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Contemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Researchers have identified genetic and neural risk factors for externalizing behaviors. However, it has not yet been determined if genetic liability is conferred in part through associations with more proximal neurophysiological risk markers., Methods: Participants from the Collaborative Study on the Genetics of Alcoholism, a large, family-based study of alcohol use disorders were genotyped and polygenic scores for externalizing (EXT PGS) were calculated. Associations with target P3 amplitude from a visual oddball task (P3) and broad endorsement of externalizing behaviors (indexed via self-report of alcohol and cannabis use, and antisocial behavior) were assessed in participants of European (EA; N = 2851) and African ancestry (AA; N = 1402). Analyses were also stratified by age (adolescents, age 12-17 and young adults, age 18-32)., Results: The EXT PGS was significantly associated with higher levels of externalizing behaviors among EA adolescents and young adults as well as AA young adults. P3 was inversely associated with externalizing behaviors among EA young adults. EXT PGS was not significantly associated with P3 amplitude and therefore, there was no evidence that P3 amplitude indirectly accounted for the association between EXT PGS and externalizing behaviors., Conclusions: Both the EXT PGS and P3 amplitude were significantly associated with externalizing behaviors among EA young adults. However, these associations with externalizing behaviors appear to be independent of each other, suggesting that they may index different facets of externalizing.

Alcohol use disorders (AUD) are commonly occurring, heritable and polygenic disorders with etiological origins in the brain and the environment. To outline the causes and consequences of alcohol-related milestones, including AUD, and their related psychiatric comorbidities, the Collaborative Study on the Genetics of Alcoholism (COGA) was launched in 1989 with a gene-brain-behavior framework. COGA is a family based, diverse (~25% self-identified African American, ~52% female) sample, including data on 17,878 individuals, ages 7-97 years, in 2246 families of which a proportion are densely affected for AUD. All participants responded to questionnaires (e.g., personality) and the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) which gathers information on psychiatric diagnoses, conditions and related behaviors (e.g., parental monitoring). In addition, 9871 individuals have brain function data from electroencephalogram (EEG) recordings while 12,009 individuals have been genotyped on genome-wide association study (GWAS) arrays. A series of functional genomics studies examine the specific cellular and molecular mechanisms underlying AUD. This overview provides the framework for the development of COGA as a scientific resource in the past three decades, with individual reviews providing in-depth descriptions of data on and discoveries from behavioral and clinical, brain function, genetic and functional genomics data. The value of COGA also resides in its data sharing policies, its efforts to communicate scientific findings to the broader community via a project website and its potential to nurture early career investigators and to generate independent research that has broadened the impact of gene-brain-behavior research into AUD., (© 2023 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

This review describes the genetic approaches and results from the family-based Collaborative Study on the Genetics of Alcoholism (COGA). COGA was designed during the linkage era to identify genes affecting the risk for alcohol use disorder (AUD) and related problems, and was among the first AUD-focused studies to subsequently adopt a genome-wide association (GWAS) approach. COGA's family-based structure, multimodal assessment with gold-standard clinical and neurophysiological data, and the availability of prospective longitudinal phenotyping continues to provide insights into the etiology of AUD and related disorders. These include investigations of genetic risk and trajectories of substance use and use disorders, phenome-wide association studies of loci of interest, and investigations of pleiotropy, social genomics, genetic nurture, and within-family comparisons. COGA is one of the few AUD genetics projects that includes a substantial number of participants of African ancestry. The sharing of data and biospecimens has been a cornerstone of the COGA project, and COGA is a key contributor to large-scale GWAS consortia. COGA's wealth of publicly available genetic and extensive phenotyping data continues to provide a unique and adaptable resource for our understanding of the genetic etiology of AUD and related traits., (© 2023 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

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., (© 2023. The Author(s).)

