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.

Community testing practices for autism within the autism and developmental disabilities monitoring network.

BACKGROUND: No data exist at the population level on what tests are used to aid in the diagnosis of autism spectrum disorder in community practice. OBJECTIVES: To describe autism spectrum disorder testing practices to inform autism spectrum disorder identification efforts. METHODS: Data are from the Autism and Developmental Disabilities Monitoring Network, a multi-site surveillance system reporting prevalence estimates and characteristics of 8-year-old children with autism spectrum disorder. Percentages of children with autism spectrum disorder who received any autism spectrum disorder test or a 'gold standard' test were calculated by site, sex, race, median household income, and intellectual ability status. Risk ratios were calculated to compare group differences. RESULTS: Of 5058 8-year-old children with autism spectrum disorder across 11 sites, 3236 (64.0%) had a record of any autism spectrum disorder test and 2136 (42.2%) had a 'gold standard' ADOS or ADI-R test. Overall, 115 children (2.3%) had both the ADOS and ADI-R in their records. Differences persisted across race, median household income, and intellectual ability status. Asian/Pacific Islander children had the highest percent receiving any ASD test (71.8%; other groups range: 57.4-66.0%) and White children had the highest percent receiving 'gold standard' tests (46.4%; other groups range: 35.6-43.2%). Children in low-income neighbourhoods had a lower percent of any test (62.5%) and 'gold standard' tests (39.4%) compared to medium (70.2% and 47.5%, respectively) and high (69.6% and 46.8%, respectively) income neighbourhoods. Children with intellectual disability had a lower percent of any ASD test (81.7%) and 'gold standard' tests (52.6%) compared to children without intellectual disability (84.0% and 57.6%, respectively). CONCLUSIONS: Autism spectrum disorder testing practices vary widely by site and differ by race and presence of co-occurring intellectual disability, suggesting opportunities to standardise and/or improve autism spectrum disorder identification practices.

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.

Trimester-specific ambient PM2.5 exposures and risk of intellectual disability in Utah.

Prenatal fine particulate matter (PM2.5) exposure is an understudied risk factor for neurodevelopmental outcomes, including intellectual disability (ID). Associations among prenatal exposures and neurodevelopmental outcomes may vary depending on the timing of exposure. Limited numbers of studies examining PM2.5 and neurodevelopmental outcomes have considered exposures occurring during the preconception period. To address these gaps, we conducted a case-control study of children born in Utah between 2002 and 2008 (n = 1032). Cases were identified using methods developed by the Centers for Disease Control and Prevention's Autism and Developmental Disabilities Monitoring Network and matched with controls on birth year, sex, and birth county. We estimated the daily average PM2.5 concentration during a period spanning 12 weeks before the estimated conception date, as well as during each of the three trimesters at the maternal residential address listed on the child's birth certificate. In a multivariable model, the third (OR: 2.119, CI: 1.123-3.998, p = .021) and fourth (OR: 2.631, CI: 1.750-3.956, p < .001) quartiles for preconception average PM2.5 demonstrated significantly increased risk of ID relative to the first quartile. Second quartile preconception exposure was also associated with increased risk, though it did not reach significance (OR: 1.385, CI: 0.979-1.959, p = .07). The fourth quartile of first trimester average PM2.5 was positive and significant (OR: 2.278, CI: 1.522-3.411, p < .001); the third quartile was positive, but not significant (OR: 1.159, CI: 0.870-1.544, p = .312). Quartiles of second and third trimester were not associated with higher risk of ID. These findings from Utah, which were robust to a variety of sensitivity analyses, provide initial evidence that preconception and prenatal PM2.5 exposure may be associated with ID. Future studies are needed across other geographic locations and populations.

Evidence of transgenerational effects on autism spectrum disorder using multigenerational space-time cluster detection.

