Relationships between altered brain activity, childhood trauma, neurotransmitter, and genetic traits in Chinese early adulthood with gender dysphoria

Background Although early-life stress and trauma may influence cortical development and increase vulnerability to gender dysphoria (GD), the relationship between brain function and childhood traumatic experiences in GD remains unexplored. This study aims to investigate the neurobiological mechanisms underlying GD by examining functional brain alterations and their associations with childhood trauma, neurotransmitter systems, and gene expression patterns. Methods This study recruited 44 transgender women (TW), 40 cisgender male, and 42 cisgender female controls. Participants were assessed using the Childhood Trauma Questionnaire (CTQ) and Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults (GIDYQ-AA), while resting-state fMRI data were analyzed for amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) measures. The transcriptional data were sourced from the Allen Human Brain Atlas. The JuSpace toolbox was used to investigate the atlas-based nuclear imaging-derived neurotransmitter maps. Results Compared to cisgender controls, TW showed decreased ALFF in the posterior cingulate cortex (PCC) but increased ALFF in the cerebellar lobule IX. TW exhibited decreased fALFF in the right PCC compared to cisgender women. TW also reported higher CTQ total and subscale scores. Notably, CTQ total and its subscale scores [emotional abuse and emotional neglect (EN)] were positively correlated with increased ALFF in the PCC. Multivariate regression analysis further revealed that interactions between fALFF value of the right PCC × CTQ total and fALFF value of the right PCC × EN independently predicted GIDYQ-AA scores in TW. The abnormal brain activity in TW was linked to genes enriched in mRNA catabolism and synaptic function, and was correlated with dopaminergic and serotonergic neurotransmission. Conclusions TW involves the PCC hypofunction and the cerebellar hyperactivation, synergistically modulated by childhood trauma, especially emotional neglect. These neural alterations are linked to gene regulatory and neurotransmitter pathways, revealing a multilevel neurophysiological framework of TW.