Convergence of recent GWAS data for suicidality with previous blood biomarkers: independent reproducibility using independent methodologies in independent cohorts

Recent genetic studies for suicidality, including four independent GWAS, have not reproduced each other’s top implicated genes. While arguments of heterogeneity, methodology, and sample sizes can be invoked, heterogeneity is a feature, not a “bug” (as is well understood in biology and in personalized medicine). A comprehensive body of work on blood biomarkers for suicidality has previously been published by our group. We examine the issue of reproducibility using these different approaches, and provide reassuring evidence for convergence of findings, as well as some generalizable insights

Assessing Risk of Future Suicidality in Emergency Department Patients

Background. Emergency Departments (ED) are the first line of evaluation for patients at risk and in crisis, with or without overt suicidality (ideation, attempts). Currently employed triage and assessments methods miss some of the individuals who subsequently become suicidal. The Convergent Functional Information for Suicidality (CFI-S) 22 item checklist of risk factors, that does not ask directly about suicidal ideation, has demonstrated good predictive ability for suicidality in previous studies in psychiatric outpatients, but has not been tested in the real world-setting of emergency departments (EDs). Methods. We administered CFI-S prospectively to a convenience sample of consecutive ED patients. Median administration time was 3 minutes. Patients were also asked at triage about suicidal thoughts or intentions per standard ED suicide clinical screening (SCS), and the treating ED physician was asked to fill a physician gestalt visual analog scale (VAS) for likelihood of future suicidality spectrum events (SSE) (ideation, preparatory acts, attempts, completed suicide). We performed structured chart review and telephone follow-up at 6 months post index visit. Results. The median time to complete the CFI-S was three minutes (1st to 3rd quartile 3–6 minutes). Of the 338 patients enrolled, 45 (13.3%) were positive on the initial SCS, and 32 (9.5%) experienced a SSE in the 6 months follow-up. Overall, across genders, SCS had a modest diagnostic discrimination for future SSE (ROC AUC 0.63,). The physician VAS was better (AUC 0.76 CI 0.66–0.85), and the CFI-S was slightly higher (AUC 0.81, CI 0.76–0.87). The top CFI-S differentiating items were psychiatric illness, perceived uselessness, and social isolation. The top CFI-S items were family history of suicide, age, and past history of suicidal acts. Conclusions. Using CFI-S, or some of its items, in busy EDs may help improve the detection of patients at high risk for future suicidality

Evidence for genetic association of RORB with bipolar disorder

<p>Abstract</p> <p>Background</p> <p>Bipolar disorder, particularly in children, is characterized by rapid cycling and switching, making circadian clock genes plausible molecular underpinnings for bipolar disorder. We previously reported work establishing mice lacking the clock gene D-box binding protein (<it>DBP</it>) as a stress-reactive genetic animal model of bipolar disorder. Microarray studies revealed that expression of two closely related clock genes, <it>RAR</it>-related orphan receptors alpha (<it>RORA</it>) and beta (<it>RORB</it>), was altered in these mice. These retinoid-related receptors are involved in a number of pathways including neurogenesis, stress response, and modulation of circadian rhythms. Here we report association studies between bipolar disorder and single-nucleotide polymorphisms (SNPs) in <it>RORA </it>and <it>RORB</it>.</p> <p>Methods</p> <p>We genotyped 355 <it>RORA </it>and <it>RORB </it>SNPs in a pediatric cohort consisting of a family-based sample of 153 trios and an independent, non-overlapping case-control sample of 152 cases and 140 controls. Bipolar disorder in children and adolescents is characterized by increased stress reactivity and frequent episodes of shorter duration; thus our cohort provides a potentially enriched sample for identifying genes involved in cycling and switching.</p> <p>Results</p> <p>We report that four intronic <it>RORB </it>SNPs showed positive associations with the pediatric bipolar phenotype that survived Bonferroni correction for multiple comparisons in the case-control sample. Three <it>RORB </it>haplotype blocks implicating an additional 11 SNPs were also associated with the disease in the case-control sample. However, these significant associations were not replicated in the sample of trios. There was no evidence for association between pediatric bipolar disorder and any <it>RORA </it>SNPs or haplotype blocks after multiple-test correction. In addition, we found no strong evidence for association between the age-at-onset of bipolar disorder with any <it>RORA </it>or <it>RORB </it>SNPs.</p> <p>Conclusion</p> <p>Our findings suggest that clock genes in general and <it>RORB </it>in particular may be important candidates for further investigation in the search for the molecular basis of bipolar disorder.</p