Whole-genome sequencing analysis of suicide deaths integrating brain-regulatory eQTLs data to identify risk loci and genes.

Recent large-scale genome-wide association studies (GWAS) have started to identify potential genetic risk loci associated with risk of suicide; however, a large portion of suicide-associated genetic factors affecting gene expression remain elusive. Dysregulated gene expression, not assessed by GWAS, may play a significant role in increasing the risk of suicide death. We performed the first comprehensive genomic association analysis prioritizing brain expression quantitative trait loci (eQTLs) within regulatory regions in suicide deaths from the Utah Suicide Genetic Risk Study (USGRS). 440,324 brain-regulatory eQTLs were obtained by integrating brain eQTLs, histone modification ChIP-seq, ATAC-seq, DNase-seq, and Hi-C results from publicly available data. Subsequent genomic analyses were conducted in whole-genome sequencing (WGS) data from 986 suicide deaths of non-Finnish European (NFE) ancestry and 415 ancestrally matched controls. Additional independent USGRS suicide deaths with genotyping array data (n = 4657) and controls from the Genome Aggregation Database were explored for WGS result replication. One significant eQTL locus, rs926308 (p = 3.24e-06), was identified. The rs926308-T is associated with lower expression of RFPL3S, a gene important for neocortex development and implicated in arousal. Gene-based analyses performed using Sherlock Bayesian statistical integrative analysis also detected 20 genes with expression changes that may contribute to suicide risk. From analyzing publicly available transcriptomic data, ten of these genes have previous evidence of differential expression in suicide death or in psychiatric disorders that may be associated with suicide, including schizophrenia and autism (ZNF501, ZNF502, CNN3, IGF1R, KLHL36, NBL1, PDCD6IP, SNX19, BCAP29, and ARSA). Electronic health records (EHR) data was further merged to evaluate if there were clinically relevant subsets of suicide deaths associated with genetic variants. In summary, our study identified one risk locus and ten genes associated with suicide risk via gene expression, providing new insight into possible genetic and molecular mechanisms leading to suicide.

Understanding heterogeneity in suicidal thoughts and behaviours and the implications for genetic studies - a commentary on Lannoy et al. (2022).

Preventing suicidal thoughts and behaviours (STB) among youth is a global public health priority. STB are known to have a heritable basis, and the development of risk for STB likely arises from complex gene-environment interactions across the life course. Lannoy et al. (Journal of Child Psychology and Psychiatry, 63, 2022 and 1164) describe a study in which polygenic risk for suicide attempt, as well as recent negative life events, were related to recent suicidal ideation in adolescents of about 17 years old. Building on this important work, we highlight several critical areas of focus for research in suicide genetics, including problems of measurement, as well as priorities for better uncovering the specific aetiological pathways to STB.

Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10-4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.

Response of US psychiatric programs to the COVID-19 pandemic and the impact on trainees.

BACKGROUND: Medical training program and hospital response to the COVID-19 pandemic has varied greatly and has impacted trainee well-being. Which factors have specifically related to trainee wellness, however, has not yet been examined in depth. The aim of the study was to understand trainee perspectives on the individual psychiatry trainee programs' hospitals' objective COVID-19 preparedness management. We also sought and to gauge how program changes, and general pandemic-related concerns, have been associated with trainee satisfaction and burnout. METHODS: A cross-sectional survey study of psychiatric trainees was distributed electronically throughout the country via various psychiatry residency program listservs in April 2020. Statistical analyses were performed utilizing simple linear regression. RESULTS: From 352 respondents (346 complete responses and 6 partial responses), the most frequent program changes were "decreased number of rotations requiring in-person patient care" and "increased call hours or duties." Of pandemic-related concerns surveyed, the two greatest were "spreading COVID-19 to family/friends" and "co-residents' burnout and anxiety." A positive relationship was found between trainee satisfaction with perceived COVID-19 departmental response and comfort level of residents/fellows in expressing concerns with attending clinicians and department leadership. CONCLUSIONS: Since the start of the COVID-19 pandemic, trainees have experienced a variety of changes to trainee program policies and guidelines. Overall, poor communication and trainee dissatisfaction with departmental response correlated with concern of infection and anxiety/burnout. Insights garnered from this study could provide scaffolding for the best practices to reduce trainee physician anxiety/burnout for the current and future pandemics of this variety and magnitude.

Extended familial risk of suicide death is associated with younger age at death and elevated polygenic risk of suicide.

