Altered brain activity and childhood trauma associate with gene and neurotransmitter patterns in transgender women with gender dysphoria

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. This study recruited 44 transgender women (TW) with GD, 40 cisgender men, and 42 cisgender women 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. Compared to cisgender controls, TW with GD showed decreased ALFF in the posterior cingulate cortex (PCC) but increased ALFF in the cerebellar lobule IX. TW with GD exhibited decreased fALFF in the right PCC compared to cisgender women. TW with GD also reported higher CTQ total and subscale scores. GIDYQ-AA scores were negatively correlated with ALFF in the PCC. Notably, CTQ total and its subscale scores [emotional abuse and emotional neglect (EN)] were negatively correlated with decreased 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 with GD. The altered brain activity in TW with GD was linked to genes enriched in mRNA catabolism and synaptic function, and was correlated with dopaminergic and serotonergic neurotransmission. TW with GD shows PCC hypofunction and cerebellar hyperactivation, which are associated with childhood trauma, especially emotional neglect. These neural alterations are correlated with gene expression and neurotransmitter pathways, suggesting a multilevel neurophysiological framework in TW with GD.