BACKGROUND: Transgenerational epigenetic risks associated with complex health outcomes, such as autism spectrum disorder (ASD), have attracted increasing attention. Transgenerational environmental risk exposures with potential for epigenetic effects can be effectively identified using space-time clustering. Specifically applied to ancestors of individuals with disease outcomes, space-time clustering characterized for vulnerable developmental stages of growth can provide a measure of relative risk for disease outcomes in descendants. OBJECTIVES: (1) Identify space-time clusters of ancestors with a descendent with a clinical ASD diagnosis and matched controls. (2) Identify developmental windows of ancestors with the highest relative risk for ASD in descendants. (3) Identify how the relative risk may vary through the maternal or paternal line. METHODS: Family pedigrees linked to residential locations of ASD cases in Utah have been used to identify space-time clusters of ancestors. Control family pedigrees of none-cases based on age and sex have been matched to cases 2:1. The data have been categorized by maternal or paternal lineage at birth, childhood, and adolescence. A total of 3957 children, both parents, and maternal and paternal grandparents were identified. Bernoulli space-time binomial relative risk (RR) scan statistic was used to identify clusters. Monte Carlo simulation was used for statistical significance testing. RESULTS: Twenty statistically significant clusters were identified. Thirteen increased RR (> 1.0) space-time clusters were identified from the maternal and paternal lines at a p-value < 0.05. The paternal grandparents carry the greatest RR (2.86-2.96) during birth and childhood in the 1950's-1960, which represent the smallest size clusters, and occur in urban areas. Additionally, seven statistically significant clusters with RR < 1 were relatively large in area, covering more rural areas of the state. CONCLUSION: This study has identified statistically significant space-time clusters during critical developmental windows that are associated with ASD risk in descendants. The geographic space and time clusters family pedigrees with over 3 + generations, which we refer to as a person's geographic legacy, is a powerful tool for studying transgenerational effects that may be epigenetic in nature. Our novel use of space-time clustering can be applied to any disease where family pedigree data is available.

Genetics and epigenetics of self-injurious thoughts and behaviors: Systematic review of the suicide literature and methodological considerations.

Suicide is a multifaceted and poorly understood clinical outcome, and there is an urgent need to advance research on its phenomenology and etiology. Epidemiological studies have demonstrated that suicidal behavior is heritable, suggesting that genetic and epigenetic information may serve as biomarkers for suicide risk. Here we systematically review the literature on genetic and epigenetic alterations observed in phenotypes across the full range of self-injurious thoughts and behaviors (SITB). We included 577 studies focused on genome-wide and epigenome-wide associations, candidate genes (SNP and methylation), noncoding RNAs, and histones. Convergence of specific genes is limited across units of analysis, although pathway-based analyses do indicate nervous system development and function and immunity/inflammation as potential underlying mechanisms of SITB. We provide suggestions for future work on the genetic and epigenetic correlates of SITB with a specific focus on measurement issues.

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.

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.

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.

Altitude and risk of depression and anxiety: findings from the intern health study.

Multiple studies suggest that the risks of depression and suicide increase with increasing altitude of residence, but no studies have assessed whether changing altitude changes these risks. To address this gap, this study used data from the Intern Health Study, which follows students from the end of medical school through the first year of residency, recording depression via the 9-item Patient Health Questionnaire (PHQ-9), anxiety via the 7-item Generalized Anxiety Disorder Questionnaire (GAD-7), and multiple risk factors for these symptoms. Data from 3764 medical students representing 46 schools and 282 residencies were available. Odds ratios (OR) representing the effects of altitude on psychiatric symptoms were estimated using generalized linear models. After excluding participants with missing altitude data, 3731 medical students were analyzed. High altitude residence (> 900 m) was significantly associated with PHQ-9 total score (OR = 1.32, 95% CI = 1.001-1.75, p < 0.05), and PHQ-9 suicidal ideation (OR = 1.79, 95% CI = 1.08-0.02, p = 0.02). Moving from low to high altitude was significantly associated with PHQ-9 total score (OR = 1.47, 95% CI = 1.087-1.98, p = 0.01), GAD-7 total score (OR = 1.40, 95% CI = 1.0040-1.95, p < 0.05), and PHQ-9 suicidal ideation (OR = 1.10, 95% CI = 1.01-1.19, p = 0.02). The data suggest that moving from low to high altitude is associated with increasing symptoms of depression, anxiety, and suicidal ideation.

CYP2A6 Longitudinal Effects in Young Smokers.

INTRODUCTION: The present study sought to identify time-dependent within-participant effects of CYP2A6 genotypes on smoking frequency and nicotine dependence in young smokers. METHODS: Predicted nicotine metabolic rate based on CYP2A6 diplotypes (CYP2A6 diplotype predicted rate [CDPR]) was partitioned into Normal, Intermediate, and Slow categories using a metabolism metric. Growth-curve models characterized baseline and longitudinal CDPR effects with data from eight longitudinal assessments during a 6-year period (from approximately age 16-22) in young smokers of European descent (N = 296, 57% female) who had smoked less than 100 cigarettes lifetime at baseline and more than that amount by Year 6. Phenotypes were number of days smoked during the previous 30 days and a youth version of the Nicotine Dependence Syndrome Scale (NDSS). A zero-inflated Poisson growth-curve model was used to account for the preponderance of zero days smoked. RESULTS: At baseline, Intermediate CDPR was a risk factor relative to both Normal and Slow CDPR for smoking frequency and the NDSS. Slow CDPR was associated with the highest probability of smoking discontinuation at baseline. However, due to CDPR time trend differences, by young adulthood these baseline effects had been reordered such that the greatest risks for smoking frequency and the NDSS were associated with Normal CDPR. CONCLUSIONS: Reduced metabolism CYP2A6 genotypes are associated with both risk and protective effects in novice smokers. However, differences in the time-by-CDPR effects result in a reordering of genotype effects such that normal metabolism becomes the risk variant by young adulthood, as has been reliably reported in older smokers.

