Adolescence is a critical developmental period marked by significant physiological, psychological, and behavioural changes. Sex-specific biological factors can play a major role in their progression. 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. Orthogonal partial least squares discriminant analysis (OPLS-DA) revealed clear sex-based proteomic distinctions, with 76 proteins significantly differing between males and females after correcting for age and BMI. Gene Ontology enrichment analysis of these proteins highlighted pathways related to cell adhesion and extracellular matrix organization reflecting sex-specific developmental trajectories during puberty. Bioinformatic analysis revealed 37 proteins significantly associated with the total score of the Strengths and Difficulties Questionnaire (SDQ), with additional sex-specific associations emerging in subgroup analyses. 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. Immune response and blood coagulation pathways were implicated in these associations, particularly in females, while no significant pathway enrichment was observed for males. These findings highlight both shared and sex-specific proteomic features associated with the SDQ scores in adolescents, emphasising the need to consider sex differences in proteomic studies. The results provide a critical step toward identifying biomarkers and pathways underlying sex-specific psychological and developmental processes in adolescence.

The authors have declared no competing interest.

The data analysed in this study is subject to the following licenses/restrictions: The Walnuts data is not publicly available due to the restrictions of informed consent. The data contains personal information of children and according to the ethical approval, they should be kept confidential. Proteomics data is not publicly available due to the restrictions of informed consent. Reasonable requests to access these datasets should be directed to Katja Kanninen, University of Eastern Finland. To ensure the protection of privacy and compliance with national data protection legislation, a data use/transfer agreement is needed, the content and specific clauses of which will depend on the nature of the requested data.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The studies were reviewed and approved by CEIC Parc Salut Mar Clinical Research Ethics Committee (approval numbers: 2015/6026 Walnuts and 2020/9688-Equal-life). Written informed consent to participate in the original WALNUTs study was provided by the participants' legal guardian/next of kin.

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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The data analysed in this study is subject to the following licenses/restrictions: The Walnuts data is not publicly available due to the restrictions of informed consent. The data contains personal information of children and according to the ethical approval, they should be kept confidential. Proteomics data is not publicly available due to the restrictions of informed consent. Reasonable requests to access these datasets should be directed to Katja Kanninen, University of Eastern Finland. To ensure the protection of privacy and compliance with national data protection legislation, a data use/transfer agreement is needed, the content and specific clauses of which will depend on the nature of the requested data.