Plasma proteome demonstrates sex-specific associations with mental health risks in adolescents.

Adolescence is a critical developmental period marked by significant physiological, psychological, and behavioural changes, many of which differ between the sexes. We aimed to investigate sex-specific associations between the plasma proteome and questionnaire-based mental health measures in adolescents. Liquid chromatography - tandem mass spectrometry proteomic analysis was used to measure the plasma proteome abundances in 197 adolescents (11-16 years old) from the WALNUTs cohort. Baseline analysis of sexual dimorphism revealed 76 proteins significantly differentially abundant between sexes, which were enriched in cell adhesion, collagen fibril organisation, and ossification pathways. Bioinformatic analysis revealed 37 proteins significantly associated with the total score of the Strengths and Difficulties Questionnaire (SDQ). Modelling the sex-specificity via interaction terms revealed 40 proteins with significant associations with SDQ in females and 1 protein in males. Plasma protein abundancies in males exhibited stronger correlations with SDQ externalizing subscale scores, while in females the associations with the internalizing score were more prominent, consistent with known behavioural sex differences. Female-associated proteins were enriched for haemostasis and complement pathways, while male-associated signals suggested distinct immune and cytoskeletal processes. These findings indicate that both shared and sex-specific plasma proteomic signatures are associated with SDQ scores in adolescents and that models adjusting only for sex may obscure sex-divergent biology. These exploratory results are hypothesis-generating and support the use of sex-aware proteomic analyses to refine biomarker discovery for adolescent mental health.