Plasma proteome demonstrates sex-specific associations with mental health risks in adolescents, 2024, Afonin et al

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

Alexey Afonin, Aino-Kaisa Piironen, Jordi Julvez, Irene van Kamp, Katja M Kanninen

[Pre-print]

Abstract
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.

Link | PDF (Pre-print)

 

From discussion:

In this study, we used untargeted LC-MS/MS plasma proteomics to investigate the sex-specific associations between plasma protein abundances and mental health indicator scores in adolescents. Overall, 37 proteins were significantly associated with the total SDQ score using the 197 adolescents participating in the WALNUTs cohort. Of all the 76 plasma proteins found to be associated with sex, there were four proteins (Vitronectin, Prothrombin, Ficolin 2, And Alpha-1B-Glycoprotein) that was shown to be associated with the SDQ in the sub-cohort [27]. This coupled with the knowledge that SDQ is sex-specific, motivated us to split the cohort by sex and investigate the associations of the plasma proteome with SDQ separately for females and males.

As splitting the cohort by sex inevitably decreases the power of the statistical analysis we opted to use nominal p-values for these analyses. The analyses of the split cohorts showed individual proteins to be significantly and sex-specifically associated with the total SDQ score; N-acetylgalactosaminyltransferase 7 in males, and prothrombin and antithrombin-III in females. In a previous study, the level of N-acetylgalactosaminyltransferase in the brain was connected to sex differences in depressive, anxious behaviours in a rat model [41]. The female-specific proteins both play a role in blood coagulation which has been previously linked to depression and anxiety [42], and is in line with our previous study [27]. The deregulation of blood coagulation proteins was previously reported to be associated with acute stress [43] and depression [44].