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.

Screening for symptoms of childhood traumatic stress in the primary care pediatric clinic.

BACKGROUND: Childhood traumatic experiences may result in post-traumatic stress disorder. Although pediatricians are encouraged to address these traumas in clinical encounters, measures of childhood traumatic stress have not been adopted by primary care clinicians. In this study, we describe the feasibility and potential utility of the UCLA Brief Screen, a validated screener for childhood traumatic stress symptoms, in pediatric primary care clinics. METHODS: Children 6-17 years of age presenting for routine well-child care in community-based pediatric clinics were eligible for traumatic stress screening. We described the feasibility and acceptability of screening based on screener adoption by eligible pediatric clinicians. We assessed the potential utility of screening based on prevalence and distribution of potentially traumatic events and traumatic stress symptoms in this general pediatric population. Finally, we compared results of the UCLA Brief Screen with those of the Patient Health Questionnaire-A to evaluate associations between symptoms of traumatic stress, depression, and suicidality among adolescents in this community setting. RESULTS: 14/18 (77.8%) pediatric clinicians in two clinics offered an adapted UCLA Brief Screen during 2359/4959 (47.6%) eligible well-child checks over 14 months. 1472/2359 (62.4%) of offered screeners were completed, returned, and scored. One-third (32.5%) of completed screeners captured a potentially traumatic event experience described by either children or caregivers. Moderate to severe traumatic stress symptoms were identified in 10.7% and 5.2% of patients, respectively. Concurrent depression screening revealed that 68.3% of adolescents with depressive symptoms reported a potentially traumatic event (PTE) and 80.5% had concurrent traumatic stress symptoms. Adolescents reporting a PTE were 3.5 times more likely to report thoughts of suicide or self-harm than those without this history. CONCLUSIONS: Results from this pilot study suggest that traumatic stress screening in the pediatric primary care setting may be feasible and may identify and classify mental health symptoms missed with current screening practices for depression. The prevalence of PTEs and traumatic stress symptoms associated with PTEs support the potential utility of a standardized screening in early identification of and response to children with clinically important symptoms of childhood traumatic stress. Future research should evaluate meaningful clinical outcomes associated with traumatic stress screening.

A population-wide analysis of the familial risk of suicide in Utah, USA.

BACKGROUND: The degree to which suicide risk aggregates in US families is unknown. The authors aimed to determine the familial risk of suicide in Utah, and tested whether familial risk varies based on the characteristics of the suicides and their relatives. METHODS: A population-based sample of 12 160 suicides from 1904 to 2014 were identified from the Utah Population Database and matched 1:5 to controls based on sex and age using at-risk sampling. All first through third- and fifth-degree relatives of suicide probands and controls were identified (N = 13 480 122). The familial risk of suicide was estimated based on hazard ratios (HR) from an unsupervised Cox regression model in a unified framework. Moderation by sex of the proband or relative and age of the proband at time of suicide (<25 v. ⩾25 years) was examined. RESULTS: Significantly elevated HRs were observed in first- (HR 3.45; 95% CI 3.12-3.82) through fifth-degree relatives (HR 1.07; 95% CI 1.02-1.12) of suicide probands. Among first-degree relatives of female suicide probands, the HR of suicide was 6.99 (95% CI 3.99-12.25) in mothers, 6.39 in sisters (95% CI 3.78-10.82), and 5.65 (95% CI 3.38-9.44) in daughters. The HR in first-degree relatives of suicide probands under 25 years at death was 4.29 (95% CI 3.49-5.26). CONCLUSIONS: Elevated familial suicide risk in relatives of female and younger suicide probands suggests that there are unique risk groups to which prevention efforts should be directed - namely suicidal young adults and women with a strong family history of 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.

Neurexin 1 variants as risk factors for suicide death.

Suicide is a significant public health concern with complex etiology. Although the genetic component of suicide is well established, the scope of gene networks and biological mechanisms underlying suicide has yet to be defined. Previously, we reported genome-wide evidence that neurexin 1 (NRXN1), a key synapse organizing molecule, is associated with familial suicide risk. Here we present new evidence for two non-synonymous variants (rs78540316; P469S and rs199784139; H885Y) associated with increased familial risk of suicide death. We tested the impact of these variants on binding interactions with known partners and assessed functionality in a hemi-synapse formation assay. Although the formation of hemi-synapses was not altered with the P469S variant relative to wild-type, both variants increased binding to the postsynaptic binding partner, leucine-rich repeat transmembrane neuronal 2 (LRRTM2) in vitro. Our findings indicate that variants in NRXN1 and related synaptic genes warrant further study as risk factors for suicide death.

Implementation of A Care Process Model for Pediatric Traumatic Stress in Child Advocacy Centers: A Mixed Methods Study.

