Background: Suicide is the second leading cause of death among adolescents and young adults. Several studies have indicated significant genetic influences on suicide-related phenotypes and mounting evidence from neurobiological research has linked deficits in neurocognitive abilities to suicide phenotypes. The goal of the present study was to estimate the heritability of suicidal ideation (SI) in a large sample of adolescents and determine if SI is genetically correlated with neurocognitive functioning. Methods: Genome-wide data (N = 3564 unrelated individuals of European Ancestry) were drawn from the Philadelphia Neurodevelopment Cohort. Adolescents completed a psychiatric assessment, as well as a computerized neurocognitive battery to assess performance across four domains: memory, executive function, social cognition, and complex cognition. Genomic-relatedness-matrix restricted maximum likelihood (GREML) estimation was used to determine SNP-heritability (h 2SNP ) of SI and the genetic correlation (r G ) between SI and neurocognitive domains. Results: Nearly 17% of adolescents reported SI. The SNP-heritability estimate for SI was marginally significant (h 2SNP = 11%, SE = 8%, p = 0.086). Bivariate analyses indicated a significant r G between SI and emotion identification (r G = 0.79, SE = 0.45, p = 0.006; phenotypic correlation r = 0.04, p = 0.017). Limitations: It is possible that SI may represent a related, but differentially heritable construct from suicide attempts/completion and other comorbid psychopathology. Additionally, though genetic correlations point to shared genetic factors across traits, direct causal mechanisms cannot be deduced. Conclusions: Common heritable factors contribute to variation in SI and neurocognitive functioning. Genetic factors influencing emotion identification have significant genetic overlap with SI.

Background: Alcoholism is a multifactorial disorder influenced by multiple gene loci, each with small effect. Studies suggest shared genetic influences across DSM-IV alcohol dependence symptoms, but shared effects across DSM-5 alcohol use disorder remains unknown. We aimed to test the assumption of genetic homogeneity across the 11 criteria of DSM-5 alcohol use disorder (AUD). Methods: Data from 2596 alcohol using individuals of European ancestry from the Study of Addiction: Genetics and Environment were used to examine the genomewide SNP-heritability (h2SNP) and SNP-covariance (rGSNP) between 11 DSM-5 AUD symptoms. Phenotypic relationships between symptoms were examined to confirm an underlying liability of AUD and the SNP-heritability of the observed latent trait and the co-heritabilityamong AUD symptoms was assessed using Genomic-Relatedness-Matrix-Restricted-Maximum-Likelihood. Genetic covariance among symptoms was examined using factor analysis. Results: Phenotypic relationships confirmed a unidimensional underlying liability to AUD. Factor and parallel analyses of the observed genetic variance/covariance provided evidence of genetic homogeneity. Additive genetic effects on DSM-5 AUD symptoms varied from 0.10 to 0.37 and largely overlapped (rG-SNP across symptoms ranged from 0.49 - 0.92). The additive genetic effect on the DSM-5 AUD factor was 0.36, 0.14 for DSM-5 AUD diagnosis, and was 0.22 for DSM-5 AUD severity. Conclusions: Common genetic variants influence DSM-5 AUD symptoms. Despite evidence for a common AUD factor, the evidence of only partially overlapping genetic effects across AUD symptoms further substantiates the need to simultaneously model common and symptom-specific genetic effects in molecular genetic studies in order to best characterize the genetic liability.

Maternal smoking during pregnancy (SDP) has been linked to poorer offspring executive function across development, but SDP does not occur independent of other familial risk factors. As such, poor and inconsistent control for potential confounds, notably shared familial (i.e., genetic and environmental) confounds, preclude concluding causal effects of SDP on child outcomes. We examined the withinfamily association between SDP and one component of executive function, inhibitory control, in a sample of families (N=173) specifically selected for sibling pairs discordant for exposure to SDP. Thus, the present study examines if the SDP-inhibitory control association withstands rigorous control for potential child and familial confounds. 79% of the variation in child inhibitory control was attributable to within-family differences and 21% was attributable to differences between families, indicating that the variability in inhibitory control was primarily a function of differences between siblings rather than differences across families. Further, the association between SDP and inhibitory control was fully attenuated when confounds were considered. These findings suggest that co-occurring vulnerabilities act as more salient risk factors for poorer child inhibitory control than SDP and may serve as effective targets of interventions seeking to improve children's inhibitory control in families with nicotine dependent mothers.

