Predicting Cognitive Executive Functioning with Polygenic Risk Scores for Psychiatric Disorders.

Executive functions (EFs) have been proposed as an endophenotype for psychopathology because EF deficits are associated with most psychiatric disorders. To examine this hypothesis, we derived polygenic risk scores for autism, attention-deficit/hyperactive disorder (ADHD), bipolar disorder, major depression (MDD), and schizophrenia, using genome-wide data from the Psychiatric Genomics Consortium as discovery samples. We then examined the relationships between these polygenic risk scores and three separable EF components measured with a latent variable model. We also examined the relationship between genetic risk for ADHD and MDD and their respective symptom counts and lifetime diagnoses. We found no evidence for larger effect sizes for EFs as endophenotypes for psychiatric disorders. However, larger sample sizes will be important in examining this relationship further.

Characteristics of American Indian/Alaskan Native Quitline Callers Across 14 States.

BACKGROUND: American Indians and Alaska Natives (AI/AN) have the highest smoking prevalence (29.2%) of any other racial/ethnic group in the United States and lower quit rates. Comprehensive health care services, including commercial tobacco cessation treatments, are difficult to access for many AI/AN individuals due to poverty, the rural distribution of tribal territories, cultural barriers and the lack of funding for these programs. Due, in part, to these health care gaps, AI/AN communities are disproportionally affected by nicotine dependence and associated chronic medical and psychiatric conditions. METHODS: We report on data from National Jewish Health that provides telephonic tobacco cessation services for 14 states in the United States. We examine how AI/AN callers who were predominately AI callers differ from their counterparts (i.e., callers identifying as other ethnic groups) in terms of demographic characteristics, commercial tobacco use history, rates of emotional or mental health issues, and rates of chronic illness. RESULTS: Findings from the quitline analyses show a higher rate of preadolescent onset of commercial tobacco use in the AI/AN callers. AI/AN callers are also more likely to live with another commercial tobacco user. Results demonstrate that AI/AN callers are disproportionately impacted by mental health challenges, including high levels of stress, anxiety, and depression. Similarly, AI/AN callers report more chronic medical issues including diseases of the lungs and cardiovascular system. CONCLUSIONS: These findings stress the critical need for tailored efforts to better reach AI/AN commercial tobacco users who are considering treatment, in order to make meaningful gains in commercial tobacco cessation for this vulnerable population. IMPLICATIONS: These findings demonstrate the disproportionate impact of commercial tobacco use on the AI/AN population who utilizes quitline services. These data stress the critical need for tailored efforts to better reach AI/AN commercial tobacco users who are considering treatment, in order to make meaningful gains in commercial tobacco cessation for this vulnerable population.

Adolescent Male Conduct-Disordered Patients in Substance Use Disorder Treatment: Examining the "Limited Prosocial Emotions" Specifier.

To our knowledge, this is the first study to examine the DSM-5-defined conduct disorder (CD) with limited prosocial emotions (LPE) among adolescents in substance use disorder (SUD) treatment, despite the high rates of CD in this population. We tested previously published methods of LPE categorization in a sample of male conduct-disordered patients in SUD treatment (n=196). CD with LPE patients did not demonstrate a distinct pattern in terms of demographics or co-morbidity regardless of the categorization method utilized. In conclusion, LPE, as operationalized here, does not identify a distinct subgroup of patients based on psychiatric comorbidity, SUD diagnoses, or demographics.

Genome-Wide Association Study of Behavioral Disinhibition in a Selected Adolescent Sample.

Behavioral disinhibition (BD) is a quantitative measure designed to capture the heritable variation encompassing risky and impulsive behaviors. As a result, BD represents an ideal target for discovering genetic loci that predispose individuals to a wide range of antisocial behaviors and substance misuse that together represent a large cost to society as a whole. Published genome-wide association studies (GWAS) have examined specific phenotypes that fall under the umbrella of BD (e.g. alcohol dependence, conduct disorder); however no GWAS has specifically examined the overall BD construct. We conducted a GWAS of BD using a sample of 1,901 adolescents over-selected for characteristics that define high BD, such as substance and antisocial behavior problems, finding no individual locus that surpassed genome-wide significance. Although no single SNP was significantly associated with BD, restricted maximum likelihood analysis estimated that 49.3 % of the variance in BD within the Caucasian sub-sample was accounted for by the genotyped SNPs (p = 0.06). Gene-based tests identified seven genes associated with BD (p ≤ 2.0 × 10(-6)). Although the current study was unable to identify specific SNPs or pathways with replicable effects on BD, the substantial sample variance that could be explained by all genotyped SNPs suggests that larger studies could successfully identify common variants associated with BD.