Child Advocacy Centers (CACs) are well-positioned to identify children with mental health needs and facilitate access to evidence-based treatment. However, use of evidence-based screening tools and referral protocols varies across CACs. Understanding barriers and facilitators can inform efforts to implement mental health screening and referral protocols in CACs. We describe statewide efforts implementing a standardized screening and referral protocol, the Care Process Model for Pediatric Traumatic Stress (CPM-PTS), in CACs. Twenty-three CACs were invited to implement the CPM-PTS. We used mixed methods to evaluate the first two years of implementation. We quantitatively assessed adoption, reach, and acceptability; qualitatively assessed facilitators and barriers; and integrated quantitative and qualitative data to understand implementation of mental health screening in CACs. Eighteen CACs adopted the CPM-PTS. Across CACs, screening rates ranged from 10% to 100%. Caregiver ratings indicated high acceptability. Facilitators and barriers were identified within domains of the Consolidated Framework for Implementation Research. Qualitative findings provided insight into adoption, reach, and caregivers' responses. Our findings suggest screening for traumatic stress and suicidality in CACs is valued, acceptable, and feasible. Implementation of mental health screening and referral protocols in CACs may improve identification of children with mental health needs and support treatment engagement.

A Scoping Review and Content Analysis of Common Depressive Symptoms of Young People.

School nurses are the most accessible health care providers for many young people including adolescents and young adults. Early identification of depression results in improved outcomes, but little information is available comprehensively describing depressive symptoms specific to this population. The aim of this study was to develop a taxonomy of depressive symptoms that were manifested and described by young people based on a scoping review and content analysis. Twenty-five journal articles that included narrative descriptions of depressive symptoms in young people were included. A total of 60 depressive symptoms were identified and categorized into five dimensions: behavioral (n = 8), cognitive (n = 14), emotional (n = 15), interpersonal (n = 13), and somatic (n = 10). This comprehensive depression symptom taxonomy can help school nurses to identify young people who may experience depression and will support future research to better screen for depression.

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.

Ethical and public health implications of genetic testing for suicide risk: family and survivor perspectives.

PURPOSE: Death from suicide has an estimated heritability of ~50%. Research may soon allow calculation of polygenic risk scores (PRS) for suicide death, which could be marketed directly to consumers. This raises ethical concerns. Understanding how consumers will utilize this information is urgent. METHODS: We conducted three focus groups involving suicide attempt survivors ("survivors") and family members of suicide decedents ("family members") to gauge their reactions to this technology. Questions focused on positive and negative implications of PRS results. Qualitative research methods were used to summarize studio results. RESULTS: Eight survivors and 13 family members participated. Both groups postulated benefits of suicide PRS, including prevention and reduced stigma. Their concerns ranged from increased stigma to adverse psychological effects. They suggested that suicide PRS should be accompanied by extensive education and counseling. Participants experienced no adverse effects. CONCLUSION: Many ethical, legal, and social implications of genetic testing for suicide risk are highly salient to community stakeholders. Our participants hoped that suicide PRS could have significant individual and community-level benefits, but had concerns about effects in several domains, including stigma, access to insurance and employment, and increased anxiety and depression.

Genome-wide significant regions in 43 Utah high-risk families implicate multiple genes involved in risk for completed suicide.

Suicide is the 10th leading cause of death in the United States. Although environment has undeniable impact, evidence suggests that genetic factors play a significant role in completed suicide. We linked a resource of ~ 4500 DNA samples from completed suicides obtained from the Utah Medical Examiner to genealogical records and medical records data available on over eight million individuals. This linking has resulted in the identification of high-risk extended families (7-9 generations) with significant familial risk of completed suicide. Familial aggregation across distant relatives minimizes effects of shared environment, provides more genetically homogeneous risk groups, and magnifies genetic risks through familial repetition. We analyzed Illumina PsychArray genotypes from suicide cases in 43 high-risk families, identifying 30 distinct shared genomic segments with genome-wide evidence (p = 2.02E-07-1.30E-18) of segregation with completed suicide. The 207 genes implicated by the shared regions provide a focused set of genes for further study; 18 have been previously associated with suicide risk. Although PsychArray variants do not represent exhaustive variation within the 207 genes, we investigated these for specific segregation within the high-risk families, and for association of variants with predicted functional impact in ~ 1300 additional Utah suicides unrelated to the discovery families. None of the limited PsychArray variants explained the high-risk family segregation; sequencing of these regions will be needed to discover segregating risk variants, which may be rarer or regulatory. However, additional association tests yielded four significant PsychArray variants (SP110, rs181058279; AGBL2, rs76215382; SUCLA2, rs121908538; APH1B, rs745918508), raising the likelihood that these genes confer risk of completed suicide.

Ethical concerns relating to genetic risk scores for suicide.