Alcohol dependence (AD) affects individuals from all racial/ethnic groups, and previous research suggests that there is considerable variation in AD risk between and among various ancestrally defined groups in the United States. Although the reasons for these differences are likely due in part to contributions of complex sociocultural factors, limited research has attempted to examine whether similar genetic variation plays a role across ancestral groups. Using a pooled sample of individuals of African and European ancestry (AA/EA) obtained through data shared within the Database for Genotypes and Phenotypes, we estimated the extent to which additive genetic similarity for AD between AA and EAs using common single nucleotide polymorphisms overlapped across the two populations. AD was represented as a factor score by using Diagnostic and Statistical Manual dependence criteria, and genetic data were imputed by using the 1000 Genomes Reference Panel. Analyses revealed a significant single nucleotide polymorphism-based heritability of 17 percent (SE = 5) in EAs and 24 percent (SE = 15) in AAs. Further, a significant genetic correlation of 0.77 (SE = 0.46) suggests that the allelic architecture influencing the AD factor for EAs and AAs is largely similar across the two populations. Analyses indicated that investigating the genetic underpinnings of alcohol dependence in different ethnic groups may serve to highlight core etiological factors common to both groups and unique etiological factors specific to each ethnic group.

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to (1) identify genetic variation associated with self-reported childhood maltreatment, (2) estimate SNP-based heritability (h2snp), (3) assess predictive value of polygenic risk scores (PRS) for childhood maltreatment, and (4) quantify genetic overlap of childhood maltreatment with mental and physical health-related phenotypes, and condition the top hits from our analyses when such overlap is present. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n = 124,000) and a replication sample from the Psychiatric Genomics Consortium-posttraumatic stress disorder group (PGC-PTSD) (n = 26,290). h2snp for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression. PRS was calculated using PRSice and mtCOJO was used to perform conditional analysis. Two genome-wide significant loci associated with childhood maltreatment (rs142346759, p = 4.35 × 10−8, FOXP1; rs10262462, p = 3.24 × 10−8, FOXP2) were identified in the discovery dataset but were not replicated in PGC-PTSD. h2snp for childhood maltreatment was ~6% and the PRS derived from the UKBB was significantly predictive of childhood maltreatment in PGC-PTSD (r2 = 0.0025; p = 1.8 × 10−15). The most significant genetic correlation of childhood maltreatment was with depressive symptoms (rg = 0.70, p = 4.65 × 10−40), although we show evidence that our top hits may be specific to childhood maltreatment. This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment. Speculatively, FOXP genes might influence externalizing traits and so be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with a range of phenotypes, may ultimately be useful in in developing targeted treatment and prevention strategies.

Familial risk for depression is associated with youth exposure to self-generated dependent stressful life events and independent events that are out of youth’s control. Familial risk includes both genetic and environmental influences, raising the question of whether genetic influences, specifically, are associated with youth exposure to both dependent and independent stressful life events. To address this question, this study examined the relation between a genome-wide association study (GWAS)-derived depression-based polygenic risk score (DEP-PRS) and youth experiences of dependent and independent stress. Participants were 180 youth (ages 8–14, 52.2% female) of European ancestry and their biological mothers recruited based on the presence versus absence of a history of major depressive disorder (MDD) in the mothers. Youth and mothers were interviewed every 6 months for 2 years regarding the occurrence of stressful life events, which were coded as independent or dependent (self-generated). Results indicated that youth’s DEP-PRS and maternal history of MDD were uniquely associated with increased exposure to both dependent and independent events. Similar results were observed when examining major versus minor events separately, with the additional finding of a DEP-PRS × mother MDD interaction for major dependent events such that levels of moderate to severe dependent life stressors were highest among youth with high DEP-PRSs who also had mothers with MDD. These results not only support the presence of depression-relevant gene-environment correlations (rGEs), but also highlight the possibility that rather than only capturing depression-specific genetic liability, GWAS-derived polygenic risk scores may also capture genetic variance contributing to stress exposure.

Purpose: Posttraumatic Stress Disorder (PTSD) is associated with increased alcohol use and alcohol use disorder (AUD), which are all moderately heritable. Studies suggest the genetic association between PTSD and alcohol use differs from that of PTSD and AUD, but further analysis is needed. Basic procedures: We used genomic Structural Equation Modeling (genomicSEM) to analyze summary statistics from large-scale genome-wide association studies (GWAS) of European Ancestry participants to investigate the genetic relationships between PTSD (both diagnosis and re-experiencing symptom severity) and a range of alcohol use and AUD phenotypes. Main findings: When we differentiated genetic factors for alcohol use and AUD we observed improved model fit relative to models with all alcohol-related indicators loading onto a single factor. The genetic correlations (rG) of PTSD were quite discrepant for the alcohol use and AUD factors. This was true when modeled as a three-correlated-factor model (PTSD-AUD rG:.36, p < .001; PTSD-alcohol use rG: −0.17, p < .001) and as a Bifactor model, in which the common and unique portions of alcohol phenotypes were pulled out into an AUD-specific factor (rG with PTSD:.40, p < .001), AU-specific factor (rG with PTSD: −0.57, p < .001), and a common alcohol factor (rG with PTSD:.16, NS). Principal conclusions: These results indicate the genetic architecture of alcohol use and AUD are differentially associated with PTSD. When the portions of variance unique to alcohol use and AUD are extracted, their genetic associations with PTSD vary substantially, suggesting different genetic architectures of alcohol phenotypes in people with PTSD.

