Despite increasing mental health problems among young people, few studies have examined associations between plasma proteins and mental health, and interactions between proteins and metabolites in association with mental health problems remain underexplored. In 730 twins, we quantified associations between plasma proteins measured at age 22 with 21 indicators representing either depressive symptoms or the pfactor, collected from questionnaires and interviews completed by different raters (e.g., self report, teachers) through adolescence to young adulthood (12 to 22 years), and tested for interactions with metabolites. We found 47 proteins associated with depressive symptoms or the pfactor (FDR<0.2), 9 being associated with both. Two proteins, contactin-1 and mast/stem cell growth factor receptor kit, positively interacted with valine levels in explaining p-factor variability. In conclusion, our study demonstrates strong associations between plasma proteins and mental health and provides evidence for proteome–metabolome interactions in explaining higher levels of mental health problems.

The authors have declared no competing interest.

Data collection has been supported by the National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, and AA-09203 to R J Rose; AA15416 and AA018755 to D M Dick) and the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248 to J Kaprio). J Kaprio acknowledges the support of the Academy of Finland Center of Excellence in Complex Disease Genetics (grant # 352792).

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

Ethical approval for all data collection waves was obtained from the ethical committee of the Helsinki and Uusimaa University Hospital District and Indiana University Institutional Review Board

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