Genome-wide association studies (GWAS) provide valuable information in research contexts regarding genomic changes that contribute to risks for complex psychiatric conditions like major depressive disorder. GWAS results can be used to calculate polygenic risk scores (PRS) for psychiatric conditions, such as bipolar disorder or schizophrenia, as well as for other traits, such as obesity or hypertension. Private companies that provide direct-to-consumer (DTC) genetic testing sometimes report PRS for a variety of traits. Recently, the first well-powered GWAS study for suicide death was published. PRS reports that claim to assess suicide risk are therefore likely to appear soon in the DTC setting. We describe ethical concerns regarding the commercial use of GWAS results related to suicide. We identify several issues that must be addressed before PRS for suicide risk is made available to the public through DTC: (a) the potential for misinterpretation of results, (b) consumers' perceptions about determinism and behavior change, (c) potential contributions to stigma, discrimination, and health disparities; and (d) ethical problems regarding the testing of children and vulnerable adults. Tests for genetic prediction of suicidality may eventually have clinical significance, but until then, the potential for individual and public harm significantly outweighs any potential benefit. Even if genetic prediction of suicidality improves significantly, information about genetic risk scores must be distributed cautiously, with genetic counseling, and with adequate safeguards.

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.

Screening for Trauma in Pediatric Primary Care.

PURPOSE OF REVIEW: Provided the high prevalence of trauma exposure in childhood as well as the risk for morbidity, this article examines evidence, a recommended approach, and key implementation factors relevant to screening for trauma in pediatric primary care. RECENT FINDINGS: A standardized approach to trauma screening is possible, but previous attempts have relied heavily upon exposure screening and failed to guide an individualized response specific to the impact of trauma on the child and family. Trauma screening tools for pediatric primary care should be brief and inform the care response based on screening for trauma exposure, traumatic stress symptoms, functional impact, and suicidality. Clinicians should use trauma screening to (1) identify if the child has any ongoing risk of harm and report where required; (2) determine risk of suicidality and respond appropriately; (3) assess need for evidence-based trauma treatment based on symptoms and functional impact; and (4) provide a skill or guidance targeting the most severe or pressing traumatic stress symptoms.

Suicidality in psychiatrically hospitalized children and adolescents: Demographics, treatment, and outcome.

BACKGROUND: Despite the high prevalence of suicidality in psychiatrically hospitalized youth, its risk factors and impact on inpatient psychopharmacologic treatment are unknown. We identified characteristics associated with suicidality in psychiatrically hospitalized youth and determined the association of suicidality with subsequent psychopharmacologic interventions. METHODS: Medical records from consecutive psychiatric admissions to a large, acute care, urban, pediatric hospital were analyzed retrospectively (N = 1,309). Demographic, clinical, and treatment-related features of suicidal and nonsuicidal youth were characterized. Logistic regression identified predictors of suicidality, and multiple comparison analyses evaluated the association between suicidality and changes to antidepressant prescribing during inpatient course. RESULTS: Compared with nonsuicidal patients, inpatients who were suicidal were more likely to have a mood disorder or posttraumatic stress disorder, as well as Cannabis and alcohol use, were more commonly girls, and at least 13 years of age (all P ≤ .05). Hospitalization was shorter for suicidal patients, was more likely to be associated with antidepressant treatment (P ≤ .001), and among suicidal patients prescribed antidepressants at the time of admission, was associated with a greater likelihood of changing antidepressant treatment compared with nonsuicidal inpatients (P ≤ .05). CONCLUSIONS: These findings reveal differences between suicidal and nonsuicidal psychiatrically hospitalized youth and suggest that suicidality is associated with specific pharmacologic treatment approaches within this population.

Efficacy and tolerability of antidepressants in pediatric anxiety disorders: a systematic review and meta-analysis.

BACKGROUND: Randomized controlled trials have demonstrated that antidepressants are efficacious in the treatment of anxiety disorders in youth. However, there are no recent, systematic analyses of the efficacy, safety, or tolerability of these medications in pediatric anxiety disorders. METHODS: A systematic review and meta-analysis of prospective, randomized, parallel-group, controlled trials of selective serotonin reuptake inhibitors (SSRIs) and selective serotonin-norepinephrine reuptake inhibitors (SSNRIs) in pediatric patients with non-obsessive compulsive disorder (OCD) anxiety disorders was undertaken using a search of PubMed/Medline (1966-2014). The meta-analysis utilized random-effects models to evaluate change in the Pediatric Anxiety Rating Scale or similar anxiety scale, suicidality, and adverse events. Additionally, pharmacologic variables were explored with regard to effect size, although no correction for multiple comparisons was made with regard to these relationships. RESULTS: Nine trials involving 1,673 patients and six medications were included. All SSRI/SSNRIs evaluated demonstrated efficacy, and the meta-analytic estimate of effect was of moderate magnitude (Cohen's d = 0.62, confidence interval [CI]: 0.34-0.89, P = .009) and there was evidence of modest heterogeneity (I(2) = 0.29, P = .103). Activation trended toward being more likely with antidepressant treatment (OR: 1.86, CI: 0.98-3.53, P = .054), but no increased risk was observed for nausea/abdominal symptoms (P = .262), discontinuation as a result of an adverse event (P = .132), or suicidality (OR: 1.3, CI: 0.53-3.2, P = .514). Finally, the effect size correlated with the serotonergic specificity of the agent (R = .79, P = .021). CONCLUSIONS: Data for nine SSRI/SSNRIs suggest superiority of antidepressants relative to placebo for the treatment of pediatric anxiety disorders with a moderate effect size.

