Polygenic influences on the behavioral effects of alcohol withdrawal in a mixed-ancestry population from the collaborative study on the genetics of alcoholism (COGA).

Alcohol withdrawal (AW) is a feature of alcohol use disorder that may occur in up to half of individuals with chronic, heavy alcohol consumption whenever alcohol use is abruptly stopped or significantly reduced. To date, few genes have been robustly associated with AW; this may be partly due to most studies defining AW as a binary construct despite the multiple symptoms and their range in severity from mild to severe. The current study examined the effects of genome-wide loci on a factor score for AW in high risk and community family samples in the Collaborative Study for the Genetics of Alcoholism (COGA). In addition, we tested whether differentially expressed genes associated with alcohol withdrawal in model organisms are enriched in human genome-wide association study (GWAS) effects. Analyses employed roughly equal numbers of males and females (mean age 35, standard deviation = 15; total N = 8009) and included individuals from multiple ancestral backgrounds. Genomic data were imputed to the HRC reference panel and underwent strict quality control procedures using Plink2. Analyses controlled for age, sex, and population stratification effects using ancestral principal components. We found support that AW is a polygenic disease (SNP-heritability = 0.08 [95 % CI = 0.01, 0.15; pedigree-based heritability = 0.12 [0.08,0.16]. We identified five single nucleotide variants that met genomewide significance, some of which have previously been associated with alcohol phenotypes. Gene-level analyses suggest a role for COL19A1 in AW; H-MAGMA analyses implicated 12 genes associated with AW. Cross-species enrichment analyses indicated that variation within genes identified in model organism studies explained <1 % of the phenotypic variability in human AW. Notably, the surrounding regulatory regions of model organism genes explained more variance than expected by chance, indicating that these regulatory regions and gene sets may be important for human AW. Lastly, when comparing the overlap in genes identified from the human GWAS and H-MAGMA analyses with the genes identified from the animal studies, there was modest overlap, indicating some convergence between the methods and organisms.

Associating broad and clinically defined polygenic scores for depression with depression-related phenotypes.

Twin studies indicate that 30-40% of the disease liability for depression can be attributed to genetic differences. Here, we assess the explanatory ability of polygenic scores (PGS) based on broad- (PGSBD) and clinical- (PGSMDD) depression summary statistics from the UK Biobank in an independent sample of adults (N = 210; 100% European Ancestry) who were extensively phenotyped for depression and related neurocognitive traits (e.g., rumination, emotion regulation, anhedonia, and resting frontal alpha asymmetry). The UK Biobank-derived PGSBD had small associations with MDD, depression severity, anhedonia, cognitive reappraisal, brooding, and suicidal ideation but only the association with suicidal ideation remained statistically significant after correcting for multiple comparisons. Similarly small associations were observed for the PGSMDD but none remained significant after correcting for multiple comparisons. These findings provide important initial guidance about the expected effect sizes between current UKB PGSs for depression and depression-related neurocognitive phenotypes.

Genetic associations among internalizing and externalizing traits with polysubstance use among young adults.

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.

Genome- and transcriptome-wide splicing associations with alcohol use disorder.

Genetic mechanisms of alternative mRNA splicing have been shown in the brain for a variety of neuropsychiatric traits, but not substance use disorders. Our study utilized RNA-sequencing data on alcohol use disorder (AUD) in four brain regions (n = 56; ages 40-73; 100% 'Caucasian'; PFC, NAc, BLA and CEA) and genome-wide association data on AUD (n = 435,563, ages 22-90; 100% European-American). Polygenic scores of AUD were associated with AUD-related alternative mRNA splicing in the brain. We identified 714 differentially spliced genes between AUD vs controls, which included both putative addiction genes and novel gene targets. We found 6463 splicing quantitative trait loci (sQTLs) that linked to the AUD differentially spliced genes. sQTLs were enriched in loose chromatin genomic regions and downstream gene targets. Additionally, the heritability of AUD was enriched for DNA variants in and around differentially spliced genes associated with AUD. Our study also performed splicing transcriptome-wide association studies (TWASs) of AUD and other drug use traits that unveiled specific genes for follow-up and splicing correlations across SUDs. Finally, we showed that differentially spliced genes between AUD vs control were also associated with primate models of chronic alcohol consumption in similar brain regions. Our study found substantial genetic contributions of alternative mRNA splicing in AUD.

Genome-wide Association Study Shows That Executive Functioning Is Influenced by GABAergic Processes and Is a Neurocognitive Genetic Correlate of Psychiatric Disorders.