Quitline Outcomes for Smokers in 6 States: Rates of Successful Quitting Vary by Mental Health Status.

INTRODUCTION: Tobacco cessation quitlines are generally effective in assisting smokers who want to quit. However, up to half of quitline callers report a history of mental health conditions and/or recent emotional challenges (MH+), and there has been little study of cessation outcomes for this population. Moreover, evidence suggests that callers who expect their MH+ to interfere with quit attempts have less success with quitting. This study compares rates of quitting among MH+ callers and callers with no mental health conditions or recent emotional challenges (MH-). It also compares rates of quitting between those who felt that mental health issues would interfere with their quit attempt (MHIQ+) and those who did not (MHIQ-). METHODS: National Jewish Health collected telephone data from 6 state quitlines. Participants received up to 5 coaching sessions and up to 8 weeks of nicotine replacement therapy. Smoking status was assessed during 3-month and 6-month post-intervention calls in a subset of participants (n = 4,960) for whom follow-up interviews were completed. RESULTS: Participation in follow-up interviews was not significantly different between callers with MH+ and those without MH- (p = .13). However, at follow-up MH+ participants were less likely to report a successful quit compared with MH- (3-month: 31% vs. 43%; 6-month: 33% vs. 43%; both p < .001). Among MH+ participants, those reporting MHIQ+ were significantly less likely to quit compared with those who were MHIQ- (3-month: 24% vs. 34%; 6-month: 26% vs. 35%; both p ≤ .001). CONCLUSIONS: These findings highlight the importance of evaluating both the mental health status of individuals seeking support for smoking cessation as well as the individuals' expectations for success, because they may need more tailored intervention to ensure the potential for better compared with outcomes.

Early concern and disregard for others as predictors of antisocial behavior.

BACKGROUND: Prediction of antisocial behavior is important, given its adverse impact on both the individuals engaging in antisocial behavior and society. Additional research identifying early predictors of future antisocial behavior, or antisocial propensity, is needed. The present study tested the hypothesis that both concern for others and active disregard for others in distress in toddlers and young children predict antisocial behavior during middle childhood and adolescence. METHODS: A representative sample of same-sex twins (N=956) recruited in Colorado was examined. Mother-rated and researcher-observed concern and disregard for others assessed at age 14-36 months were examined as predictors of parent- (age 4-12), teacher- (age 7-12), and self-reported (age 17) antisocial behavior. RESULTS: Observed disregard for others predicted antisocial behavior assessed by three different informants (parents, teachers, and self), including antisocial behavior assessed 14 years later. It also predicted a higher order antisocial behavior factor (ß=.58, p<.01) after controlling for observed concern for others. Mother-rated disregard for others predicted parent-reported antisocial behavior. Contrary to predictions, neither mother-rated nor observed concern for others inversely predicted antisocial behavior. RESULTS of twin analyses suggested that the covariation between observed disregard for others and antisocial behavior was due to shared environmental influences. CONCLUSIONS: Disregard for others in toddlerhood/early childhood is a strong predictor of antisocial behavior in middle childhood and adolescence. The results suggest the potential need for early assessment of disregard for others and the development of potential interventions.

Externalizing behaviors are associated with SNPs in the CHRNA5/CHRNA3/CHRNB4 gene cluster.