Background and Hypothesis: Risk for cannabis use and schizophrenia is influenced in part by genetic factors, and there is evidence that genetic risk for schizophrenia is associated with subclinical psychotic-like experiences (PLEs). Few studies to date have examined whether genetic risk for schizophrenia is associated with cannabis-related PLEs., Study Design: We tested whether measures of cannabis involvement and polygenic risk scores (PRS) for schizophrenia were associated with self-reported cannabis-related experiences in a sample ascertained for alcohol use disorders (AUDs), the Collaborative Study on the Genetics of Alcoholism (COGA). We analyzed 4832 subjects (3128 of European ancestry and 1704 of African ancestry; 42% female; 74% meeting lifetime criteria for an AUD)., Study Results: Cannabis use disorder (CUD) was prevalent in this analytic sample (70%), with 40% classified as mild, 25% as moderate, and 35% as severe. Polygenic risk for schizophrenia was positively associated with cannabis-related paranoia, feeling depressed or anhedonia, social withdrawal, and cognitive difficulties, even when controlling for duration of daily cannabis use, CUD, and age at first cannabis use. The schizophrenia PRS was most robustly associated with cannabis-related cognitive difficulties (β = 0.22, SE = 0.04, P = 5.2e-7). In an independent replication sample (N = 1446), associations between the schizophrenia PRS and cannabis-related experiences were in the expected direction and not statistically different in magnitude from those in the COGA sample., Conclusions: Among individuals who regularly use cannabis, genetic liability for schizophrenia-even in those without clinical features-may increase the likelihood of reporting unusual experiences related to cannabis use., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Genome-wide association studies (GWAS) in admixed populations such as African Americans (AA) have limited sample sizes, resulting in poor performance of polygenic risk scores (PRS). Based on the observations that many disease-causing genes are shared between AA and European ancestry (EA) populations, and some disease-causing variants are located within the boundaries of these genes, we proposed a novel gene-based PRS framework (PRS gene ) by using variants located within disease-associated genes. Using the AA GWAS of alcohol use disorder (AUD) from the Million Veteran Program and the EA GWAS of problematic alcohol use as the discovery GWAS, we identified 858 variants from 410 genes that were AUD-related in both AA and EA. PRS gene calculated using these variants were significantly associated with AUD in three AA target datasets (P-values ranged from 7.61E-05 to 6.27E-03; Betas ranged from 0.15 to 0.21) and outperformed PRS calculated using all variants (P-values ranged from 7.28E-03 to 0.16; Betas ranged from 0.06 to 0.18). PRS gene were also associated with AUD in an EA target dataset (P-value = 0.02, Beta = 0.11). In AA, individuals in the highest PRS gene decile had an odds ratio of 1.76 (95% CI: 1.32-2.34) to develop AUD compared to those in the lowest decile. The 410 genes were enriched in 54 Gene Ontology biological processes, including ethanol oxidation and processes involving the synaptic system, which are known to be AUD-related. In addition, 26 genes were targets of drugs used to treat AUD or other diseases that might be considered for repurposing to treat AUD. Our study demonstrated that the gene-based PRS had improved performance in evaluating AUD risk in AA and provided new insight into AUD genetics., (© 2022. The Author(s).)