Suicide accounts for >800,000 deaths annually worldwide; prevention is an urgent public health issue. Identification of risk factors remains challenging due to complexity and heterogeneity. The study of suicide deaths with increased extended familial risk provides an avenue to reduce etiological heterogeneity and explore traits associated with increased genetic liability. Using extensive genealogical records, we identified high-risk families where distant relatedness of suicides implicates genetic risk. We compared phenotypic and polygenic risk score (PRS) data between suicides in high-risk extended families (high familial risk (HFR), n = 1,634), suicides linked to genealogical data not in any high-risk families (low familial risk (LFR), n = 147), and suicides not linked to genealogical data with unknown familial risk (UFR, n = 1,865). HFR suicides were associated with lower age at death (mean = 39.34 years), more suicide attempts, and more PTSD and trauma diagnoses. For PRS tests, we included only suicides with >90% European ancestry and adjusted for residual ancestry effects. HFR suicides showed markedly higher PRS of suicide death (calculated using cross-validation), supporting specific elevation of genetic risk of suicide in this subgroup, and also showed increased PRS of PTSD, suicide attempt, and risk taking. LFR suicides were substantially older at death (mean = 49.10 years), had fewer psychiatric diagnoses of depression and pain, and significantly lower PRS of depression. Results suggest extended familiality and trauma/PTSD may provide specificity in identifying individuals at genetic risk for suicide death, especially among younger ages, and that LFR of suicide warrants further study regarding the contribution of demographic and medical risks.

Rare protein-coding variants implicate genes involved in risk of suicide death.

Identification of genetic factors leading to increased risk of suicide death is critical to combat rising suicide rates, however, only a fraction of the genetic variation influencing risk has been accounted for. To address this limitation, we conducted the first comprehensive analysis of rare genetic variation in suicide death leveraging the largest suicide death biobank, the Utah Suicide Genetic Risk Study (USGRS). We conducted a single-variant association analysis of rare (minor allele frequency <1%) putatively functional single-nucleotide polymorphisms (SNPs) present on the Illumina PsychArray genotyping array in 2,672 USGRS suicide deaths of non-Finnish European (NFE) ancestry and 51,583 NFE controls from the Genome Aggregation Database. Secondary analyses used an independent control sample of 21,324 NFE controls from the Psychiatric Genomics Consortium. Five novel, high-impact, rare SNPs were identified with significant associations with suicide death (SNAPC1, rs75418419; TNKS1BP1, rs143883793; ADGRF5, rs149197213; PER1, rs145053802; and ESS2, rs62223875). 119 suicide decedents carried these high-impact SNPs. Both PER1 and SNAPC1 have other supporting gene-level evidence of suicide risk, and psychiatric associations exist for PER1 (bipolar disorder, schizophrenia), and for TNKS1BP1 and ESS2 (schizophrenia). Three of the genes (PER1, TNKS1BP1, and ADGRF5), together with additional genes implicated by genome-wide association studies on suicidal behavior, showed significant enrichment in immune system, homeostatic and signal transduction processes. No specific diagnostic phenotypes were associated with the subset of suicide deaths with the identified rare variants. These findings suggest an important role for rare variants in suicide risk and implicate genes and gene pathways for targeted replication.

Targeted sequencing of the LRRTM gene family in suicide attempters with bipolar disorder.

Glutamatergic signaling is the primary excitatory neurotransmission pathway in the brain, and its relationship to neuropsychiatric disorders is of considerable interest. Our previous attempted suicide genome-wide association study, and numerous studies investigating gene expression, genetic variation, and DNA methylation have implicated aberrant glutamatergic signaling in suicide risk. The glutamatergic pathway gene LRRTM4 was an associated gene identified in our attempted suicide genome-wide association study, with association support seen primarily in females. Recent evidence has also shown that glutamatergic signaling is partly regulated by sex-related hormones. The LRRTM gene family encodes neuronal leucine-rich transmembrane proteins that localize to and promote glutamatergic synapse development. In this study, we sequenced the coding and regulatory regions of all four LRRTM gene members plus a large intronic region of LRRTM4 in 476 bipolar disorder suicide attempters and 473 bipolar disorder nonattempters. We identified two male-specific variants, one female- and five male-specific haplotypes significantly associated with attempted suicide in LRRTM4. Furthermore, variants within significant haplotypes may be brain expression quantitative trait loci for LRRTM4 and some of these variants overlap with predicted hormone response elements. Overall, these results provide supporting evidence for a sex-specific association of genetic variation in LRRTM4 with attempted suicide.

