ReHo-related Gene Modules Associated With Psychiatric Disorders

Objective:Mapping gene expression profiles to neuroimaging phenotypes in the same anatomical space provides opportunities to discover new molecular insights on human brain functional properties.As a highly reliable image-derived index,Re Ho has been widely used to map the local activity of the human functional connectome and identify brain functional abnormalities in many neuropsychiatric disorders.However,the molecular substrates underlying Re Ho of spontaneous brain activity still remain elusive.Here,we aimed to identify cell-type specific gene modules associated with regional homogeneity(Re Ho)of spontaneous brain activity,and their associations with neuropsychiatric disorders.Materials and Methods:Four hundred and nine healthy adults were recruited to discover possible genetic mechanism for Re Ho value,while another two independent datasets(n = 692 and n = 100)of healthy adults were prepared to validate the results of the discovery group.For each of the three groups(one discovery group and two validation groups),the corresponding group-level z Re Ho map was calculated by voxel-wised one sample t-test.A region × gene matrix was constructed following a standardized pipeline proposed for AHBA data processing to link gene expression and neuroimaging phenotypes.Gene modules with similar expression profiles were generated by weighted gene co-expression network analysis(WGCNA)based on the region × gene expression correlation matrix.The Re Ho-related gene modules were identified by spatial Spearman correlation between the ME of each module and z Re Ho across the neocortical regions.The cell-type specific analyses were performed to identify which brain cell-types the modules belonged to.gene ontology(GO)enrichment analysis was performed to characterize the possible biological processes,molecular functions and cellular components of each Re Ho-related cell-type specific gene module.And genome-wide association enrichment analyses(GWAS)summary statistics were employed to test associations between the identified modules and neuropsychiatric disorders.Results:Fourteen gene modules were consistently associated with Re Ho in the three datasets,five of which showed cell-type specific expression(one neuron-endothelial module,one neuron module,one astrocyte module and two microglia modules)in two independent cell serials of human cerebral cortex.Neuron-endothelial module was mainly enriched for transporter complex,neuron module for synaptic membrane,astrocyte module for amino acid metabolism,and microglia modules for leukocyte activation and ribose phosphate biosynthesis.In GWAS enrichment analyses of cell-type specific modules for 10 common neuropsychiatric disorders,only the microglia module was significantly enriched for multiple sclerosis(MS)and Alzheimer’s disease(AD).Conclusion:Regional homogeneity of spontaneous brain activity has a complex genetic architecture and is at least associated with gene expression profiles of neuron,astrocyte,microglia and endothelial cell.Association of microglia module with MS and AD may provide a possible molecular substrate for Re Ho abnormality in both brain disorders.