Some styles of alcohol consumption are riskier than others. How the level and rate of alcohol exposure contribute to the increased risk of alcohol use disorder is unclear, but likely depends on the alcohol concentration time course. We hypothesized that the brain is sensitive to the alcohol concentration rate of change and that people at greater risk would self-administer faster. We developed a novel intravenous alcohol self-administration paradigm to allow participants direct and reproducible control over how quickly their breath alcohol concentration changes. We used drinking intensity and the density of biological family history of alcohol dependence as proxies for risk. Thirty-five alcohol drinking participants aged 21-28 years provided analytical data from a single, intravenous alcohol self-administration session using our computer-assisted alcohol infusion system rate control paradigm. A shorter time to reach 80 mg/dl was associated with increasing multiples of the binge drinking definition (p = 0.004), which was in turn related to higher density of family history of alcoholism (FHD, p = 0.04). Rate-dependent changes in subjective response (intoxication and stimulation) were also associated with FHD (each p = 0.001). Subsequently, given the limited sample size and FHD range, associations between multiples of the binge drinking definition and FHD were replicated and extended in analyses of the Collaborative Study on the Genetics of Alcoholism database. The rate control paradigm models binge and high-intensity drinking in the laboratory and provides a novel way to examine the relationship between the pharmacokinetics and pharmacodynamics of alcohol and potentially the risk for the development of alcohol use disorders., (© 2022 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Identification of causal variants and genes underlying genome-wide association study (GWAS) loci is essential to understand the biology of alcohol use disorder (AUD) and drinks per week (DPW). Multi-omics integration approaches have shown potential for fine mapping complex loci to obtain biological insights to disease mechanisms. In this study, we use multi-omics approaches, to fine-map AUD and DPW associations at single SNP resolution to demonstrate that rs56030824 on chromosome 11 significantly reduces SPI1 mRNA expression in myeloid cells and lowers risk for AUD and DPW. Our analysis also identifies MAPT as a candidate causal gene specifically associated with DPW. Genes prioritized in this study show overlap with causal genes associated with neurodegenerative disorders. Multi-omics integration analyses highlight, genetic similarities and differences between alcohol intake and disordered drinking, suggesting molecular heterogeneity that might inform future targeted functional and cross-species studies., (© 2021. The Author(s).)

African Americans (AA) have lower prevalence of alcohol dependence and higher subjective response to alcohol than European Americans. Genome-wide association studies (GWAS) have identified genes/variants associated with alcohol dependence specifically in AA; however, the sample sizes are still not large enough to detect variants with small effects. Admixture mapping is an alternative way to identify alcohol dependence genes/variants that may be unique to AA. In this study, we performed the first admixture mapping of DSM-IV alcohol dependence diagnosis, DSM-IV alcohol dependence criterion count, and two scores from the self-rating of effects of ethanol (SRE) as measures of response to alcohol: the first five times of using alcohol (SRE-5) and average of SRE across three times (SRE-T). Findings revealed a region on chromosome 4 that was genome-wide significant for SRE-5 (p value = 4.18E-05). Fine mapping did not identify a single causal variant to be associated with SRE-5; instead, conditional analysis concluded that multiple variants collectively explained the admixture mapping signal. PPARGC1A, a gene that has been linked to alcohol consumption in previous studies, is located in this region. Our finding suggests that admixture mapping is a useful tool to identify genes/variants that may have been missed by current GWAS approaches in admixed populations., (© 2020 Wiley Periodicals, LLC.)

Predictive models for recovering from alcohol use disorder (AUD) and identifying related predisposition biomarkers can have a tremendous impact on addiction treatment outcomes and cost reduction. Our sample (N = 1376) included individuals of European (EA) and African (AA) ancestry from the Collaborative Study on the Genetics of Alcoholism (COGA) who were initially assessed as having AUD (DSM-5) and reassessed years later as either having AUD or in remission. To predict this difference in AUD recovery status, we analyzed the initial data using multimodal, multi-features machine learning applications including EEG source-level functional brain connectivity, Polygenic Risk Scores (PRS), medications, and demographic information. Sex and ancestry age-matched stratified analyses were performed with supervised linear Support Vector Machine application and were calculated twice, once when the ancestry was defined by self-report and once defined by genetic data. Multifeatured prediction models achieved higher accuracy scores than models based on a single domain and higher scores in male models when the ancestry was based on genetic data. The AA male group model with PRS, EEG functional connectivity, marital and employment status features achieved the highest accuracy of 86.04%. Several discriminative features were identified, including collections of PRS related to neuroticism, depression, aggression, years of education, and alcohol consumption phenotypes. Other discriminated features included being married, employed, medication, lower default mode network and fusiform connectivity, and higher insula connectivity. Results highlight the importance of increasing genetic homogeneity of analyzed groups, identifying sex, and ancestry-specific features to increase prediction scores revealing biomarkers related to AUD remission.