Male suspected suicide decedents in Utah: A comparison of Veterans and nonveterans.

UNLABELLED: There has been significant debate regarding suicide risk in Veterans compared to nonveterans. However, few studies have examined similarities and differences between Veteran and nonveteran suicide decedents using a combination of next of kin psychological autopsy and data from a state Office of the Medical Examiner (OME). For the current study, next of kin of a one-year cohort of male suspected suicide decedents in Utah completed psychological autopsy interviews with trained research staff. Next of kin of 70 Veterans and 356 nonveterans completed the interviews, which included demographic, behavioral, psychosocial, and clinical variables. The psychological autopsy data then were combined with OME data for the presented analyses. Results showed that Veteran and nonveteran suicide decedents differed on multiple factors, including age at death. Specifically, male nonveteran suicide decedents were younger at age of death compared to Utah Veterans and to a national sample. Veteran decedents also were more likely to have a history of suicide attempts and more likely to have access to firearms compared to nonveterans. Other between-group differences, including Veterans being more likely to have lived alone and method of death (e.g., gunshot, hanging, etc.), were no longer statistically significant after adjustment for age at death. CONCLUSIONS: these findings have significant clinical and practical importance, as they highlight the risk for suicide in younger nonveterans and older Veterans in Utah.

Autism spectrum disorder prevalence and associations with air concentrations of lead, mercury, and arsenic.

Lead, mercury, and arsenic are neurotoxicants with known effects on neurodevelopment. Autism spectrum disorder (ASD) is a neurodevelopmental disorder apparent by early childhood. Using data on 4486 children with ASD residing in 2489 census tracts in five sites of the Centers for Disease Control and Prevention's Autism and Developmental Disabilities Monitoring (ADDM) Network, we used multi-level negative binomial models to investigate if ambient lead, mercury, and arsenic concentrations, as measured by the US Environmental Protection Agency National-Scale Air Toxics Assessment (EPA-NATA), were associated with ASD prevalence. In unadjusted analyses, ambient metal concentrations were negatively associated with ASD prevalence. After adjusting for confounding factors, tracts with air concentrations of lead in the highest quartile had significantly higher ASD prevalence than tracts with lead concentrations in the lowest quartile (prevalence ratio (PR) = 1.36; 95 '% CI: 1.18, 1.57). In addition, tracts with mercury concentrations above the 75th percentile (>1.7 ng/m(3)) and arsenic concentrations below the 75th percentile (≤0.13 ng/m(3)) had a significantly higher ASD prevalence (adjusted RR = 1.20; 95 % CI: 1.03, 1.40) compared to tracts with arsenic, lead, and mercury concentrations below the 75th percentile. Our results suggest a possible association between ambient lead concentrations and ASD prevalence and demonstrate that exposure to multiple metals may have synergistic effects on ASD prevalence.

Acute air pollution exposure and risk of suicide completion.

Research into environmental factors associated with suicide has historically focused on meteorological variables. Recently, a heightened risk of suicide related to short-term exposure to airborne particulate matter was reported. Here, we examined the associations between short-term exposure to nitrogen dioxide, particulate matter, and sulfur dioxide and completed suicide in Salt Lake County, Utah (n = 1,546) from 2000 to 2010. We used a time-stratified case-crossover design to estimate adjusted odds ratios for the relationship between suicide and exposure to air pollutants on the day of the suicide and during the days preceding the suicide. We observed maximum heightened odds of suicide associated with interquartile-range increases in nitrogen dioxide during cumulative lag 3 (average of the 3 days preceding suicide; odds ratio (OR) = 1.20, 95% confidence interval (CI): 1.04, 1.39) and fine particulate matter (diameter ≤2.5 µm) on lag day 2 (day 2 before suicide; OR = 1.05, 95% CI: 1.01, 1.10). Following stratification by season, an increased suicide risk was associated with exposure to nitrogen dioxide during the spring/fall transition period (OR = 1.35, 95% CI: 1.09, 1.66) and fine particulate matter in the spring (OR = 1.28, 95% CI: 1.01, 1.61) during cumulative lag 3. Findings of positive associations between air pollution and suicide appear to be consistent across study locations with vastly different meteorological, geographical, and cultural characteristics.