There is strong evidence for shared genetic factors contributing to childhood externalizing disorders and substance abuse. Externalizing disorders often precede early substance experimentation, leading to the idea that individuals inherit a genetic vulnerability to generalized disinhibitory psychopathology. Genetic variation in the CHRNA5/CHRNA3/CHRNB4 gene cluster has been associated with early substance experimentation, nicotine dependence, and other drug behaviors. This study examines whether the CHRNA5/CHRNA3/CHRNB4 locus is correlated also with externalizing behaviors in three independent longitudinally assessed adolescent samples. We developed a common externalizing behavior phenotype from the available measures in the three samples, and tested for association with 10 SNPs in the gene cluster. Significant results were detected in two of the samples, including rs8040868, which remained significant after controlling for smoking quantity. These results expand on previous work focused mainly on drug behaviors, and support the hypothesis that variation in the CHRNA5/CHRNA3/CHRNB4 locus is associated with early externalizing behaviors.

The Association between Positive Parenting and Externalizing Behavior.

The present study examined the role of positive parenting on externalizing behaviors in a longitudinal, genetically informative sample. It often is assumed that positive parenting prevents behavior problems in children via an environmentally mediated process. Alternatively, the association may be due to either an evocative gene-environment correlation, in which parents react to children's genetically-influenced behavior in a positive way, or a passive gene-environment correlation, where parents passively transmit a risk environment and the genetic risk factor for the behavioral outcome to their children. The present study estimated the contribution of these processes in the association between positive parenting and children's externalizing behavior. Positive parenting was assessed via observations at ages 7, 9, 14, 24, and 36 months and externalizing behaviors were assessed through parent report at ages 4, 5, 7, 9, 10, 11, and 12 years. The significant association between positive parenting and externalizing behavior was negative, with children of mothers who showed significantly more positive parenting during toddlerhood having lower levels of externalizing behavior in childhood; however, there was not adequate power to distinguish whether this covariation was due to genetic, shared environmental, or nonshared environmental influences.

Executive Functions and Impulsivity are Genetically Distinct and Independently Predict Psychopathology: Results from Two Adult Twin Studies.

Laboratory executive function (EF) constructs, such as response inhibition, are often conceptually linked with self-report measures of impulsivity, yet their empirical correlations are low. We examined, in two twin studies (Ns=749 and 761 individuals with EF data), the phenotypic and genetic overlap of three EF latent variables (a Common EF factor predicting response inhibition, working memory updating, and mental set shifting tasks, and Updating- and Shifting-specific factors) with five impulsivity dimensions (negative and positive urgency, lack of premeditation and perseverance, and sensation seeking). In both samples, impulsivity dimensions only modestly correlated phenotypically (rs= -.20-.11) and genetically (rAs= -.44-.04) with Common EF. In both samples, Common EF and multiple impulsivity dimensions, particularly negative urgency, independently predicted Externalizing psychopathology, and multiple impulsivity dimensions, but not Common EF, predicted Internalizing psychopathology. These results suggest that EFs and self-reported impulsivity tap different aspects of control that are both relevant for psychopathology.

Individual differences in executive functions are almost entirely genetic in origin.

Recent psychological and neuropsychological research suggests that executive functions--the cognitive control processes that regulate thought and action--are multifaceted and that different types of executive functions are correlated but separable. The present multivariate twin study of 3 executive functions (inhibiting dominant responses, updating working memory representations, and shifting between task sets), measured as latent variables, examined why people vary in these executive control abilities and why these abilities are correlated but separable from a behavioral genetic perspective. Results indicated that executive functions are correlated because they are influenced by a highly heritable (99%) common factor that goes beyond general intelligence or perceptual speed, and they are separable because of additional genetic influences unique to particular executive functions. This combination of general and specific genetic influences places executive functions among the most heritable psychological traits. These results highlight the potential of genetic approaches for uncovering the biological underpinnings of executive functions and suggest a need for examining multiple types of executive functions to distinguish different levels of genetic influences.

Case-control and within-family tests for an association between conduct disorder and DAT1.

