A Prospective Comparison of Bipolar I and II Subjects with and without Comorbid Cannabis Use Disorders from the COGA Dataset.

OBJECTIVE: The comorbidity of alcohol and substance use disorders among persons with bipolar disorder is elevated, as indicated by epidemiological and clinical studies. Following alcohol use, cannabis is the most frequently used and abused illicit substance among bipolar individuals, and such use may lead to comorbid cannabis use disorders (CUD). Previous research indicated that CUDs were related to a more severe course of bipolar disorder and higher rates of other comorbid alcohol and substance use disorders. Few studies, however, have conducted longitudinal research on this comorbidity. The aim of this study is to investigate the influence of CUD on the course of bipolar I and II individuals during a 5-year follow-up. METHODS: The characteristics of bipolar disorder, cannabis use disorders, and other alcohol and substance use disorders, as well as comorbid mental disorders, were assessed using a standardized semi-structured interview (SSAGA) at both baseline and the 5-year follow-up. N = 180 bipolar I and II patients were subdivided into groups of with and without comorbid cannabis use disorders (CUD). RESULTS: Of the 77 bipolar I and 103 bipolar II patients, n = 65 (36.1%) had a comorbid diagnosis of any CUD (DSM-IV cannabis abuse or dependence). Comorbid bipolar patients with CUD had higher rates of other substance use disorders and posttraumatic stress disorders, more affective symptoms, and less psychosocial functioning at baseline and at 5-year follow-up. In contrast to previously reported findings, higher rates of anxiety disorders and bipolar disorder complications (e.g., mixed episodes, rapid cycling, and manic or hypomanic episodes) were not found. The effect of CUD on other substance use disorders was confirmed using moderation analyses. CONCLUSIONS: A 5-year prospective evaluation of bipolar patients with and without CUD confirmed previous investigations, suggesting that the risk of other substance use disorders is significantly increased in comorbid individuals. CUD has a moderation effect, while no effect was found for other mental disorders. Findings from this study and previous research may be due to the examination of different phenotypes (Cannabis use vs. CUD) and sample variation (family study vs. clinical and epidemiological populations).

Genomic risk for post-traumatic stress disorder in families densely affected with alcohol use disorders.

Recent genome-wide association studies (GWAS) have identified genetic markers of post-traumatic stress disorder (PTSD) in civilian and military populations. However, studies have yet to examine the genetics of PTSD while factoring in risk for alcohol dependence, which commonly co-occur. We examined genome-wide associations for DSM-IV PTSD among 4,978 trauma-exposed participants (31% with alcohol dependence, 50% female, 30% African ancestry) from the Collaborative Study on the Genetics of Alcoholism (COGA). We also examined associations of polygenic risk scores (PRS) derived from the Psychiatric Genomics Consortium (PGC)-PTSD Freeze 2 (N = 3533) and Million Veterans Program GWAS of PTSD (N = 5200) with PTSD and substance dependence in COGA, and moderating effects of sex and alcohol dependence. 7.3% of COGA participants met criteria for PTSD, with higher rates in females (10.1%) and those with alcohol dependence (12.3%). No independent loci met genome-wide significance in the PTSD meta-analysis of European (EA) and African ancestry (AA) participants. The PGC-PTSD PRS was associated with increased risk for PTSD (B = 0.126, p < 0.001), alcohol dependence (B = 0.231, p < 0.001), and cocaine dependence (B = 0.086, p < 0.01) in EA individuals. A significant interaction was observed, such that EA individuals with alcohol dependence and higher polygenic risk for PTSD were more likely to have PTSD (B = 0.090, p < 0.01) than those without alcohol dependence. These results further support the importance of examining substance dependence, specifically alcohol dependence, and PTSD together when investigating genetic influence on these disorders.

Signal in the noise: Altered brain activation among adolescent alcohol users detected via the analysis of intra-individual variability1.