Differentially methylated regions in bipolar disorder and suicide.

The addition of a methyl group to, typically, a cytosine-guanine dinucleotide (CpG) creates distinct DNA methylation patterns across the genome that can regulate gene expression. Aberrant DNA methylation of CpG sites has been associated with many psychiatric disorders including bipolar disorder (BD) and suicide. Using the SureSelectXT system, Methyl-Seq, we investigated the DNA methylation status of CpG sites throughout the genome in 50 BD individuals (23 subjects who died by suicide and 27 subjects who died from other causes) and 31 nonpsychiatric controls. We identified differentially methylated regions (DMRs) from three analyses: (a) BD subjects compared to nonpsychiatric controls (BD-NC), (b) BD subjects who died by suicide compared to nonpsychiatric controls (BDS-NC), and (c) BDS subjects compared to BD subjects who died from other causes (BDS-BDNS). One DMR from the BDS-NC analysis, located in ARHGEF38, was significantly hypomethylated (23.4%) in BDS subjects. This finding remained significant after multiple testing (PBootstrapped = 9.0 × 10-3 ), was validated using pyrosequencing, and was more significant in males. A secondary analysis utilized Ingenuity Pathway Analysis to identify enrichment in nominally significant DMRs. This identified an association with several pathways including axonal guidance signaling, calcium signaling, ß-adrenergic signaling, and opioid signaling. Our comprehensive study provides further support that DNA methylation alterations influence the risk for BD and suicide. However, further investigation is required to confirm these associations and identify their functional consequences.

A targeted sequencing study of glutamatergic candidate genes in suicide attempters with bipolar disorder.

Suicidal behavior has been shown to have a heritable component that is partly driven by psychiatric disorders [Brent and Mann, 2005]. However, there is also an independent factor contributing to the heritability of suicidal behavior. We previously conducted a genome-wide association study (GWAS) of bipolar suicide attempters and bipolar non-attempters to assess this independent factor [Willour et al., 2012]. This GWAS implicated glutamatergic neurotransmission in attempted suicide. In the current study, we have conducted a targeted next-generation sequencing study of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, neurexin, and neuroligin gene families in 476 bipolar suicide attempters and 473 bipolar non-attempters. The goal of this study was to gather sequence information from coding and regulatory regions of these glutamatergic genes to identify variants associated with attempted suicide. We identified 186 coding variants and 4,298 regulatory variants predicted to be functional in these genes. No individual variants were overrepresented in cases or controls to a degree that was statistically significant after correction for multiple testing. Additionally, none of the gene-level results were statistically significant following correction. While this study provides no direct support for a role of the examined glutamatergic candidate genes, further sequencing in expanded gene sets and datasets will be required to ultimately determine whether genetic variation in glutamatergic signaling influences suicidal behavior. © 2016 Wiley Periodicals, Inc.

Whole-gene sequencing investigation of SAT1 in attempted suicide.

Suicidal behavior imposes a tremendous cost, with current US estimates reporting approximately 1.3 million suicide attempts and more than 40,000 suicide deaths each year. Several recent research efforts have identified an association between suicidal behavior and the expression level of the spermidine/spermine N1-acetyltransferase 1 (SAT1) gene. To date, several SAT1 genetic variants have been inconsistently associated with altered gene expression and/or directly with suicidal behavior. To clarify the role SAT1 genetic variation plays in suicidal behavior risk, we present a whole-gene sequencing effort of SAT1 in 476 bipolar disorder subjects with a history of suicide attempt and 473 subjects with bipolar disorder but no suicide attempts. Agilent SureSelect target enrichment was used to sequence all exons, introns, promoter regions, and putative regulatory regions identified from the ENCODE project within 10 kb of SAT1. Individual variant, haplotype, and collapsing variant tests were performed. Our results identified no variant or assessed region of SAT1 that showed a significant association with attempted suicide, nor did any assessment show evidence for replication of previously reported associations. Overall, no evidence for SAT1 sequence variation contributing to the risk for attempted suicide could be identified. It is possible that past associations of SAT1 expression with suicidal behavior arise from variation not captured in this study, or that causal variants in the region are too rare to be detected within our sample. Larger sample sizes and broader sequencing efforts will likely be required to identify the source of SAT1 expression level associations with suicidal behavior. © 2016 Wiley Periodicals, Inc.

Absence of nonfatal suicidal behavior preceding suicide death reveals differences in clinical risks.