BACKGROUND: Conduct disorder (CD) is characterized by a persistent pattern of violating age-appropriate norms and the rights of others, and is one of the most frequently diagnosed disorders among children. CD is moderately heritable, but we know of no reliable associations with specific genes. Evidence suggests that a variable number tandem repeat polymorphism of the dopamine transporter (DAT1) gene may be associated with externalizing behavior in children. OBJECTIVE: To test for an association between the DAT1 gene and CD. DESIGN: Case-control analyses and a transmission disequilibrium test (TDT) were conducted. SETTING/PARTICIPANTS: Cases were (n=210) adolescents enrolled in a Colorado treatment program for conduct and substance use problems. Controls included adolescents matched to the probands in the treatment program and their siblings (n=162). The TDT was conducted using case families in which DNA from both parents was available (95 trios). RESULTS: The case-control analysis of the full sample did not result in a significant association [chi2 (2,372)=0.13, P=0.94]. Cases with early-onset conduct problems had slightly more 10-repeat alleles than controls, although this difference was not significant [chi2 (2,264)=2.19, P=0.33, 9/10 odds ratio (OR)=1.58, 10/10 OR=2.14]. The TDT also did not result in a significant association [chi2(1)=0.12, P=0.94]. CONCLUSION: Results did not support an association between this polymorphism of the DAT1 gene and CD in adolescents.

Item response theory analysis of DSM-IV cannabis abuse and dependence criteria in adolescents.

OBJECTIVE: To examine three aspects of adolescent cannabis problems: do DSM-IV cannabis abuse and dependence criteria represent two different levels of severity of substance involvement, to what degree do each of the 11 abuse and dependence criteria assess adolescent cannabis problems, and do the DSM-IV items function similarly across different adolescent populations? METHOD: We examined 5,587 adolescents ages 11 to 19, including 615 youths in treatment for substance use disorders, 179 adjudicated youths, and 4,793 youths from the community. All of the subjects were assessed with a structured diagnostic interview. Item response theory was used to analyze symptom endorsement patterns. RESULTS: Abuse and dependence criteria were not found to represent different levels of severity of problem cannabis use in any of the samples. Among the 11 abuse and dependence criteria, problems cutting down and legal problems were the least informative for distinguishing problem users. Two dependence criteria and three of the four abuse criteria indicated different severities of cannabis problems across samples. CONCLUSIONS: We found little evidence to support the idea that abuse and dependence are separate constructs for adolescent cannabis problems. Furthermore, certain abuse criteria may indicate severe substance problems, whereas specific dependence items may indicate less severe problems. The abuse items in particular need further study. These results have implications for the refinement of the current substance use disorder criteria for DSM-V.

Association of candidate genes with antisocial drug dependence in adolescents.

The Colorado Center For Antisocial Drug Dependence (CADD) is using several research designs and strategies in its study of the genetic basis for antisocial drug dependence in adolescents. This study reports single nucleotide polymorphism (SNP) association results from a targeted gene assay (SNP chip) of 231 primarily Caucasian male probands in treatment with antisocial drug dependence and a matched set of community controls. The SNP chip was designed to assay 1500 SNPs distributed across 50 candidate genes that have had associations with substance use disorders and conduct disorder. There was an average gene-wide inter-SNP interval of 3000 base pairs. After eliminating SNPs with poor signals and low minor allele frequencies, 60 nominally significant associations were found among the remaining 1073 SNPs in 18 of 49 candidate genes. Although none of the SNPs achieved genome-wide association significance levels (defined as p<.000001), two genes probed with multiple SNPs (OPRM1 and CHRNA2) emerged as plausible candidates for a role in antisocial drug dependence after gene-based permutation tests. The custom-designed SNP chip served as an effective and flexible platform for rapid interrogation of a large number of plausible candidate genes.

Common genetic and environmental influences on major depressive disorder and conduct disorder.

The evidence for common genetic and environmental influences on conduct disorder (CD) and major depressive disorder (MDD) in adolescents was examined. A sample of 570 monozygotic twin pairs, 592 dizygotic twin pairs, and 426 non-twin siblings, aged 12-18 years, was recruited from the Colorado Twin Registry. For the past year data, there was a significant correlation between the genetic influences on MDD and CD and, for the lifetime data, there was a significant correlation between the genetic influences on MDD and CD, and a significant correlation between the nonshared environmental influences on MDD and CD. Our results suggest that some genetic factors will increase an individual's vulnerability to both MDD and CD in adolescence.