RATIONALE: Unlike its average level, the variability in brain activation over time or trials can capture subtle and brief disruptions likely to occur among participants with low-to-moderate levels of substance use or misuse. OBJECTIVE: The present study used this intra-individual variability measurement approach to detect neural processing differences associated with light-to-moderate use of alcohol among 14-19-year-old adolescents. METHOD: A total of 128 participants reporting any level of alcohol use during the previous 6 months and 87 participants reporting no use during this period completed intake questionnaires and interviews as well as an assessment of P300 electroencephalographic responses to novel stimuli recorded during two separate tasks. RESULTS: In addition to differing in recent alcohol use, the groups differed in nicotine and cannabis use, risk-taking behavior and conduct disorder symptoms, and P300 amplitude inter-trial variability (ITV) across both tasks. Across all participants, P300 ITV was positively correlated with a family history of depression but not with a family history of alcohol dependence. There were no group differences in P300 amplitude averaged across trials. CONCLUSIONS: Recent reports attributing brain volume or brain function differences to an effect of light-to-moderate alcohol use should be viewed with great caution. In the present analysis of brain function differences among substance-using adolescents, the group differences were small, complicated by many factors coinciding with or preceding alcohol use, and not reflected in a stable central tendency.

Subtypes of Alcohol Dependence and 36-Year Mortality.

BACKGROUND: Chronic, heavy alcohol use is associated with multiple health problems, including premature death. Further, the clinical presentation of alcohol dependence may differentially affect and predict the long-term health consequences of affected individuals. Subtypes of alcohol dependence based upon treatment intake information can help identify homogenous groups of patients for treatment purposes, but have not been used to predict long-term outcomes. The current study examined mortality in a 36-year posttreatment interval among 4 subtypes of alcohol-dependent patients based upon their initial intake data. METHODS: Extensive baseline data were collected from n = 316 male and female patients receiving inpatient treatment for alcohol dependence between 1980 and 1982. Four alcohol dependent subtypes (Del Boca & Hesselbrock, Alcohol Health Res World, 20:56, 1996) derived from the baseline data were used to examine the 1-year posttreatment drinking status and the risk of death 36 years postdischarge. Public records were used to determine patient deaths in the 36 years since discharge. RESULTS: At the 36-year follow-up interval since discharge, 68.4% of the sample had died. The 4 subtypes were found to be associated with different rates of resumption of regular drinking in the first year posttreatment and a differential risk of mortality. An increased risk for returning to regular drinking (once a week or more) and early death were associated with subtypes defined, in part, by conduct problems and externalizing disorders. Regardless of subtype membership, women had the highest risk of death following treatment. CONCLUSIONS: This study demonstrates the clinical usefulness of subtypes of alcohol dependence for examining different alcohol use outcomes, including predicting mortality. The increased risks for returning to regular drinking once a week or more and early death posttreatment among subtypes associated with conduct problems and externalizing disorders suggest the need for continued monitoring and possible additional intervention postdischarge.

Associations of parental alcohol use disorders and parental separation with offspring initiation of alcohol, cigarette and cannabis use and sexual debut in high-risk families.

BACKGROUND AND AIMS: Parental alcohol use disorders (AUDs) and parental separation are associated with increased risk for early use of alcohol in offspring, but whether they increase risks for early use of other substances and for early sexual debut is under-studied. We focused on associations of parental AUDs and parental separation with substance initiation and sexual debut to (1) test the strength of the associations of parental AUDs and parental separation with time to initiation (age in years) of alcohol, tobacco and cannabis use and sexual debut and (2) compare the strength of association of parental AUD and parental separation with initiation. DESIGN: Prospective adolescent and young adult cohort of a high-risk family study, the Collaborative Study on the Genetics of Alcoholism (COGA). SETTING: Six sites in the United States. PARTICIPANTS: A total of 3257 offspring (aged 14-33 years) first assessed in 2004 and sought for interview approximately every 2 years thereafter; 1945 (59.7%) offspring had a parent with an AUD. MEASUREMENTS: Diagnostic interview data on offspring substance use and sexual debut were based on first report of these experiences. Parental life-time AUD was based on their own self-report when parents were interviewed (1991-2005) for most parents, or on offspring and other family member reports for parents who were not interviewed. Parental separation was based on offspring reports of not living with both biological parents most of the time between ages 12 and 17 years. FINDINGS: Parental AUDs were associated with increased hazards for all outcomes, with cumulative hazards ranging from 1.19 to 2.71. Parental separation was also an independent and consistent predictor of early substance use and sexual debut, with hazards ranging from 1.19 to 2.34. The strength of association of parental separation with substance initiation was equal to that of having two AUD-affected parents, and its association with sexual debut was stronger than the association of parental AUD in one or both parents. CONCLUSIONS: Parental alcohol use disorders (AUDs) and parental separation are independent and consistent predictors of increased risk for early alcohol, tobacco and cannabis use and sexual debut in offspring from families with a high risk of parental AUDs.