BACKGROUND: Deficits in executive functions (EFs), cognitive processes that control goal-directed behaviors, are associated with psychopathology and neurologic disorders. Little is known about the molecular bases of individual differences in EFs. Prior candidate gene studies have been underpowered in their search for dopaminergic processes involved in cognitive functioning, and existing genome-wide association studies of EFs used small sample sizes and/or focused on individual tasks that are imprecise measures of EFs. METHODS: We conducted a genome-wide association study of a common EF (cEF) factor score based on multiple tasks in the UK Biobank (n = 427,037 individuals of European descent). RESULTS: We found 129 independent genome-wide significant lead variants in 112 distinct loci. cEF was associated with fast synaptic transmission processes (synaptic, potassium channel, and GABA [gamma-aminobutyric acid] pathways) in gene-based analyses. cEF was genetically correlated with measures of intelligence (IQ) and cognitive processing speed, but cEF and IQ showed differential genetic associations with psychiatric disorders and educational attainment. CONCLUSIONS: Results suggest that cEF is a genetically distinct cognitive construct that is particularly relevant to understanding the genetic variance in psychiatric disorders.

Associations between neuroticism, subjective sleep quality, and depressive symptoms across the first year of college.

OBJECTIVE: Examine neuroticism's impact on the relationship between depressive symptoms and sleep quality during the college transition. PARTICIPANTS: First-year students (N = 302) from a southeastern university in the USA. METHODS: A longitudinal cross-lagged panel model assessed direct and indirect effects between self-reported sleep and depressed mood. RESULTS: Higher neuroticism was directly associated with both greater depressed mood and sleep quality. Poorer sleep quality was associated with depressive symptoms at baseline (ß = 0.250, [95% CI = 0.123,0.362]) and during spring semester (ß = 0.261, [95% CI = 0.126,0.383]). Baseline depressive symptoms predicted sleep quality during fall semester (ß = 0.140, [95% CI = 0.031, 0.247]), and fall semester sleep quality predicted spring semester depression symptoms (ß = 0.106, [95% CI = 0.007,0.201]). DISCUSSION: Neuroticism is an indicator of emotional distress and disrupted sleep upon college entry. Furthermore, there was evidence for both within time-point and prospective associations between sleep quality and depression symptoms albeit at different times throughout the first year of college.

Multi-Polygenic Analysis of Nicotine Dependence in Individuals of European Ancestry.

INTRODUCTION: Heritability estimates of nicotine dependence (ND) range from 40% to 70%, but discovery GWAS of ND are underpowered and have limited predictive utility. In this work, we leverage genetically correlated traits and diseases to increase the accuracy of polygenic risk prediction. METHODS: We employed a multi-trait model using summary statistic-based best linear unbiased predictors (SBLUP) of genetic correlates of DSM-IV diagnosis of ND in 6394 individuals of European Ancestry (prevalence = 45.3%, %female = 46.8%, µâ€Šage = 40.08 [s.d. = 10.43]) and 3061 individuals from a nationally-representative sample with Fagerström Test for Nicotine Dependence symptom count (FTND; 51.32% female, mean age = 28.9 [s.d. = 1.70]). Polygenic predictors were derived from GWASs known to be phenotypically and genetically correlated with ND (i.e., Cigarettes per Day [CPD], the Alcohol Use Disorders Identification Test [AUDIT-Consumption and AUDIT-Problems], Neuroticism, Depression, Schizophrenia, Educational Attainment, Body Mass Index [BMI], and Self-Perceived Risk-Taking); including Height as a negative control. Analyses controlled for age, gender, study site, and the first 10 ancestral principal components. RESULTS: The multi-trait model accounted for 3.6% of the total trait variance in DSM-IV ND. Educational Attainment (ß = -0.125; 95% CI: [-0.149,-0.101]), CPD (0.071 [0.047,0.095]), and Self-Perceived Risk-Taking (0.051 [0.026,0.075]) were the most robust predictors. PGS effects on FTND were limited. CONCLUSIONS: Risk for ND is not only polygenic, but also pleiotropic. Polygenic effects on ND that are accessible by these traits are limited in size and act additively to explain risk. IMPLICATIONS: These findings enhance our understanding of inherited genetic factors for nicotine dependence. The data show that genome-wide association study (GWAS) findings across pre- and comorbid conditions of smoking are differentially associated with nicotine dependence and that when combined explain significantly more trait variance. These findings underscore the utility of multivariate approaches to understand the validity of polygenic scores for nicotine dependence, especially as the power of GWAS of broadly-defined smoking behaviors increases. Realizing the potential of GWAS to inform complex smoking behaviors will require similar theory-driven models that reflect the myriad of mechanisms that drive individual differences.

