Altered inter-subject variability of morphological brain networks and its association with neurotransmitters and gene expression in major depression disorder

• Published in: Journal of affective disorders Vol. 391; p. 119985
• Main Authors: Yao, Chi, Xiao, Yang, Wang, Peng, Zheng, Yuhong, Sun, Jie, Wang, Jinhui, Xue, Shao-Wei
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.12.2025
• Subjects: Heterogeneity; Inter-subject variability; Major depressive disorder; Morphological brain networks; Psychiatric/Mental Health; Heterogeneity; Inter-subject variability; Morphological brain networks; Major depressive disorder
• ISSN: 0165-0327; 1573-2517; 1573-2517
• DOI: 10.1016/j.jad.2025.119985

Major depressive disorder (MDD) exhibits considerable heterogeneity, with marked inter-subject variability in clinical manifestations, which may reflect differences in brain function and structure. Thereinto, the inter-subject variability of morphological brain networks in MDD remains largely unexamined. Data from 669 patients with MDD and 706 healthy controls (HC) were obtained from the REST-meta-MDD project. Morphological brain networks were constructed, and the inter-subject variability of morphological connectivity (IVMC) was calculated based on interregional similarity in gray matter volume distribution using the Kullback-Leibler divergence measure. Alterations in IVMC patterns in MDD patients and their clinical relevance were investigated. Additionally, correlations between MDD-related IVMC alterations and densities of neurotransmitter systems, as well as gene expression information, were assessed. Our analysis revealed altered IVMC patterns in MDD, characterized by increased IVMC within the limbic network (LIM) and ventral attention network (VAN) and decreased IVMC in the frontoparietal network (FPN). These altered IVMC patterns were spatially correlated with densities of neurotransmitter systems, including serotonin and dopamine receptors, and gene expression enriched in transmembrane and molecular transport, signal transduction, and immune response pathways. Our findings demonstrate an abnormal distribution of IVMC in MDD patients, highlighting potential underlying neurochemical and genetic mechanisms. These results contribute to our understanding of the inter-subject variability observed in MDD and provide insights into the neurophysiological mechanisms underlying the disorder. •Distinct IVMC alterations were identified in MDD patients, with abnormal inter-subject variability patterns compared to HC.•Increased IVMC regions linked to sensory/affective domains, while decreased IVMC regions associated with cognitive/motor functions.•IVMC alterations spatially correlate with neurotransmitter receptor densities and gene expression pathways.