CYP2A6 metabolism in the development of smoking behaviors in young adults.

Cytochrome P450 2A6 (CYP2A6) encodes the enzyme responsible for the majority of nicotine metabolism. Previous studies support that slow metabolizers smoke fewer cigarettes once nicotine dependent but provide conflicting results on the role of CYP2A6 in the development of dependence. By focusing on the critical period of young adulthood, this study examines the relationship of CYP2A6 variation and smoking milestones. A total of 1209 European American young adults enrolled in the Collaborative Study on the Genetics of Alcoholism were genotyped for CYP2A6 variants to calculate a previously well-validated metric that estimates nicotine metabolism. This metric was not associated with the transition from never smoking to smoking initiation nor with the transition from initiation to daily smoking (P > 0.4). But among young adults who had become daily smokers (n = 506), decreased metabolism was associated with increased risk of nicotine dependence (P = 0.03) (defined as Fagerström Test for Nicotine Dependence score ≥4). This finding was replicated in the Collaborative Genetic Study of Nicotine Dependence with 335 young adult daily smokers (P = 0.02). Secondary meta-analysis indicated that slow metabolizers had a 53 percent increased odds (OR = 1.53, 95 percent CI 1.11-2.11, P = 0.009) of developing nicotine dependence compared with normal metabolizers. Furthermore, secondary analyses examining four-level response of time to first cigarette after waking (>60, 31-60, 6-30, ≤5 minutes) demonstrated a robust effect of the metabolism metric in Collaborative Study on the Genetics of Alcoholism (P = 0.03) and Collaborative Genetic Study of Nicotine Dependence (P = 0.004), illustrating the important role of this measure of dependence. These findings highlight the complex role of CYP2A6 variation across different developmental stages of smoking behaviors.

Introduction: Special issue on genetic research of alcohol use disorder in diverse racial/ethnic populations.

This special issue of The American Journal on Addictions is an extension of a workshop held at the Research Society on Alcoholism (2015) highlighting several important issues related to studies of the genetic bases of alcohol use disorder among racially/ethnically diverse populations. While not exhaustive in their coverage, the papers in this special issue focus on three important topics: (1) the importance of considering the social and environmental context in genetic analyses; (2) social and cultural considerations for engaging diverse communities in genetic research; and (3) methodologies related to phenotype development for use with racially/ethnically diverse populations. A brief overview of each paper included in these three sections is presented. The issue concludes with additional considerations for genetic research with racially/ethnically diverse population groups along with a commentary. (Am J Addict 2017;26:422-423).

Conclusion: Special issue on genetic and alcohol use disorder research with diverse racial/ethnic groups: Key findings and potential next steps.

BACKGROUND AND OBJECTIVES: This special issue brings together papers focusing on a wide range of topics relevant to the research and understanding of the role of race/ethnicity and genetic variation for the susceptibility of developing an alcohol use disorder (AUD). METHODS: The key findings from the issue's 10 articles are reviewed and organized here around three topics: I: addictive behaviors and potential environmental influences; II: a focus on four racial/ethnic groups; and III: special methodologies. RESULTS: Several potential next steps in improving effective research strategies are highlighted: (1) implementing best practices for outreach and community engagement may reduce reluctance to participate; (2) recruiting adequately sized and racially/ethnically diverse samples will require new collaborations with investigators who successfully work in diverse communities; (3) identifying and assessing environmental influences that are both unique to, and common among, racial/ethnic groups may inform preventions for AUD; (4) use of standardized measures will facilitate the generation of larger samples and meta-analysis of research findings; and (5) use of better analytic approaches and experimental methods will improve replication in gene finding research and help advance new areas of research. CONCLUSIONS: Genetic research of AUD in diverse racial/ethnic populations is advancing. The articles in this issue examined the general theme of including diverse population groups in genetic studies and offered potential strategies for addressing some common problems. SCIENTIFIC SIGNIFICANCE: Greater inclusion of diverse racial/ethnic populations in this research is important to ensure that the benefits of new knowledge and technology are equally shared. (Am J Addict 2017;26:532-537).