Though most genetic studies of substance use focus on specific substances in isolation or generalized vulnerability across multiple substances, few studies to date focus on the concurrent use of two or more substances within a specified time frame (i.e., polysubstance use; PSU). We evaluated whether distinct genetic factors underlying internalizing and externalizing traits were associated with past 30-day PSU above variance shared across general psychopathology and substance use (SU). Using Genomic Structural Equation Modeling, we constructed theory-driven, multivariate genetic factors of 16 internalizing, externalizing, and SU traits using genome-wide association studies (GWAS) summary statistics. Next, we fit a model with a higher order SU-related psychopathology factor as well as genetic variance specific to externalizing and internalizing (i.e., residual genetic variance not explained by SU or general psychopathology). GWAS-by-subtraction was used to obtain single nucleotide polymorphism effects on each of these factors. Polygenic scores (PGS) were then created in an independent target sample with data on PSU, the National Longitudinal Study of Adolescent to Adult Health. To evaluate the effect of genetic variance due to internalizing and externalizing traits independent of variance related to SU, we regressed PSU on the PGSs, controlling for sex, age, and genetic principal components. PGSs for SU-related psychopathology and non-SU externalizing traits were associated with higher PSU factor scores, while the non-SU internalizing PGS was not significantly associated with PSU. In total, the three PGSs accounted for an additional 4% of the variance in PSU above and beyond a null model with only age, sex, and genetic principal components as predictors. These findings suggest that there may be unique genetic variance in externalizing traits contributing to liability for PSU that is independent of the genetic variance shared with SU.

Substance use disorders (SUDs) take an enormous toll on US Veterans and civilians alike. Existing empirically supported interventions vary by substance and demonstrate only moderate efficacy. Non-invasive brain stimulation represents an innovative treatment for SUDs, yet aspects of traditional neurostimulation may hinder its implementation in SUD populations. Synchronised transcranial magnetic stimulation (sTMS) uses rotating rare earth magnets to deliver low-field stimulation synchronised to an individual’s alpha peak frequency that is safe for at-home administration. The current trial aims to assess the acceptability and feasibility of sTMS, as well as the safety of at-home sTMS administration for substance-disordered Veterans.

Background and Aims: Cannabis use (CU) is an etiologically complex behavior with several social, temperamental, neurocognitive, and behavioral precursors. Biometrical and molecular studies suggest an interplay of environmental and pleiotropic influences. However, it remains unclear whether identified genetic effects related to behavioral and temperamental characteristics have developmentally direct or indirect mechanisms on CU behavior. The Transmissible Liability Index (TLI) is a measure of continuous liability based on developmental precursors of substance use disorders. This study aimed to examine if the TLI plays a role in understanding genetic risk for CU behaviors. Design: Genome-wide association studies (n > 10 000; European Ancestry [EA]) of CU, risk tolerance, neuroticism, anxiety, and depression were used to construct polygenic scores (PGSs). Analyses assessed whether PGSs indirectly impacted risk for repeated use via TLI. Setting: United States of America. Participants: From Add Health study, 4077 individuals of EA age 11 to 21 during baseline interview collection. Measurements: Outcomes were initiation and repeated cannabis use (>5× in lifetime). The TLI was parameterized using a latent factor from 21 questions assessing for precursors of disordered use. Findings: The marker-based heritability of TLI, initiation, and repeated use were significant, but modest (14%, P = 0.033; 15%, P = 0.025; and 17%, P = 0.008, respectively). TLI and repeated use were genetically correlated (rg = 0.76, P = 0.033). The PGS for CU was associated with increased risk for repeated use and PGS for risk tolerance and depression were associated with TLI. Mediation analyses indicated significant, but very weak, indirect effects of PGS for risk tolerance and depression on repeated CU via the TLI. Conclusions: Adolescent behavioral and temperamental characteristics (i.e. the Transmissible Liability Index) appear to be early indicators of repeated cannabis use in adulthood. Although polygenic scores for cannabis use directly increased risk for repeated cannabis use, weak evidence was found for the role of polygenic scores of other internalizing/externalizing traits acting through adolescent derived Transmissible Liability Index on cannabis use behavior.