Nonfatal suicidality is the most robust predictor of suicide death. However, only ~10% of those who survive an attempt go on to die by suicide. Moreover, ~50% of suicide deaths occur in the absence of prior known attempts, suggesting risks other than nonfatal suicide attempt need to be identified. We studied data from 4,000 population-ascertained suicide deaths and 26,191 population controls to improve understanding of risks leading to suicide death. This study included 2,253 suicide deaths and 3,375 controls with evidence of nonfatal suicidality (SUI_SI/SB and CTL_SI/SB) from diagnostic codes and natural language processing of electronic health records notes. Characteristics of these groups were compared to 1,669 suicides with no prior nonfatal SI/SB (SUI_None) and 22,816 controls with no lifetime suicidality (CTL_None). The SUI_None and CTL_None groups had fewer diagnoses and were older than SUI_SI/SB and CTL_SI/SB. Mental health diagnoses were far less common in both the SUI_None and CTL_None groups; mental health problems were less associated with suicide death than with presence of SI/SB. Physical health diagnoses were conversely more often associated with risk of suicide death than with presence of SI/SB. Pending replication, results indicate highly significant clinical differences among suicide deaths with versus without prior nonfatal SI/SB.

Defining Suicidal Thought and Behavior Phenotypes for Genetic Studies.

Background: Standardized definitions of suicidality phenotypes, including suicidal ideation (SI), attempt (SA), and death (SD) are a critical step towards improving understanding and comparison of results in suicide research. The complexity of suicidality contributes to heterogeneity in phenotype definitions, impeding evaluation of clinical and genetic risk factors across studies and efforts to combine samples within consortia. Here, we present expert and data-supported recommendations for defining suicidality and control phenotypes to facilitate merging current/legacy samples with definition variability and aid future sample creation. Methods: A subgroup of clinician researchers and experts from the Suicide Workgroup of the Psychiatric Genomics Consortium (PGC) reviewed existing PGC definitions for SI, SA, SD, and control groups and generated preliminary consensus guidelines for instrument-derived and international classification of disease (ICD) data. ICD lists were validated in two independent datasets (N = 9,151 and 12,394). Results: Recommendations are provided for evaluated instruments for SA and SI, emphasizing selection of lifetime measures phenotype-specific wording. Recommendations are also provided for defining SI and SD from ICD data. As the SA ICD definition is complex, SA code list recommendations were validated against instrument results with sensitivity (range = 15.4% to 80.6%), specificity (range = 67.6% to 97.4%), and positive predictive values (range = 0.59-0.93) reported. Conclusions: Best-practice guidelines are presented for the use of existing information to define SI/SA/SD in consortia research. These proposed definitions are expected to facilitate more homogeneous data aggregation for genetic and multisite studies. Future research should involve refinement, improved generalizability, and validation in diverse populations.

A model for migratory B cell oscillations from receptor down-regulation induced by external chemokine fields.

A long-standing paradigm in B cell immunology is that effective somatic hypermutation and affinity maturation require cycling between the dark zone and light zone of the germinal center. The cyclic re-entry hypothesis was first proposed based on considerations of the efficiency of affinity maturation using an ordinary differential equations model for B cell population dynamics. More recently, two-photon microscopy studies of B cell motility within lymph nodes in situ have revealed the complex migration patterns of B lymphocytes both in the preactivation follicle and post-activation germinal center. There is strong evidence that chemokines secreted by stromal cells and the regulation of cognate G-protein coupled receptors by these chemokines are necessary for the observed spatial cell distributions. For example, the distribution of B cells within the light and dark zones of the germinal center appears to be determined by the reciprocal interaction between the level of the CXCR4 and CXCR5 receptors and the spatial distribution of their respective chemokines CXCL12 and CXCL13. Computer simulations of individual-based models have been used to study the complex biophysical and mechanistic processes at the individual cell level, but such simulations can be challenging to parameterize and analyze. In contrast, ordinary differential equations are more tractable, but traditional compartment model formalizations ignore the spatial chemokine distribution that drives B cell redistribution. Motivated by the desire to understand the motility patterns observed in an individual-based simulation of B cell migration in the lymph node, we propose and analyze the dynamics of an ordinary differential equation model incorporating explicit chemokine spatial distributions. While there is experimental evidence that B cell migration patterns in the germinal center are driven by extrinsically regulated differentiation programs, the model shows, perhaps surprisingly, that feedback from receptor down-regulation induced by external chemokine fields can give rise to spontaneous interzonal and intrazonal oscillations in the absence of any extrinsic regulation. While the extent to which such simple feedback mechanisms contributes to B cell migration patterns in the germinal center is unknown, the model provides an alternative hypothesis for how complex B cell migration patterns might arise from very simple mechanisms.