Reciprocal relationships between substance use and disorders and suicidal ideation and suicide attempts in the Collaborative Study of the Genetics of Alcoholism.

BACKGROUND: Substance use and misuse and suicidal thoughts and behaviors tend to co-occur. The purpose of this study was to examine whether (a) suicidal ideation and attempt are related to onset of alcohol, nicotine and cannabis use and dependence; (b) early use of alcohol, nicotine and cannabis is associated with onset of suicidal ideation and attempt; and (c) whether these associations persist while controlling for covariates, such as family history of alcohol problems, major depression and other internalizing and externalizing disorders. METHODS: The prospective cohort of the Collaborative Study of the Genetics of Alcoholism (COGA; N=3277) was used. Cross-sectional and discrete time logistic regression (i.e. survival) analyses examined associations between suicidal ideation and attempt and onset of alcohol, nicotine and cannabis use and dependence. Survival models also examined whether individual early substance use was related to onset of ideation and attempt. RESULTS: Ideation was related to 0.71-0.77 odds of onset of subsequent alcohol, nicotine and cannabis use. Attempt was associated with 1.44-1.61 odds of later alcohol, nicotine and cannabis dependence, even after accounting for covariates. Evidence for early substance use being related to subsequent onset of ideation or attempt was limited. Several sex and race differences emerged. LIMITATIONS: The sample was ascertained for family history of alcoholism; not all participants had been followed up allowing for censored observations; reporting bias. CONCLUSION: Suicide attempts are associated with increased likelihood of onset of substance dependence.

Comparison of Parent, Peer, Psychiatric, and Cannabis Use Influences Across Stages of Offspring Alcohol Involvement: Evidence from the COGA Prospective Study.

BACKGROUND: All stages of development of alcohol use disorder (AUD) have not been equally studied. While initiation of drinking has been given considerable attention, other stages have not been as thoroughly investigated. It is not clear whether the same factors are associated consistently across early and late transitions in AUD involvement. High-risk family samples that are enriched for AUD vulnerability and transitions in AUD development offer an opportunity to examine influences across multiple stages of AUD development. METHODS: Data from adolescents and young adults from high-risk families were used to study 4 transitions in AUD development-time to first drink, first drink to first problem, first drink to first diagnosis, and first problem to first diagnosis. Cox modeling was used to compare associations of parental AUD, parental separation, peer substance use, offspring ever-use of cannabis, trauma exposures, and internalizing and externalizing psychopathology across transitions. RESULTS: Hazards of most transitions were elevated for those who had ever used cannabis, those who attributed substance use to their peers, those with externalizing disorders, and those with parents with AUD. Many risk factors were linked to early initiation of alcohol, particularly cannabis use. Internalizing disorders were associated with later stages. Nonassaultive trauma was associated only with early initiation; assaultive trauma was not associated with any transition. CONCLUSIONS: In this large, ethnically diverse sample of high-risk youth, significant influences across transitions were fairly consistent, with externalizing disorders and cannabis ever-use elevating the likelihood of each stage, and peer and parental (and especially maternal AUD) influences linked to initiation and some later stages. Finally, in light of the increasingly permissive legal and social stances toward cannabis in the United States, the marked elevations of all alcohol outcomes observed for cannabis use underscore the importance of studying the underpinnings of this relationship.

Interactions Between Alcohol Metabolism Genes and Religious Involvement in Association With Maximum Drinks and Alcohol Dependence Symptoms.