Background: Aggression often occurs alongside alcohol and drug misuse. However, it is not clear whether the latent and manifest relations among alcohol-related, drug-related, and non-substance-related aggression are separate manifestations of a single construct or instead are 3 distinct constructs., Methods: To examine these associations, we conducted a preregistered analysis of 13,490 participants in the Collaborative Study on the Genetics of Alcoholism. In a structured interview, participants reported their lifetime perpetration of these 3 aggression phenotypes., Results: The data were better fit by a model that treated these aggression phenotypes as 3 distinct latent factors, as compared to models in which the items all loaded onto 1 ("general") or 2 ("substance-related" and "non-substance-related") aggression factors. This 3-factor model fit better for men than women. Subsequent exploratory analyses then showed that among these 3 factors, alcohol-related aggression explained the variance of overall aggression better than the other 2 factors., Conclusions: Our findings suggest that these 3 forms of aggression are distinct phenotypes (especially among men). Yet, people's alcohol-related aggression can accurately characterize their overall aggressive tendencies across these domains. Future research will benefit from articulating the unique and shared pathways and risk factors underlying each of these facets of aggression., (© 2020 by the Research Society on Alcoholism.)

Background: Alcohol consumption and problems are increasing among older adults, who are at elevated risk for alcohol-related accidents and medical problems. This paper describes a pilot follow-up of older adults with a history of alcohol dependence that was designed to determine the feasibility of conducting a more extensive investigation., Methods: The sample consisted of previously assessed subjects in the Collaborative Studies on the Genetics of Alcoholism who: (i) were age 50+; (ii) had lifetime DSM-IV AD; and (iii) had DNA available. Individuals were located through family contacts, Internet searches, and death registries. A brief telephone interview assessed demographics, health, and alcohol involvement., Results: Of the total sample (N = 2,174), 36% were contacted, 24% were deceased, and 40% were not yet located. Most (89%) contacted subjects were interviewed, and 99% of them agreed to future evaluation. Thirty percent of interviewed subjects reported abstinence for 10+ years, 56% reported drinking within the past year, and 14% last drank between >1 and 10 years ago. There were no age-related past-year differences in weekly consumption (overall sample mean: 16 drinks), number of drinking weeks (30.8), maximum number of drinks in 24 hours (8.1), or prevalence of weekly risky drinking (19%). Among those who drank within the past 5 years, the 3 most common alcohol-related problems were spending excessive time drinking or recovering (49%), drinking more/longer than intended (35%), and driving while intoxicated (35%); and about a third (32%) received some form of treatment., Conclusions: Over a 1-year period, we located 60% of individuals last seen an average of 23 years ago. The majority of contacted individuals were interviewed and willing to be evaluated again. Although the proportion of individuals currently drinking diminished with age, subjects exhibited troublesome levels of alcohol consumption and problems. Our findings suggest the importance and feasibility of a more comprehensive follow-up., (© 2019 by the Research Society on Alcoholism.)

Genome-wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (eg, ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWAS of DSM-IV AD (primary analysis), DSM-IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7418 (1121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans-ancestral meta-analyses combined these results with data from 3175 (585 families) African-American (AA) individuals from COGA. In the EA GWAS, three loci were genome-wide significant: rs1229984 in ADH1B for AD criterion count (P = 4.16E-11) and Desire to cut drinking (P = 1.21E-11); rs188227250 (chromosome 8, Drinking more than intended, P = 6.72E-09); rs1912461 (chromosome 15, Time spent drinking, P = 1.77E-08). In the trans-ancestral meta-analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome-wide significant: rs61826952 (chromosome 1, DSM-IV AD, P = 8.42E-11); rs7597960 (chromosome 2, Time spent drinking, P = 1.22E-08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (P < .01; 0.61%-1.82% of variance). Identified novel variants (ie, rs1912461, rs61826952) were associated with differential central evoked theta power (loss - gain; P = .0037) and reward-related ventral striatum reactivity (P = .008), respectively. This study suggests that studying individual criteria may unveil new insights into the genetic etiology of AD liability., (© 2019 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10 -13 ) and African ancestries (rs2066702; P = 2.2 × 10 -9 ). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