Integration of evidence across human and model organism studies: A meeting report.

The National Institute on Drug Abuse and Joint Institute for Biological Sciences at the Oak Ridge National Laboratory hosted a meeting attended by a diverse group of scientists with expertise in substance use disorders (SUDs), computational biology, and FAIR (Findability, Accessibility, Interoperability, and Reusability) data sharing. The meeting's objective was to discuss and evaluate better strategies to integrate genetic, epigenetic, and 'omics data across human and model organisms to achieve deeper mechanistic insight into SUDs. Specific topics were to (a) evaluate the current state of substance use genetics and genomics research and fundamental gaps, (b) identify opportunities and challenges of integration and sharing across species and data types, (c) identify current tools and resources for integration of genetic, epigenetic, and phenotypic data, (d) discuss steps and impediment related to data integration, and (e) outline future steps to support more effective collaboration-particularly between animal model research communities and human genetics and clinical research teams. This review summarizes key facets of this catalytic discussion with a focus on new opportunities and gaps in resources and knowledge on SUDs.

The intermediary role of adolescent temperamental and behavioral traits on the prospective associations between polygenic risk and cannabis use among young adults of European Ancestry.

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.

Examining the differential effects of latent impulsivity factors on substance use outcomes in African American men.

African Americans have elevated substance use-related problems during adulthood despite initiating use later than individuals of other racial/ethnic backgrounds. The present study first validated the structure of the UPPS-P Impulsive Behavior Scale and then examined impulsivity as a prospective risk factor for future alcohol, cannabis, and tobacco use, as well as generalized substance problems, in African American men. Data were drawn from the African-American Men's Project, which recruited participants (NWAVE-1 = 504; Mean ageWAVE-1 = 20.7; NWAVE-3 = 379; Mean ageWAVE-3 = 23.6) from rural counties of Georgia. Participants responded to an adapted version of the UPPS-P at Wave 1. Confirmatory factor analyses determined that a 5-factor model of impulsivity and a 3-factor hierarchical model of impulsivity described the data equally well, in comparison to 1-factor, 4-factor, or bifactor models. This supports that the structure of the abbreviated UPPS-P in African Americans is likely consistent with observations in White, Hispanic/Latino, and admixed samples. Notably, all second-order factors of the UPPS-P are not alike in predicting substance use outcomes when examined jointly in African American men. Only Deficits in Conscientiousness, which is a second-order factor comprised of Lack of Premeditation and Lack of Perseverance, affected whether individuals met any criteria for future substance use problems. Our findings provide novel insight into the relationship between impulsivity and substance involvement during emerging adulthood in African American men.

Multi-omic and multi-species meta-analyses of nicotine consumption.

Cross-species translational approaches to human genomic analyses are lacking. The present study uses an integrative framework to investigate how genes associated with nicotine use in model organisms contribute to the genetic architecture of human tobacco consumption. First, we created a model organism geneset by collecting results from five animal models of nicotine exposure (RNA expression changes in brain) and then tested the relevance of these genes and flanking genetic variation using genetic data from human cigarettes per day (UK BioBank N = 123,844; all European Ancestry). We tested three hypotheses: (1) DNA variation in, or around, the 'model organism geneset' will contribute to the heritability to human tobacco consumption, (2) that the model organism genes will be enriched for genes associated with human tobacco consumption, and (3) that a polygenic score based off our model organism geneset will predict tobacco consumption in the AddHealth sample (N = 1667; all European Ancestry). Our results suggested that: (1) model organism genes accounted for ~5-36% of the observed SNP-heritability in human tobacco consumption (enrichment: 1.60-31.45), (2) model organism genes, but not negative control genes, were enriched for the gene-based associations (MAGMA, H-MAGMA, SMultiXcan) for human cigarettes per day, and (3) polygenic scores based on our model organism geneset predicted cigarettes per day in an independent sample. Altogether, these findings highlight the advantages of using multiple species evidence to isolate genetic factors to better understand the etiological complexity of tobacco and other nicotine consumption.

Risk for alcohol use/misuse among entering college students: The role of personality and stress.

