's disease (PD), yet its genetic mechanisms are largely unknown. To achieve a more thorough characterization of gray matter alterations in PD, we performed a comprehensive neuroimaging meta-analysis of previous literature including 1,831 PD patients and 1,378 controls as well as examined group gray matter differences in an independent dataset. Utilizing the Allen Human Brain Atlas, we performed spatial association analyses linking transcriptome data to neuroimaging findings to identify genes correlated with gray matter atrophy in PD. Subsequently, we conducted enrichment analyses for the identified genes associated with gray matter atrophy in PD patients and performed a series of gene functional feature analyses (i.e., specific expression, protein-protein interaction (PPI) and behavioral relevance analyses) for deep understanding. Our meta-analysis and independent dataset neuroimaging analysis consistently revealed significant gray matter atrophy in the superior temporal gyrus of PD patients. Transcriptome-neuroimaging correlation analysis identified 1,952 genes whose expression correlated with gray matter atrophy in PD. These genes were enriched in biologically significant processes and exhibited selective expression in brain tissue, dopamine receptor cells, and neurons. Regarding behavioral relevance, these genes were linked to perception and motion domains. Our findings suggest that prominent gray matter atrophy in PD may be a consequence of intricate interactions among a diverse set of genes with various functional features.