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Objective: Preschool internalizing problems (INT) are highly heritable and moderately genetically stable from childhood into adulthood. Gene-finding studies are scarce. In this study, the influence of genome-wide measured single nucleotide polymorphisms (SNPs) was investigated in 3 cohorts (total N = 4,596 children) in which INT was assessed with the same instrument, the Child Behavior Checklist (CBCL). Method: First, genome-wide association (GWA) results were used for density estimation and genome-wide complex trait analysis (GCTA) to calculate the variance explained by all SNPs. Next, a fixed-effect inverse variance meta-analysis of the 3 GWA analyses was carried out. Finally, the overlap in results with prior GWA studies of childhood and adulthood psychiatric disorders and treatment responses was tested by examining whether SNPs associated with these traits jointly showed a significant signal for INT. Results: Genome-wide SNPs explained 13% to 43% of the total variance. This indicates that the genetic architecture of INT mirrors the polygenic model underlying adult psychiatric traits. The meta-analysis did not yield a genome-wide significant signal but was suggestive for the PCSK2 gene located on chromosome 20p12.1. SNPs associated with other psychiatric disorders appeared to be enriched for signals with INT (λ = 1.26, p < .03). Conclusion: Our study provides evidence that INT is influenced by many common genetic variants, each with a very small effect, and that, even as early as age 3, genetic variants influencing INT overlap with variants that play a role in childhood and adulthood psychiatric disorders. [ABSTRACT FROM AUTHOR]

Learning health systems use data to generate knowledge that informs clinical care, but few studies have evaluated how to leverage patient-reported mental health symptoms and substance use data to make patient-specific predictions. We developed a general Bayesian prediction algorithm that uses self-reported psychiatric symptoms and substance use within a population to predict future symptoms and substance use for individuals in that population. We validated our approach in 2444 participants from two clinical cohorts – the National Network of Depression Centers and the Johns Hopkins HIV Clinical Cohort – by predicting symptoms of depression, anxiety, and mania as well as alcohol, heroin, and cocaine use and comparing our predictions to observed symptoms and substance use. When we dichotomized mental health symptoms as moderate-severe vs. none-mild, individual predictions yielded areas under the ROC curve (AUCs) of 0.84 [95% confidence interval 0.80–0.88] and 0.85 [0.82–0.88] for symptoms of depression in the two cohorts, AUCs of 0.84 [0.79–0.88] and 0.85 [0.82–0.88] for symptoms of anxiety, and an AUC of 0.77 [0.72–0.82] for manic symptoms. Predictions of substance use yielded an AUC of 0.92 [0.88–0.97] for heroin use, 0.90 [0.82–0.97] for cocaine use, and 0.90 [0.88–092] for alcohol misuse. This rigorous, mathematically grounded approach could provide patient-specific predictions at the point of care. It can be applied to other psychiatric symptoms and substance use indicators, and is customizable to specific health systems. Such approaches can realize the potential of a learning health system to transform ever-increasing quantities of data into tangible guidance for patient care. [ABSTRACT FROM AUTHOR]

Externalizing disorders have been extensively linked to substance use problems. However, less is known about whether genetic factors underpinning externalizing disorders and environmental features interact to predict substance use disorders (i.e., marijuana abuse and dependence) among urban African Americans. We examined whether polygenic risk scores (PRS) for conduct disorder (CD) and attention-deficit hyperactivity disorder (ADHD) interacted with contextual factors (i.e., parental monitoring, community disadvantage) to influence risk for marijuana use disorders in a sample of African American youth. Participants (N=1,050; 44.2% male) were initially recruited for an elementary school-based universal prevention trial in a Mid-Atlantic city and followed through age 20. Participants reported on their parental monitoring in sixth grade and whether they were diagnosed with marijuana abuse or dependence at age 20. Blood or saliva samples were genotyped using the Affymetrix 6.0 microarrays. The CD and ADHD PRS were created based on genome-wide association studies conducted by Dick et al. (2010) and Demontis et al. (2017), respectively. Community disadvantage was calculated based on census data when participants were in sixth grade. There was an interaction between the CD PRS and community disadvantage such that a higher CD PRS was associated with greater risk for a marijuana use disorder at higher levels of neighborhood disadvantage. This finding should be interpreted with caution owing to the number of significance tests performed. Implications for etiological models and future research directions are presented. [ABSTRACT FROM AUTHOR]

Objective: Bipolar disorder (BD) is one of the most heritable psychiatric conditions and is associated with high suicide risk. To explore the reasons for this link, this study examined the interaction between traumatic stress and BD polygenic risk score in relation to suicidal ideation, suicide attempt, and nonsuicidal self-injury (NSSI) in adolescent and young adult offspring and relatives of persons with BD (BD-relatives) compared with adolescent and young adult offspring of individuals without psychiatric disorders (controls).Method: Data were collected from 4 sites in the United States and 1 site in Australia from 2006 through 2012. Generalized estimating equation models were used to compare rates of ideation, attempts, and NSSI between BD-relatives (n = 307) and controls (n = 166) and to determine the contribution of demographic factors, traumatic stress exposure, lifetime mood or substance (alcohol/drug) use disorders, and BD polygenic risk score.Results: After adjusting for demographic characteristics and mood and substance use disorders, BD-relatives were at increased risk for suicidal ideation and attempts but not for NSSI. Independent of BD-relative versus control status, demographic factors, or mood and substance use disorders, exposure to trauma within the past year (including bullying, sexual abuse, and domestic violence) was associated with suicide attempts (p = .014), and BD polygenic risk score was marginally associated with attempts (p = .061). Importantly, the interaction between BD polygenic risk score and traumatic event exposures was significantly associated with attempts, independent of demographics, relative versus control status, and mood and substance use disorders (p = .041).Conclusion: BD-relatives are at increased risk for suicide attempts and ideation, especially if they are exposed to trauma and have evidence of increased genetic vulnerability. [ABSTRACT FROM AUTHOR]