The Utah psychotropic oversight program: collaboratively addressing antipsychotic use within youth in foster care without prior authorization.

Objectives: Fostered youth have increased risk of exposure to trauma. Antipsychotic medications are often utilized within the foster care system, potentially to address problematic behaviors that may be associated with trauma. The Utah Psychotropic Oversight Program (UPOP) was formed to support prescribers and encourage evidence-based treatment approaches for fostered youth. However, it is unclear what impact an oversight program can have on a high turnover population and without tools such as prior authorization. This study evaluates 4 years of collected data from the UPOP program for efficacy and to identify future intervention targets. Methods: Deidentified data were collected as a routine function of the oversight program over 4 years (01/2019-12/2022), from individuals aged 0-18 years old (total N = 8,523, 48.3% female). UPOP oversight criteria: ≤6yo + any psychotropic medication, ≥7yo + 2 or more psychotropic medications. For this analysis, youth were divided by UPOP individuals ever receiving an antipsychotic (AP) prescription (UPOP_AP; N = 755, 42.3% female) or not (UPOP_NAP, N = 1,006, 48.3% female) and non-UPOP fostered (N = 6,762, 48.9% female). Comparisons were made across demographic and clinical variables via ANOVA, Chi-square, unpaired t-test, and logistic regression. Results: UPOP_AP more likely to be older males with behavioral diagnoses, increased polypharmacy, longer duration of fostering, and higher care level. AP prescription rates dropped from 52.8 to 39.1% for males and 43.3 to 38.2% in females with unchanged number of psychotropic prescriptions and care level across 2019-2022. UPOP_AP that discontinued AP treatment had fewer average psychotropic medications, but increased antidepressant and sleep prescriptions, as compared with individuals that remained on AP. Conclusion: Youth within the foster care system receive antipsychotics at high rates and in an uneven distribution. Prescribing practices can change in the context of supportive oversight programs without components such as prior authorization, and without increasing the need for higher levels of care. Specific emphasis on the treatment of mood, anxiety, and sleep issues may also lead to greater success in discontinuing AP treatment. Oversight may support treatment providers while reducing exposure to medications with considerable side effect burden that could cause future comorbidity.

Association of Early Beta-Blocker Exposure and Functional Outcomes in Critically Ill Patients With Moderate to Severe Traumatic Brain Injury: A Transforming Clinical Research and Knowledge in Traumatic Brain Injury Study.

OBJECTIVES: We aimed to 1) describe patterns of beta-blocker utilization among critically ill patients following moderate-severe traumatic brain injury (TBI) and 2) examine the association of early beta-blocker exposure with functional and clinical outcomes following injury. DESIGN: Retrospective cohort study. SETTING: ICUs at 18 level I, U.S. trauma centers in the Transforming Clinical Research and Knowledge in TBI (TRACK-TBI) study. PATIENTS: Greater than or equal to 17 years enrolled in the TRACK-TBI study with moderate-severe TBI (Glasgow Coma Scale of <13) were admitted to the ICU after a blunt TBI. INTERVENTIONS: None. MEASUREMENTS: Primary exposure was a beta blocker during the first 7 days in the ICU, with a primary outcome of 6-month Glasgow Outcome Scale-Extended (GOSE). Secondary outcomes included: length of hospital stay, in-hospital mortality, 6-month and 12-month mortality, 12-month GOSE score, and 6-month and 12-month measures of disability, well-being, quality of life, and life satisfaction. MAIN RESULTS: Of the 450 eligible participants, 57 (13%) received early beta blockers (BB+ group). The BB+ group was on average older, more likely to be on a preinjury beta blocker, and more likely to have a history of hypertension. In the BB+ group, 34 participants (60%) received metoprolol only, 19 participants (33%) received propranolol only, 3 participants (5%) received both, and 1 participant (2%) received atenolol only. In multivariable regression, there was no difference in the odds of a higher GOSE score at 6 months between the BB+ group and BB- group (odds ratio = 0.86; 95% CI, 0.48-1.53). There was no association between BB exposure and secondary outcomes. CONCLUSIONS: About one-sixth of subjects in our study received early beta blockers, and within this group, dose, and timing of beta-blocker administration varied substantially. No significant differences in GOSE score at 6 months were demonstrated, although our ability to draw conclusions is limited by overall low total doses administered compared with prior studies.

GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.

OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. CONCLUSIONS: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.

Assessing and Responding to the Trauma of Child Maltreatment.

Child maltreatment is a significant risk factor for severe psychiatric outcomes in childhood and contributes to problematic symptoms that direct parents, teachers, or other invested parties to seek psychiatric intervention. With ongoing workforce shortages, much of the pediatric psychiatric care to this population is delivered by generalists. Child maltreatment and trauma can critically alter a child's development trajectory, affecting potential success in school and other important life pursuits. In addition, child maltreatment and resultant traumatic stress can dramatically disrupt child and adolescent development of healthy emotional regulation, distress tolerance, and the ability to form effective interpersonal relationships. Such disruption can lead to presentations within children and adolescents that mimic other symptoms of psychopathology but that typically respond poorly to traditional psychopharmacology. Ineffective treatment trials can lead to increased risk of polypharmacy and inaccurate expectations for treatment benefits. Such treatment efforts may impede addressing important environmental contributors and delay indicated therapeutic strategies. This article seeks to review child maltreatment-including core features and prevalence, overlap of child maltreatment with adverse childhood experiences, developmental impacts of exposure and resultant traumatic stress, guidance for appropriate assessment, and evidence-based interventions-and provide basic deprescribing guidelines to reduce polypharmacy burden.

Suicide and Psychosis: Results From a Population-Based Cohort of Suicide Death (N = 4380).

Approximately 5% of individuals with schizophrenia die from suicide. However, suicide in psychosis is still poorly characterized, partly due to a lack of adequate population-based clinical or genetic data on suicide death. The Utah Suicide Genetics Research Study (USGRS) provides a large population-based cohort of suicide deaths with medical record and genome-wide data (N = 4380). Examination of this cohort identified medical and genetic risks associated with type of suicide death and investigated the relative contributions of psychotic and affective symptoms to method of suicide. Key differences in method of suicide (common vs. atypical methods) were tested in relation to lifetime psychosis and genome-wide genetic risk for schizophrenia, major depressive disorder, and neuroticism. Consistent with previous studies, psychosis-spectrum disorders were observed to be common in suicide (15% of the cohort). Individuals with psychosis more frequently died from atypical methods, with rates of atypical suicide increasing across the schizophrenia spectrum. Genetic risk for schizophrenia was also associated with atypical suicide, regardless of clinical diagnosis, though this association weakened when filtering individuals with schizophrenia from the analysis. Follow-up examination indicated that high rates of atypical suicide observed in schizophrenia are not likely accounted for by restricted access to firearms. Overall, better accounting for the increased risk of atypical suicide methods in psychosis could lead to improved prevention strategies in a large portion of the suicide risk population.

Assessment of suicide attempt and death in bipolar affective disorder: a combined clinical and genetic approach.

Bipolar disorder (BP) suicide death rates are 10-30 times greater than the general population, likely arising from environmental and genetic risk factors. Though suicidal behavior in BP has been investigated, studies have not addressed combined clinical and genetic factors specific to suicide death. To address this gap, a large, harmonized BP cohort was assessed to identify clinical risk factors for suicide death and attempt which then directed testing of underlying polygenic risks. 5901 individuals of European ancestry were assessed: 353 individuals with BP and 2498 without BP who died from suicide (BPS and NBPS, respectively) from a population-derived sample along with a volunteer-derived sample of 799 individuals with BP and a history of suicide attempt (BPSA), 824 individuals with BP and no prior attempts (BPNSA), and 1427 individuals without several common psychiatric illnesses per self-report (C). Clinical and subsequent directed genetic analyses utilized multivariable logistic models accounting for critical covariates and multiple testing. There was overrepresentation of diagnosis of PTSD (OR = 4.9, 95%CI: 3.1-7.6) in BPS versus BPSA, driven by female subjects. PRS assessments showed elevations in BPS including PTSD (OR = 1.3, 95%CI:1.1-1.5, versus C), female-derived ADHD (OR = 1.2, 95%CI:1.1-1.4, versus C), and male insomnia (OR = 1.4, 95%CI: 1.1-1.7, versus BPSA). The results provide support from genetic and clinical standpoints for dysregulated traumatic response particularly increasing risk of suicide death among individuals with BP of Northern European ancestry. Such findings may direct more aggressive treatment and prevention of trauma sequelae within at-risk bipolar individuals.