Worldwide, one person dies every 40 seconds by suicide, a potentially preventable tragedy. A limiting step in our ability to intervene is the lack of objective, reliable predictors. We have previously provided proof of principle for the use of blood gene expression biomarkers to predict future hospitalizations due to suicidality, in male bipolar disorder participants. We now generalize the discovery, prioritization, validation, and testing of such markers across major psychiatric disorders (bipolar disorder, major depressive disorder, schizoaffective disorder, and schizophrenia) in male participants, to understand commonalities and differences. We used a powerful within-participant discovery approach to identify genes that change in expression between no suicidal ideation and high suicidal ideation states (n=37 participants out of a cohort of 217 psychiatric participants followed longitudinally). We then used a convergent functional genomics (CFG) approach with existing prior evidence in the field to prioritize the candidate biomarkers identified in the discovery step. Next, we validated the top biomarkers from the prioritization step for relevance to suicidal behavior, in a demographically matched cohort of suicide completers from the coroner's office (n=26). The biomarkers for suicidal ideation only are enriched for genes involved in neuronal connectivity and schizophrenia, the biomarkers also validated for suicidal behavior are enriched for genes involved in neuronal activity and mood. The 76 biomarkers that survived Bonferroni correction after validation for suicidal behavior map to biological pathways involved in immune and inflammatory response, mTOR signaling and growth factor regulation. mTOR signaling is necessary for the effects of the rapid-acting antidepressant agent ketamine, providing a novel biological rationale for its possible use in treating acute suicidality. Similarly, MAOB, a target of antidepressant inhibitors, was one of the increased biomarkers for suicidality. We also identified other potential therapeutic targets or biomarkers for drugs known to mitigate suicidality, such as omega-3 fatty acids, lithium and clozapine. Overall, 14% of the top candidate biomarkers also had evidence for involvement in psychological stress response, and 19% for involvement in programmed cell death/cellular suicide (apoptosis). It may be that in the face of adversity (stress), death mechanisms are turned on at a cellular (apoptosis) and organismal level. Finally, we tested the top increased and decreased biomarkers from the discovery for suicidal ideation (CADM1, CLIP4, DTNA, KIF2C), prioritization with CFG for prior evidence (SAT1, SKA2, SLC4A4), and validation for behavior in suicide completers (IL6, MBP, JUN, KLHDC3) steps in a completely independent test cohort of psychiatric participants for prediction of suicidal ideation (n=108), and in a future follow-up cohort of psychiatric participants (n=157) for prediction of psychiatric hospitalizations due to suicidality. The best individual biomarker across ps...

Summary Transcriptional regulation during CD4+ T cell fate decisions enables their differentiation into distinct states, guiding immune responses towards antibody production via Tfh cells or inflammation by Teff cells. Tfh–Teff fate commitment is regulated by mutual antagonism between the transcription factors Bcl6 and Blimp-1. Here we examined how T cell receptor (TCR) signals establish and arbitrate Bcl6–Blimp-1 counter-antagonism. We found that the TCR-signal induced transcription factor Irf4 is essential for the differentiation of Bcl6-expressing Tfh and Blimp-1-expressing Teff cells. Increased TCR signaling raised Irf4 amounts and promoted Teff fates at the expense of Tfh ones. Importantly, orthogonal induction of Irf4 expression redirected Tfh fate trajectories towards those of Teff. Mechanistically, we linked greater Irf4 abundance with its recruitment towards low affinity binding sites within Teff cis-regulatory elements, including those of Prdm1. We propose that the Irf4 locus functions as the “reader” of TCR signal strength, in turn, concentration-dependent activity of Irf4 “writes” T helper fate choice.

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This paper describes gambling problems among Ontario students in 2009 and examines the relationship between gambling problems and substance use problems, mental health problem indicators, and delinquent behaviors. Data were derived from the Ontario Student Drug Use and Health Survey of Ontario students in grades 7-12. Gambling problems were measured as 2 or more of 6 indicators of problem gambling. In total 2.8% of the students surveyed endorsed two or more of the problem gambling items. The odds of problem gamblers reporting mental distress was 4.2 times higher than the rest of the sample and the odds of problem gamblers reporting a suicide attempt were 17.8 times greater than the rest of the sample. In addition compared to the rest of the students, delinquent behaviors were also more common among problem gamblers, including theft (OR = 14.5), selling marijuana (OR = 19.6), gang fights (OR = 11.3) and carrying a handgun (OR = 11.2). In a multivariate analysis, substance-use problems, mental health problems, and the participation in a variety of delinquent behaviors remained significantly associated with youth problem gambling behavior. Students who report problem gambling behaviors show increased substance abuse, mental health, and delinquency/criminal problems that are similar to those seen among adult problem gamblers. The association between these problems suggests that these problems could be addressed in a unified manner.