Racial and ethnic disparities in health risk from industrial surface water pollution in the United States, 2011-2021.

Industrial chemical pollution is released into surface water at a large scale annually in the United States. However, geographic variation and racial disparities in potential exposure are poorly understood at a national scale. Using county-level Risk-Screening Environmental Indicators data for 2011-2021 and American Community Survey data, this study analyzes the spatial and temporal distribution of health risk from modeled water releases using a Gamma hurdle model. Several racial disparities in presence of risk and amount of risk were identified, particular for Black or African American and Asian populations. At least 200 million U.S. residents live in a county where health risk from this pollution is present. Exposure reduction in high-risk areas may improve health for the broader population while also reducing inequities.

Utah Latina/o/x suicide decedents less likely to die by firearm, even in rural areas: examining population-wide data from the Utah Office of the Medical Examiner.

Introduction: Suicide death remains a significantly rarer event among Latina/o/x populations compared to non-Latina/o/x populations. However, the reasons why Latina/o/x communities experience relatively lower suicide rates are not fully understood. Critical gaps exist in the examination of Latina/o/x suicide death, especially in rural settings, where suicide death by firearm is historically more common within non-Latina/o/x populations. Method: We tested whether the prevalence of Latina/o/x firearm suicide was meaningfully different in urban and rural environments and from non-Latino/a/x decedents when controlling for age, sex, and a social deprivation metric, the Area Deprivation Index. Suicide death data used in this analysis encompasses 2,989 suicide decedents ascertained in Utah from 2016 to 2019. This included death certificate data from the Utah Office of the Medical Examiner on all Utah suicide deaths linked to information by staff at the Utah Population Database. Results: Compared to non-Latina/o/x suicide decedents, Latina/o/x suicide decedents had 34.7% lower adjusted odds of dying by firearm. Additionally, among the firearm suicide decedents living only in rural counties, Latina/o/x decedents had 40.5% lower adjusted odds of dying by firearm compared to non-Latina/o/x suicide decedents. Discussion: The likelihood of firearm suicide death in Utah differed by ethnicity, even in rural populations. Our findings may suggest underlying factors contributing to lower firearm suicide rates within Latina/o/x populations, e.g., aversion to firearms or less access to firearms, especially in rural areas, though additional research on these phenomena is needed.

Observational methods for human studies of transgenerational effects.

There are substantial challenges in studying human transgenerational epigenetic outcomes resulting from environmental conditions. The task requires specialized methods and tools that incorporate specific knowledge of multigenerational relationship combinations of probands and their ancestors, phenotype data for individuals, environmental information of ancestors and their descendants, which can span historical to present datasets, and informative environmental data that chronologically aligns with ancestors and descendants over space and time. As a result, there are few epidemiologic studies of potential transgenerational effects in human populations, thus limiting the knowledge of ancestral environmental conditions and the potential impacts we face with modern human health outcomes. In an effort to overcome some of the challenges in studying human transgenerational effects, we present two transgenerational study designs: transgenerational space-time cluster detection and transgenerational case-control study design. Like other epidemiological methods, these methods determine whether there are statistical associations between phenotypic outcomes (e.g., adverse health outcomes) among probands and the shared environments and environmental factors facing their ancestors. When the ancestor is a paternal grandparent, a statistically significant association provides some evidence that a transgenerational inheritable factor may be involved. Such results may generate useful hypotheses that can be explored using epigenomic data to establish conclusive evidence of transgenerational heritable effects. Both methods are proband-centric: They are designed around the phenotype of interest in the proband generation for case selection and family pedigree creation. In the examples provided, we incorporate at least three generations of paternal lineage in both methods to observe a potential transgenerational effect.

PM2.5 threshold exceedances during the prenatal period and risk of intellectual disability.