Predictors of adult outcomes in clinically- and legally-ascertained youth with externalizing problems.

Externalizing problems (EP), including rule-breaking, aggression, and criminal involvement, are highly prevalent during adolescence, but the adult outcomes of adolescents exhibiting EP are characterized by heterogeneity. Although many youths' EP subside after adolescence, others' persists into adulthood. Characterizing the development of severe EP is essential to prevention and intervention efforts. Multiple predictors of adult antisocial personality disorder (ASPD) and legal outcomes of a large sample (N = 1205) of clinically- or legally-ascertained adolescents (ages 12-19 years) with severe EP were examined. Many psychosocial predictors hypothesized to predict persistence of EP demonstrated zero-order associations with adult outcomes, but accounted for little unique variation after accounting for baseline conduct disorder symptoms (CD) and demographic factors. Baseline measures of intelligence, which explained independent variation in legal outcomes, provided the only consistent exception to this pattern, though future work is needed to parse these effects from those of socioeconomic factors. CD severity during adolescence is a parsimonious index of liability for persistence of EP into adulthood that explains outcome variance above and beyond all other demographic and psychosocial predictors in this sample.

Cannabis use disorder and male sex predict medical cannabis card status in a sample of high risk adolescents.

OBJECTIVE: To examine if a substance use disorder (SUD), especially cannabis use disorder in adolescence, predicts future medical cannabis card status among high-risk youth. METHODS: Data collection occurred in Denver and San Diego. We recruited adolescents, with or at high risk for SUD and conduct problems (hereafter probands) and their siblings (n=654). Baseline (Wave 1) assessments took place between 1999 and 2008, and follow-up (Wave 2) took place between 2010 and 2013. In initial bivariate analyses, we examined whether baseline DSM-IV cannabis abuse/dependence (along with other potential predictors) was associated with possessing a medical cannabis card in young adulthood (Wave 2). Significant predictors were then included in a multiple binomial regression. Self-reported general physical health was also evaluated at both time points. Finally, within Wave 2, we tested whether card status was associated with concurrent substance dependence. RESULTS: About 16% of the sample self-reported having a medical cannabis card at follow-up. Though bivariate analyses demonstrated that multiple predictors were significantly associated with Wave 2 card status, in our multiple binomial regression only cannabis abuse/dependence and male sex remained significant. At Wave 2, those with a medical cannabis card were significantly more likely to endorse criteria for concurrent cannabis dependence. There was no significant difference in self-reported general physical health. CONCLUSIONS: Cannabis abuse/dependence and male sex positively predicted future medical cannabis card holder status among a sample of high risk adolescents. Physicians conducting evaluations for medical cannabis cards should carefully evaluate and consider past and concurrent cannabis addiction.

Delinquent peer affiliation and conduct problems: A twin study.

Many putative environmental risks correlate with individuals' genotypes. The association between delinquent peer affiliation and conduct problems may occur because of shared genetic liability. Five hundred fifty three monozygotic and 558 dizygotic twin pairs, aged 11 to 18 years, were assessed for delinquent peer affiliation and conduct problems. The authors investigated whether genes contribute to both delinquent peer affiliation and the correlation between delinquent peer affiliations and conduct problems. Delinquent peer affiliation was influenced by genetic, shared environmental, and nonshared environmental factors; genetic factors also contributed to the correlation between delinquent peer affiliations and conduct problems, providing evidence for genotype-environment correlation. The magnitude of the genetic variance of conduct problems was contextually dependent on levels of delinquent peer affiliation and was greater at higher levels of delinquent peer affiliation.

The role of conduct disorder in explaining the comorbidity between alcohol and illicit drug dependence in adolescence.