OBJECTIVE: Variations in the genes encoding alcohol dehydrogenase (ADH) enzymes are associated with both alcohol consumption and dependence in multiple populations. Additionally, some environmental factors have been recognized as modifiers of these relationships. This study examined the modifying effect of religious involvement on relationships between ADH gene variants and alcohol consumption-related phenotypes. METHOD: Subjects were African American, European American, and Hispanic American adults with lifetime exposure to alcohol (N = 7,716; 53% female) from the Collaborative Study on the Genetics of Alcoholism. Genetic markers included ADH1Brs1229984, ADH1B-rs2066702, ADH1C-rs698, ADH4-rs1042364, and ADH4-rs1800759. Phenotypes were maximum drinks consumed in a 24-hour period and total number of alcohol dependence symptoms according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Religious involvement was defined by self-reported religious services attendance. RESULTS: Both religious involvement and ADH1B-rs1229984 were negatively associated with the number of maximum drinks consumed and the number of lifetime alcohol dependence symptoms endorsed. The interactions of religious involvement with ADH1B-rs2066702, ADH1C-rs698, and ADH4-rs1042364 were significantly associated with maximum drinks and alcohol dependence symptoms. Risk variants had weaker associations with maximum drinks and alcohol dependence symptoms as a function of increasing religious involvement. CONCLUSIONS: This study provided initial evidence of a modifying effect for religious involvement on relationships between ADH variants and maximum drinks and alcohol dependence symptoms.

Two Studies of Connectedness to Parents and Suicidal Thoughts and Behavior in Children and Adolescents.

We tested hypotheses that greater connectedness to parent(s) is associated with lower risk for nonlethal suicidal thoughts and behavior (STB), termed direct protective effects, and that parent connectedness serves to moderate (lower) the risk for STB associated with psychopathology including major depressive episode (MDE), termed moderating protective effects. Independent samples of children and adolescents recruited for a multicenter study of familial alcoholism were studied. Generalized estimating equation models were used that adjusted for age, sex, and youth psychopathology variables. The sample for Study 1 was assessed at baseline and about 2- and 4-year follow-ups, with baseline characteristics of n = 921, M age = 14.3 ± 1.8 years, and 51.8% female. The sample for Study 2 was assessed at baseline and about 5-year follow-up, with baseline characteristics of n = 867, M age = 12.0 ± 3.2 years, and 51.0% female. In both studies, increased perceived connectedness to father but not mother was associated with lower risk for measures of STB, consistent with direct protective effects. In Study 1, measures of parent connectedness were associated with lower risk for STB but only for youth that did not experience MDE (or alcohol use disorder), inconsistent with moderating protective effects. Study 2 showed that connectedness to fathers was associated with lower risk for suicide plans or attempts (severe STB) but not frequent thoughts of death or dying (nonsevere STB). Improved connectedness to fathers may lower risk for STB in children and adolescents, consistent with direct protective effects. Hypotheses about moderating protective effects were not supported.

Deficient Event-Related Theta Oscillations in Individuals at Risk for Alcoholism: A Study of Reward Processing and Impulsivity Features.

BACKGROUND: Individuals at high risk to develop alcoholism often manifest neurocognitive deficits as well as increased impulsivity. Event-related oscillations (EROs) have been used to effectively measure brain (dys)function during cognitive tasks in individuals with alcoholism and related disorders and in those at risk to develop these disorders. The current study examines ERO theta power during reward processing as well as impulsivity in adolescent and young adult subjects at high risk for alcoholism. METHODS: EROs were recorded during a monetary gambling task (MGT) in 12-25 years old participants (N = 1821; males = 48%) from high risk alcoholic families (HR, N = 1534) and comparison low risk community families (LR, N = 287) from the Collaborative Study on the Genetics of Alcoholism (COGA). Impulsivity scores and prevalence of externalizing diagnoses were also compared between LR and HR groups. RESULTS: HR offspring showed lower theta power and decreased current source density (CSD) activity than LR offspring during loss and gain conditions. Younger males had higher theta power than younger females in both groups, while the older HR females showed more theta power than older HR males. Younger subjects showed higher theta power than older subjects in each comparison. Differences in topography (i.e., frontalization) between groups were also observed. Further, HR subjects across gender had higher impulsivity scores and increased prevalence of externalizing disorders compared to LR subjects. CONCLUSIONS: As theta power during reward processing is found to be lower not only in alcoholics, but also in HR subjects, it is proposed that reduced reward-related theta power, in addition to impulsivity and externalizing features, may be related in a predisposition to develop alcoholism and related disorders.