Utility of head computed tomography in children with a single extremity fracture.

OBJECTIVES: To determine the clinical and forensic utility of head computed tomography (CT) in children younger than 2 years of age with an acute isolated extremity fracture and an otherwise-negative skeletal survey. STUDY DESIGN: Retrospective chart review of children younger than 2 years of age who obtained a skeletal survey in the Cincinnati Children's Hospital Medical Center Emergency Department during the 159-month study period. Clinically important head injury was determined based on previously defined Pediatric Emergency Care Applied Research Network criteria. Forensically significant head injury was defined as that which increased the concern for inflicted injury. The rate of head CT relative to patient age and location of fracture (proximal vs distal extremity, upper vs. lower extremity) was determined via χ2 tests. RESULTS: Of the 320 children evaluated, 37% received neuroimaging, 95.7% of which had no signs of skull fracture or intracranial trauma. Five children (4.3%) with head imaging had traumatic findings but no children in the study had clinically significant head injury. Three of these children had previous concerns for nonaccidental trauma and findings on head CT that were forensically significant. There was a greater rate of head imaging in children in the younger age groups and those with proximal extremity fractures (P < .05). CONCLUSIONS: In young children who present with an isolated extremity fracture, clinicians should consider obtaining head CT in those who are younger than 12 months of age, have proximal extremity fractures, or who have previous evaluations for nonaccidental trauma. Evaluation with head CT in children without these risk factors may be low yield.

Cortisol awakening response in adolescents with acute sexual abuse related posttraumatic stress disorder.

BACKGROUND: Little is known regarding changes in the hypothalamic-pituitary-adrenal axis (HPA axis) of adolescent girls with and without posttraumatic stress disorder (PTSD) who have recently experienced sexual abuse. Therefore, in this pilot study, we utilized non-stressed home saliva collection three times a day for three days to assess the levels, diurnal variation and awakening response of cortisol in recently sexually abused adolescent girls. METHODS: Twenty-four adolescent girls (mean age: 15 ± 1.5 years) with a history of recent sexual abuse (sexual abuse occurred 1-6 months prior to study enrollment) and 12 healthy, nontraumatized comparison subjects (mean age: 14.8 ± 1.3 years) collected saliva at home upon awakening, 30 min after waking, and in the late afternoon on three consecutive school days. RESULTS: Among sexually abused girls, flattening of the morning cortisol awakening response was associated with PTSD severity (r = -.41, P < .05) as well as intrusive symptoms (r = -.42, P < .05). Increased adversity prior to sexual abuse was also associated with flattening of the cortisol awakening response (r = -.53, P < .01). CONCLUSIONS: Attenuation of the cortisol awakening response in recently sexually abused girls suggests that alterations in HPA-axis functioning may occur relatively proximate to the traumatic event and correlate with symptom severity of PTSD, intrusive symptoms, and hyperarousal symptoms. These data raise the possibility that subacute alterations in the dynamic secretion of cortisol are directly related to the pathophysiology of sexual abuse-related PTSD symptoms in adolescent girls.

Utilizing screening as a trauma-responsive approach in pediatric health care settings.

Given the widespread impact of child trauma, it is important that child- and family-serving systems adopt trauma-informed care. Because of their integral relationships with families, pediatricians and family medicine physicians play critical roles in disrupting negative societal and developmental cascades for trauma-exposed youth through their potential for early identification and intervention. When implemented alongside organization-wide trauma-informed care practices, trauma screening is one concrete trauma-informed care practice that has shown both feasibility and positive impacts on pediatric healthcare. In support of this practice, the Care Process Model for Pediatric Traumatic Stress (CPM-PTS) helps pediatric care providers to identify and respond to children and adolescents who may need trauma-focused supports. In this paper we discuss the importance of pediatric physicians adopting trauma-informed care and how evidence-based screening practices in pediatric settings is a trauma-responsive approach with great potential for meeting unmet needs among trauma-exposed children and families.