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.

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.

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.

Identifying Occupation Groups for Suicide Prevention: A Statewide Data Linkage Study.

OBJECTIVE: To identify suicide rates by occupation category in Utah and describe the hospital history and circumstances of suicide decedents in the occupation category that had the state's highest rate and highest number of suicides: Construction and Extraction. METHOD: We used data on suicide decedents from the National Violent Death Reporting System (NVDRS) for 2005-2015 (n = 4,590) to calculate sex- and occupation-specific suicide rates among adults 18-65 years old in Utah. For working-age men who died by suicide during the years 2014-2015 (n = 623), we linked NVDRS data with decedents' hospital histories. RESULTS: One in five working-age men who took their life in Utah worked in Construction and Extraction, the single Bureau of Labor Statistics occupation category with both the highest number (n = 719) and rate of suicides (86.4/100,000 men vs. a range of 15.3-66.2 for other occupations). For females, there was no occupation group that had both high rates of suicide and high numbers of suicides compared with other occupations, so there was no clear occupation group to focus on in the same way there was for men. Using linked data for 2014-2015 deaths, 58% of men in Construction and Extraction who died by suicide had been diagnosed in the hospital in the past three years with a substance abuse or mental health problem, and a quarter (25%) tested positive for opioids on post-mortem examination. Nearly half (48%) of 2014-2015 male suicide decedents in Construction and Extraction were reported to have intimate partner problems, about a quarter (26%) had a criminal problem, a quarter (25%) were unemployed, and over half (54%) died by gunshot. CONCLUSIONS: Linked data identified Construction and Extraction as a potentially high-impact occupation group for suicide prevention and suggested potential contexts for intervention.HIGHLIGHTSConstruction and Extraction stands out as an occupation group with a very high number and rate of suicides.Two-thirds of male decedents in Construction and Extraction had a substance abuse problem.For Utah females, there were no occupations with both high rates and high numbers of suicides.

Linking Public Safety And Public Health Data For Firearm Suicide Prevention In Utah.

In Utah, a state with a high rate of gun ownership, the shared concerns of diverse stakeholders generated bipartisan support for a state-funded study that tracked patterns of firearm suicide. The study linked sensitive public health and public safety data and identified opportunities for firearm suicide prevention. Findings reported to the state legislature included the proportion of suicide decedents who could have passed a background check for legal firearm possession at their time of death, had a permit to carry a concealed firearm, or had been seen in the hospital for a previous suicide attempt or self-harm. Within six months of the report's release, the legislature, health care and religious groups, and state agencies had launched diverse, major initiatives to reduce firearm suicide that were informed by the report's findings. We present the Utah experience as a case study in bringing diverse stakeholders-particularly gun owners-together to find common ground on firearm suicide prevention and in using linked data to support and guide their efforts.