Reward processing deficits and impulsivity in high-risk offspring of alcoholics: A study of event-related potentials during a monetary gambling task.

BACKGROUND: Individuals at high risk to develop alcoholism often manifest neurocognitive deficits as well as increased impulsivity. The goal of the present study is to elucidate reward processing deficits, externalizing disorders, and impulsivity as elicited by electrophysiological, clinical and behavioral measures in subjects at high risk for alcoholism from families densely affected by alcoholism in the context of brain maturation across age groups and gender. METHODS: Event-related potentials (ERPs) and current source density (CSD) during a monetary gambling task (MGT) were measured in 12-25 year old offspring (N=1864) of families in the Collaborative Study on the Genetics of Alcoholism (COGA) Prospective study; the high risk (HR, N=1569) subjects were from families densely affected with alcoholism and the low risk (LR, N=295) subjects were from community families. Externalizing disorders and impulsivity scores were also compared between LR and HR groups. RESULTS: HR offspring from older (16-25 years) male and younger (12-15 years) female subgroups showed lower P3 amplitude than LR subjects. The amplitude decrement was most prominent in HR males during the loss condition. Overall, P3 amplitude increase at anterior sites and decrease at posterior areas were seen in older compared to younger subjects, suggesting frontalization during brain maturation. The HR subgroups also exhibited hypofrontality manifested as weaker CSD activity during both loss and gain conditions at frontal regions. Further, the HR subjects had higher impulsivity scores and increased prevalence of externalizing disorders. P3 amplitudes during the gain condition were negatively correlated with impulsivity scores. CONCLUSIONS: Older male and younger female HR offspring, compared to their LR counterparts, manifested reward processing deficits as indexed by lower P3 amplitude and weaker CSD activity, along with higher prevalence of externalizing disorders and higher impulsivity scores. SIGNIFICANCE: Reward related P3 is a valuable measure reflecting neurocognitive dysfunction in subjects at risk for alcoholism, as well as to characterize reward processing and brain maturation across gender and age group.

An ADH1B variant and peer drinking in progression to adolescent drinking milestones: evidence of a gene-by-environment interaction.

BACKGROUND: Adolescent drinking is an important public health concern, one that is influenced by both genetic and environmental factors. The functional variant rs1229984 in alcohol dehydrogenase 1B (ADH1B) has been associated at a genome-wide level with alcohol use disorders in diverse adult populations. However, few data are available regarding whether this variant influences early drinking behaviors and whether social context moderates this effect. This study examines the interplay between rs1229984 and peer drinking in the development of adolescent drinking milestones. METHODS: One thousand five hundred and fifty European and African American individuals who had a full drink of alcohol before age 18 were selected from a longitudinal study of youth as part of the Collaborative Study on the Genetics of Alcoholism (COGA). Cox proportional hazards regression, with G × E product terms in the final models, was used to study 2 primary outcomes during adolescence: age of first intoxication and age of first DSM-5 alcohol use disorder symptom. RESULTS: The minor A allele of rs1229984 was associated with a protective effect for first intoxication (HR = 0.56, 95% CI 0.41 to 0.76) and first DSM-5 symptom (HR = 0.45, 95% CI 0.26 to 0.77) in the final models. Reporting that most or all best friends drink was associated with a hazardous effect for first intoxication (HR = 1.81, 95% CI 1.62 to 2.01) and first DSM-5 symptom (HR = 2.17, 95% 1.88 to 2.50) in the final models. Furthermore, there was a significant G × E interaction for first intoxication (p = 0.002) and first DSM-5 symptom (p = 0.01). Among individuals reporting none or few best friends drinking, the ADH1B variant had a protective effect for adolescent drinking milestones, but for those reporting most or all best friends drinking, this effect was greatly reduced. CONCLUSIONS: Our results suggest that the risk factor of best friends drinking attenuates the protective effect of a well-established ADH1B variant for 2 adolescent drinking behaviors. These findings illustrate the interplay between genetic and environmental factors in the development of drinking milestones during adolescence.