INTRODUCTION: Excessive alcohol use amongst college students is associated with low grades, poor mental health, and risks to physical safety. Neuroticism, characterized by emotional instability and anxiety, and self-reported stress have both been shown to be strong predictors of alcohol use and misuse, however, previous studies have shown that measures of stress and Neuroticism are frequently confounded. This study tests the hypothesis that personality traits, and Neuroticism in particular, predict alcohol use/misuse in matriculating freshmen above and beyond reported levels of stress. METHODS: Data were collected as part of an IRB-approved longitudinal study, MAPme, examining behavioral health in college. Participants were 303 first-year college students (70% female) with an average age of 18.58 (SD = 0.39). Data were collected during the first eight weeks of the first semester at college. RESULTS: Overall, domain-level Neuroticism was not associated with alcohol use/misuse above and beyond perceived levels of stress and other Big Five domains (ß = 0.14, p = 0.088). Notably, the depression facet of Neuroticism (Neuroticism-Depression), was positively associated with alcohol use/misuse when accounting for the shared effects of stress. Results demonstrated that the Neuroticism-Depression facet moderated the relationship between stress and alcohol use/misuse (ß = 0.18, p = 0.020). CONCLUSIONS: The Neuroticism-Depression facet is a better predictor of alcohol use/misuse than the Neuroticism domain, even when accounting for stress and other personality domains.At low levels of the Depression facet, stress was negatively associated with alcohol use/misuse, but at high levels of the Depression facet, stress was positively associated with alcohol use/misuse. Taken together, our results shed new light into the combined and independent effects of Neuroticism and stress on alcohol use/misuse.

Single nucleotide polymorphism heritability and differential patterns of genetic overlap between inattention and four neurocognitive factors in youth.

Theoretical models of attention-deficit/hyperactivity disorder implicate neurocognitive dysfunction, yet neurocognitive functioning covers a range of abilities that may not all be linked with inattention. This study (a) investigated the single nucleotide polymorphism (SNP) heritability (h2SNP) of inattention and aspects of neurocognitive efficiency (memory, social cognition, executive function, and complex cognition) based on additive genome-wide effects; (b) examined if there were shared genetic effects among inattention and each aspect of neurocognitive efficiency; and (c) conducted an exploratory genome-wide association study to identify genetic regions associated with inattention. The sample included 3,563 participants of the Philadelphia Neurodevelopmental Cohort, a general population sample aged 8-21 years who completed the Penn Neurocognitive Battery. Data on inattention was obtained with the Kiddie Schedule of Affective Disorders (adapted). Genomic relatedness matrix restricted maximum likelihood was implemented in genome-wide complex trait analysis. Analyses revealed significant h2SNP for inattention (20%, SE = 0.08), social cognition (13%, SE = 0.08), memory (17%, SE = 0.08), executive function (25%, SE = 0.08), and complex cognition (24%, SE = 0.08). There was a positive genetic correlation (0.67, SE = 0.37) and a negative residual covariance (-0.23, SE = 0.06) between inattention and social cognition. No SNPs reached genome-wide significance for inattention. Results suggest specificity in genetic overlap among inattention and different aspects of neurocognitive efficiency.

Adolescent Behavioral Characteristics Mediate Familial Effects on Alcohol Use and Problems in College-Bound Students.

BACKGROUND: Studies suggest a broad spectrum of behaviors associated with drinking. Consequently, it is unclear whether patterns of familial risk for psychopathology are directly or indirectly related to patterns of alcohol use and problems in late adolescence or mediated by behavioral characteristics, such as temperament, mood. OBJECTIVES: We examined direct and indirect effects of perceived family history of psychopathology on pre-collegiate alcohol use and problems via the Transmissible Liability Index (TLI). METHODS: Participants (N = 302; 29.6% male) provided self-report data on age of onset of drinking, past 90-day frequency of alcohol use and problems (AUP), family history of internalizing and alcohol and illicit substance use, and TLI. RESULTS: Approximately 21% of participants reported having at least one relative with a history of regular and/or problematic alcohol use, compared to 12% for illicit substance use, and -55% for internalizing problems. Higher TLI scores were associated with increased family history of substance use, alcohol use, and internalizing problems, as well as earlier age of onset of drinking. Family history of internalizing problems was the most robust indicator of AUP (ß = 0.20 [95% CI = 0.04-0.36], P = .01). Path analyses suggested that the individual-level behaviors that comprise TLI mediate the effects of family history on age of initiation and regular alcohol consumption. CONCLUSIONS: Family history of internalizing, drinking, and illicit substance use reflect generalized risk for a broad set of behaviors associated with risk for alcohol initiation and use during the transition from high school to college.

Quality and Quantity of Social Support Show Differential Associations With Stress and Depression in African Americans.