BACKGROUND: Conduct disorder (CD), alcohol dependence (AD), and illicit drug dependence (IDD) frequently co-occur. This paper describes the result of an investigation of the extent to which comorbid alcohol and illicit drug dependence in adolescents are explained by etiological factors in common with conduct disorder. METHODS: Participants were 645 MZ twin pairs, 702 DZ twin pairs, 429 biological sibling pairs, and 96 adoptive sibling pairs, aged 12-18 years, from a community based sample. Conduct disorder was measured using the Diagnostic Interview Schedule for Children-IV. Alcohol and illicit drug dependence were assessed using the Composite International Diagnostic Interview-Substance Abuse Module (CIDI-SAM). For each outcome, subjects were categorized into those with no symptoms, those with one or more symptoms but no diagnosis, and those with a diagnosis. RESULTS: The heritability estimates for CD, AD, and IDD were 58, 66, and 36%, respectively. The genetic correlation between AD and IDD was partially explained by the genetic risk they both share with conduct disorder. CONCLUSIONS: We conclude that conduct disorder in adolescents explains, in part, the co-occurrence of alcohol and illicit drug dependence. Specifically, the genetic contribution to their covariation is explained partially by the genetic contribution in common with conduct disorder.

Test of association between TaqIA A1 allele and alcohol use disorder phenotypes in a sample of adolescent patients with serious substance and behavioral problems.

UNLABELLED: Several studies have demonstrated a significant association between the A1 allele of the TaqIA polymorphism and various phenotypes of alcoholism, others have not, and two studies have shown the reversed association, where the A2 allele was associated with higher levels of alcohol consumption. We sought to test for an association between early onset (in childhood or adolescence) alcohol use disorders and the DRD2 TaqIA polymorphism and to resolve some of the hypothesized explanations for previous negative results, utilizing a larger sample than many previous studies. METHODS: We selected individuals with a lifetime alcohol abuse or dependence (n=239) diagnosis from a clinically ascertained sample of youth (ages 13-19) with serious conduct and substance problems (about 90% also met criteria for conduct disorder and a cannabis use disorder) and compared them with individuals without a lifetime alcohol use disorder diagnosis ascertained from (1) community adolescent controls (n=151), (2) siblings of patients (n=87) and (3) other adolescent patients (n=92). Cases were compared with each control group, separately, by genotype using the chi(2)-test. Using 78 adolescent patients with an alcohol use disorder where genotypic information was available for both parents, we conducted the transmission disequilibrium test (TDT). RESULTS: Case-control results were non-significant using the entire community control sample (chi(2)(2)=1.92; p=0.38) and when restricting the sample to Caucasians (chi(2)(2)=3.81; p=0.15) or Hispanics (chi(2)(2)=1.70; p=0.43). Case-control results using the other comparison groups and TDT results were also non-significant. DISCUSSION: We did not find support for an association between the TaqIA polymorphism and early onset alcohol use disorders.

A genome-wide scan for loci influencing adolescent cannabis dependence symptoms: evidence for linkage on chromosomes 3 and 9.

OBJECTIVE: Cannabis is the most frequently abused illicit substance among adolescents and young adults. Genetic risk factors account for part of the variation in the development of cannabis dependence symptoms; however, no linkage studies have been performed for cannabis dependence symptoms. This study aimed to identify such loci. METHOD: Three hundred and twenty-four sibling pairs from 192 families were assessed for cannabis dependence symptoms. Probands (13-19 years of age) were recruited from consecutive admissions to substance abuse treatment facilities. The siblings of the probands ranged in age from 12 to 25 years. A community-based sample of 4843 adolescents and young adults was utilized to define an age- and sex-corrected index of cannabis dependence vulnerability. DSM-IV cannabis dependence symptoms were assessed in youth and their family members with the Composite International Diagnostic Instrument-Substance Abuse Module. Siblings and parents were genotyped for 374 microsatellite markers distributed across the 22 autosomes (average inter-marker distance=9.2cM). Cannabis dependence symptoms were analyzed using Merlin-regress, a regression-based method that is robust to sample selection. RESULTS: Evidence for suggestive linkage was found on chromosome 3q21 near marker D3S1267 (LOD=2.61), and on chromosome 9q34 near marker D9S1826 (LOD=2.57). CONCLUSIONS: This is the first reported linkage study of cannabis dependence symptoms. Other reports of linkage regions for illicit substance dependence have been reported near 3q21, suggesting that this region may contain a quantitative trait loci influencing cannabis dependence and other substance use disorders.