On the association of common and rare genetic variation influencing body mass index: a combined SNP and CNV analysis.

BACKGROUND: As the architecture of complex traits incorporates a widening spectrum of genetic variation, analyses integrating common and rare variation are needed. Body mass index (BMI) represents a model trait, since common variation shows robust association but accounts for a fraction of the heritability. A combined analysis of single nucleotide polymorphisms (SNP) and copy number variation (CNV) was performed using 1850 European and 498 African-Americans from the Study of Addiction: Genetics and Environment. Genetic risk sum scores (GRSS) were constructed using 32 BMI-validated SNPs and aggregate-risk methods were compared: count versus weighted and proxy versus imputation. RESULTS: The weighted SNP-GRSS constructed from imputed probabilities of risk alleles performed best and was highly associated with BMI (p=4.3×10(-16)) accounting for 3% of the phenotypic variance. In addition to BMI-validated SNPs, common and rare BMI/obesity-associated CNVs were identified from the literature. Of the 84 CNVs previously reported, only 21-kilobase deletions on 16p12.3 showed evidence for association with BMI (p=0.003, frequency=16.9%), with two CNVs nominally associated with class II obesity, 1p36.1 duplications (OR=3.1, p=0.009, frequency 1.2%) and 5q13.2 deletions (OR=1.5, p=0.048, frequency 7.7%). All other CNVs, individually and in aggregate, were not associated with BMI or obesity. The combined model, including covariates, SNP-GRSS, and 16p12.3 deletion accounted for 11.5% of phenotypic variance in BMI (3.2% from genetic effects). Models significantly predicted obesity classification with maximum discriminative ability for morbid-obesity (p=3.15×10(-18)). CONCLUSION: Results show that incorporating validated effect sizes and allelic probabilities improve prediction algorithms. Although rare-CNVs did not account for significant phenotypic variation, results provide a framework for integrated analyses.

Parent and child psychopathology and suicide attempts among children of parents with alcohol use disorder.

Parents with psychopathology such as alcohol use disorder (AUD) that confers risk for suicide attempt (SA) may have children who are more likely to develop such psychopathology and to attempt suicide, suggesting that risk may be "transmitted" from parents to children. We examined this phenomenon during the transition from childhood to adolescence, when risk for SA increases dramatically. A cohort of 418 children were examined at average age 9.4 (range 7-14) years at enrollment (Time 1, childhood) and approximately 5 years later, prior to reaching age 18 (Time 2, adolescence). One or both biological parents, oversampled for AUD, were also interviewed. Structural equation models (SEM) examined father-child, mother-child, and either/both parent-child associations. The primary outcome was SA over follow-up among offspring, assessed at Time 2. As hypothesized, parental antisocial personality disorder predicted conduct disorder symptoms in offspring both during childhood and adolescence (parent-child model, father-child model) and maternal AUD predicted conduct disorder symptoms during childhood (mother-child model). However, we did not find evidence to support transmission of depression from parents to offspring either during childhood or adolescence, and parent psychopathology did not show statistically significant associations with SA during adolescence. In conclusion, we conducted a rare study of parent-to-child "transmission" of risk for SA that used a prospective research design, included diagnostic interviews with both parents and offspring, and examined the transition from childhood to adolescence, and the first such study in children of parents with AUD. Results provided mixed support for hypothesized parent-child associations.

Multiple distinct CHRNB3-CHRNA6 variants are genetic risk factors for nicotine dependence in African Americans and European Americans.