BACKGROUND: Research demonstrates that chronic exposure to fine particulates (PM2.5) increases risks of neurodevelopmental conditions, such as intellectual disability (ID). Few studies have examined neurodevelopmental health impacts of pollution spikes exceeding 24-h (24-h) PM2.5 guidelines, despite relevance to the regulatory landscape. The current potential for regulatory changes to 24-h PM2.5 standards in the United States makes research on exceedances relevant. OBJECTIVE: To examine associations between 24-h PM2.5 exceedances and the risk of ID. METHODS: We conducted a retrospective case-control study of a sample of children in Utah, USA. We used generalized estimating equations to predict odds of ID based on the number of 24-h PM2.5 exceedance days during the preconception period and three trimesters of pregnancy. Exceedance days are defined as per current World Health Organization (WHO) [≥15 µg/m3] and current US Environmental Protection Agency (EPA) [≥35 µg/m3] 24-h guidelines. RESULTS: PM2.5 exceedances are associated with ID risk during the preconception and first trimester periods and not the second and third trimesters. During the preconception period, each day exceeding 15 µg/m3 or 35 µg/m3 was associated with a 1.023 (CI: 1.011-1.040) or 1.042 (CI: 1.026-1.059, p < 0.001) increase in odds of ID, respectively. During the first trimester, each day exceeding 15 µg/m3 or 35 µg/m3 was associated with a 1.032 (CI: 1.017-1.047) or 1.059 (CI: 1.030-1.088) increase in odds of ID, respectively. IMPACT STATEMENT: Potential regulatory movement on the US 24-h PM2.5 standard makes research that explicitly studies exceedances highly relevant. Yet few studies examine health effects of exceeding 24-h guidelines for any air pollutants. This study fills important gaps in the literature by examining associations between odds of intellectual disability and the count of days exceeding current 24-h PM2.5 guidelines, as established by the World Health Organization and US Environmental Protection Agency, during the prenatal period. We find that exceedances of both sets of guidelines, during the preconception and first trimester periods, are associated with ID risk.

Association between phthalate exposure and sleep quality in pregnant women: Results from the Korean Children's Environmental Health Study with repeated assessment of exposure.

Background: Evidence linking environmental toxicants to sleep quality is growing; however, these associations during pregnancy remain unclear. We examined the associations of repeated measures of urinary phthalates in early and late pregnancy with multiple markers of sleep quality among pregnant women. Methods: The study population included 2324 pregnant women from the Korean Children's Environmental Health Study. We analyzed spot urine samples collected at two time points during pregnancy for exposure biomarkers of eight phthalate metabolites. We investigated associations between four summary phthalates (all phthalates: ∑Phthalates; di-(2-ethylhexyl) phthalate: ∑DEHP; phthalates from plastic sources: ∑Plastic; and antiandrogenic phthalates: ∑AA) and eight individual phthalates and self-reported sleep measures using generalized ordinal logistic regression and generalized estimating equations models that accounted for repeated exposure measurements. The models were adjusted for age, body mass index, education, gestational age, income, physical activity, smoking, occupation, chronic diseases, depression, and urinary cotinine levels. Results: Multiple individual phthalates and summary measures of phthalate mixtures, including ∑Plastic, ∑DEHP, ∑AA, and ∑Phthalates, were associated with lower sleep efficiency. To illustrate, every 1-unit log increase in ∑AA was associated with a reduction of sleep efficiency by 1.37 % (95% confidence interval [CI] = -2.41, -0.32). ∑AA and ∑Phthalates were also associated with shorter sleep duration and longer sleep latency. Associations between summary phthalate measures and sleep efficiency differed by urinary cotinine levels (P for subgroup difference < 0.05). Conclusions: Findings suggest that higher phthalate exposure may be related to lower sleep efficiency, shorter sleep duration, and prolonged sleep latency during pregnancy.

"It's not the 'being trans,' it's everything around that": Trans Community Perspectives for Suicide Prevention.

Trans people are at significantly elevated risk of suicide death, suicide attempts, and suicidal ideation than their cisgender peers. Suicide prevention efforts are needed that address the most important issues to the trans community. In this qualitative study conducted in the United States in 2021, we aimed to broadly explore trans community member perspectives on suicidality and suicide prevention needs. We conducted four virtual focus groups-including one exclusively for trans people of color. We also solicited additional online responses to the same focus group questions. A total of 56 trans individuals with a history of suicidality participated. We utilized reflexive thematic analysis to develop themes to inform suicide prevention efforts for the trans community. The themes were multicontextual, representing needs across healthcare, legal and political arenas, workplaces, community groups, and interpersonal relationships. The central organizing theme identified as crucial for suicide prevention was 'Having (Real) Rights and Respect.' Supporting themes were 'Being in Control of Our Own Bodies,' 'Being Safe as Ourselves,' and 'Feeling Support and Acceptance,' which also included a subtheme of 'Embracing Diversity within the Trans Community.' We provide suggestions and directions for suicide prevention, which build on these themes.