Social support (SS) is typically associated with lower emotional distress (e.g., stress and depression) in individuals. However, SS is a multifaceted construct that can vary by quality, quantity (amount), and type (i.e., it can be emotional or instrumental in nature). OBJECTIVE: The current study examined the relationships between characteristics of SS, stress, and depression in aging African Americans. PARTICIPANTS: Analyses focused on data from 705 participants aged 22-92 years from the Carolina African American Twin Study of Aging. MEASUREMENTS: Measures included the quality and quantity of emotional and instrumental support received, as well as stress and depression. DESIGN: A series of univariate and increasingly complex multivariate regression models were conducted in MPlus (using the cluster option to control for family structure) to examine the relationships between SS and emotional distress variables. RESULTS: Overall, better quality of emotional SS predicted fewer depression symptoms and less perceived stress, after controlling for age, gender, socioeconomic status variables, and the other subtypes of SS. However, more instances of emotional SS were associated with higher levels of perceived stress, depression symptoms, and more stressful life events within the past year. Likewise, more instrumental SS predicted more perceived stress, while holding the other variables constant. CONCLUSION: African Americans who experience more emotional distress report more SS, but the quality of emotional support appears to play an important role in the association between reduced levels of stress and depression. These findings suggest that interventions should include approaches to reduce emotional distress as well as enhance the quality SS.

The role of social support on the effects of stress and depression on African American tobacco and alcohol use.

OBJECTIVES: The current study explored whether social support (SS) from family and peers, influences the relationship between depressed mood (DM) and substance use (SU). We hypothesized that SS would have a protective effect on DM, and moderate the association between DM and SU. PARTICIPANTS AND METHODS: Analyses focused on 703 individuals from the Carolina African American Twin Study on Aging (mean age = 49.78 years, STD = 14.52; 51% female). Participants reported on past year frequency of cigarettes and alcohol consumption, depressed mood, and stressful life events. Social support (SS) was assessed on two domains (i.e., emotional and instrumental), as well as for perceived quality and quantity of each type. Hypotheses were tested using ordinal logistic regression in Mplus while controlling for socioeconomic status, age, and gender. RESULTS: Quality of emotional support was negatively associated with drinking. Smoking, but not drinking was associated with depressed mood. While individuals with high levels of depressed mood received more support, receiving better quality emotional support was associated with fewer mood and stress symptoms. Individuals who reported receiving better quality emotional support typically smoked fewer cigarettes. CONCLUSION: Quantity of emotional support was associated with higher levels of negative emotionality, whereas the opposite was found for quality of emotional support. Emotional support may indirectly influence smoking via depressed mood. Effecting the perceived quality of support appears to be the mechanism by which emotional support helps to reduce smoking in adult African Americans.

National Institute on Drug Abuse genomics consortium white paper: Coordinating efforts between human and animal addiction studies.

The National Institute on Drug Abuse Genetics and Epigenetics Cross-Cutting Research Team convened a diverse group of researchers, clinicians, and healthcare providers on the campus of the University of California, San Diego, in June 2018. The goal was to develop strategies to integrate genetics and phenotypes across species to achieve a better understanding of substance use disorders through associations between genotypes and addictive behaviors. This conference (a) discussed progress in harmonizing large opioid genetics cohorts, (b) discussed phenotypes that are used for genetics studies in humans, (c) examined phenotypes that are used for genetics studies in animal models, (d) identified synergies and gaps in phenotypic analyses of human and animal models and (e) identified strategies to integrate genetics and genomics data with phenotypes across species. The meeting consisted of panels that focused on phenotype harmonization (Dr. Laura Bierut, Dr. Olivier George, Dr. Dan Larach and Dr. Sesh Mudumbai), translating genetic findings between species (Dr. Elissa Chesler, Dr. Gary Peltz and Dr. Abraham Palmer), interpreting and understanding allelic variations (Dr. Vanessa Troiani and Dr. Tamara Richards) and pathway conservation in animal models and human studies (Dr. Robert Hitzemann, Dr. Huda Akil and Dr. Laura Saba). There were also updates that were provided by large consortia (Dr. Susan Tapert, Dr. Danielle Dick, Dr. Howard Edenberg and Dr. Eric Johnson). Collectively, the conference was convened to discuss progress and changes in genome-wide association studies.

Overlapping genetic effects between suicidal ideation and neurocognitive functioning.

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 (h2SNP) of SI and the genetic correlation (rG) between SI and neurocognitive domains. RESULTS: Nearly 17% of adolescents reported SI. The SNP-heritability estimate for SI was marginally significant (h2SNP = 11%, SE = 8%, p = 0.086). Bivariate analyses indicated a significant rG between SI and emotion identification (rG = 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.