AIMS: Studies have shown association between common variants in the α6-ß3 nicotinic receptor subunit gene cluster and nicotine dependence in European ancestry populations. We investigate whether this generalizes to African Americans, whether the association is specific to nicotine dependence and whether this region contains additional genetic contributors to nicotine dependence. DESIGN: We examined consistency of association across studies and race between the α6ß3 nicotinic receptor subunit locus and nicotine, alcohol, marijuana and cocaine dependence in three independent studies. SETTING: United States of America. PARTICIPANTS: European Americans and African Americans from three case-control studies of substance dependence. MEASUREMENTS: Subjects were evaluated using the Semi-Structured Assessment for the Genetics of Alcoholism. Nicotine dependence was determined using the Fagerström Test for Nicotine Dependence. FINDINGS: The single nucleotide polymorphism rs13273442 was associated significantly with nicotine dependence across all three studies in both ancestry groups [odds ratio (OR) = 0.75, P = 5.8 × 10(-4) European Americans; OR = 0.80, P = 0.05 African Americans]. No other substance dependence was associated consistently with this variant in either group. Another SNP in the region, rs4952, remains modestly associated with nicotine dependence in the combined data after conditioning on rs13273442. CONCLUSIONS: The common variant rs13273442 in the CHRNB3-CHNRA6 region is associated significantly with nicotine dependence in European Americans and African Americans across studies recruited for nicotine, alcohol and cocaine dependence. Although these data are modestly powered for other substances, our results provide no evidence that correlates of rs13273442 represent a general substance dependence liability. Additional variants probably account for some of the association of this region to nicotine dependence.

Genetic influences on alcohol use across stages of development: GABRA2 and longitudinal trajectories of drunkenness from adolescence to young adulthood.

Longitudinal analyses allow us to understand how genetic risk unfolds across development, in a way that is not possible with cross-sectional analyses of individuals at different ages. This has received little attention in genetic association analyses. In this study, we test for genetic effects of GABRA2, a gene previously associated with alcohol dependence, on trajectories of drunkenness from age 14 to 25. We use data from 1070 individuals who participated in the prospective sample of the Collaborative Study on the Genetics of Alcoholism, in order to better understand the unfolding of genetic risk across development. Piecewise linear growth models were fit to model the influence of genotype on rate of increase in drunkenness from early adolescence to young adulthood (14-18 years), the change in drunkenness during the transition to adulthood (18-19 years) and the rate of change in drunkenness across young adulthood (≥ 19 years). Variation in GABRA2 was associated with an increase in drunkenness that occurred at the transition between adolescence and adulthood. The genotypic effect was more pronounced in females. These analyses illustrate the importance of longitudinal data to characterize how genetic effects unfold across development. The findings suggest that transitions across important developmental periods may alter the relative importance of genetic effects on patterns of alcohol use. The findings also suggest the importance of considering gender when evaluating genetic effects on drinking patterns in males and females.

Consensus paper of the WFSBP task force on biological markers: biological markers for alcoholism.

OBJECTIVES: This article presents an overview of the current literature on biological markers for alcoholism, including markers associated with the pharmacological effects of alcohol and markers related to the clinical course and treatment of alcohol-related problems. Many of these studies are well known, while other studies cited are new and still being evaluated. METHODS: In this paper we first describe known biomarkers of alcohol-related disorders, review their features and the problems involved in their use. We then consider future developments on biomarkers and their possible impact on the field. RESULTS: More recent findings cited include the work on type 7 adenylcyclase (AC) polymorphism and its lower expression levels in female alcoholics. Neuroimaging studies involving biomarkers have also reported brain volume reductions of gray and white matter, including amygdala and subcortical regions in alcoholic patients, while a high association between the copy number variations (CNVs) in 6q14.1/5q13.2 and alcohol dependence has more recently been identified in genetic studies. CONCLUSIONS: In addition to their possible importance for diagnosis, biomarkers may have utility for predicting prognosis, progression of the disorder, the development of new treatments, and monitoring treatment effects. Although such findings should be verified in independent studies, the search for new biomarkers is continuing. Several potential candidate biomarkers have been found recently in blood, imaging, and genetic studies with encouraging results.