Background: Parental alcohol problems are associated with adverse adolescent outcomes such as risky drinking and conduct problems. Important questions remain about the unique roles of fathers' and mothers' alcohol problems and differences and/or similarities in pathways of risk across ethnicity and gender. In this study, we used a family systems approach to consider spillover and crossover effects of fathers' and mothers' alcohol problems (number of alcohol dependence symptoms [ADS]) and parenting behaviors in relation to adolescents' risky drinking and conduct problems., Methods: The sample included 1,282 adolescents (aged 12 to 17) and their parents from the Collaborative Study on the Genetics of Alcoholism. Parents completed the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), and adolescents completed an adolescent version of SSAGA. Data were analyzed using multivariate structural equation modeling., Results: Fathers' ADS count was associated with higher adolescent risky drinking and conduct problems indirectly via disruption to fathers' and mothers' positive parenting behaviors, whereas mothers' ADS count was not associated with adolescents' risky drinking and conduct problems directly or indirectly via positive parenting behaviors. No differences in these associations were found across ethnic background and offspring gender., Conclusions: Findings highlight the importance of considering the unique roles of fathers' and mothers' ADS in influencing family processes and adolescent outcomes., (© 2018 by the Research Society on Alcoholism.)

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., (© 2017 Society for the Study of Addiction.)

Importance: Major depressive disorder (MDD) and alcohol dependence (AD) are heritable disorders with significant public health burdens, and they are frequently comorbid. Common genetic factors that influence the co-occurrence of MDD and AD have been sought in family, twin, and adoption studies, and results to date have been promising but inconclusive., Objective: To examine whether AD and MDD overlap genetically, using a polygenic score approach., Design, Settings, and Participants: Association analyses were conducted between MDD polygenic risk score (PRS) and AD case-control status in European ancestry samples from 4 independent genome-wide association study (GWAS) data sets: the Collaborative Study on the Genetics of Alcoholism (COGA); the Study of Addiction, Genetics, and Environment (SAGE); the Yale-Penn genetic study of substance dependence; and the National Health and Resilience in Veterans Study (NHRVS). Results from a meta-analysis of MDD (9240 patients with MDD and 9519 controls) from the Psychiatric Genomics Consortium were applied to calculate PRS at thresholds from P < .05 to P ≤ .99 in each AD GWAS data set., Main Outcomes and Measures: Association between MDD PRS and AD., Results: Participants analyzed included 788 cases (548 [69.5%] men; mean [SD] age, 38.2 [10.8] years) and 522 controls (151 [28.9.%] men; age [SD], 43.9 [11.6] years) from COGA; 631 cases (333 [52.8%] men; age [SD], 35.0 [7.7] years) and 756 controls (260 [34.4%] male; age [SD] 36.1 [7.7] years) from SAGE; 2135 cases (1375 [64.4%] men; age [SD], 39.4 [11.5] years) and 350 controls (126 [36.0%] men; age [SD], 43.5 [13.9] years) from Yale-Penn; and 317 cases (295 [93.1%] men; age [SD], 59.1 [13.1] years) and 1719 controls (1545 [89.9%] men; age [SD], 64.5 [13.3] years) from NHRVS. Higher MDD PRS was associated with a significantly increased risk of AD in all samples (COGA: best P = 1.7 × 10-6, R2 = 0.026; SAGE: best P = .001, R2 = 0.01; Yale-Penn: best P = .035, R2 = 0.0018; and NHRVS: best P = .004, R2 = 0.0074), with stronger evidence for association after meta-analysis of the 4 samples (best P = 3.3 × 10-9). In analyses adjusted for MDD status in 3 AD GWAS data sets, similar patterns of association were observed (COGA: best P = 7.6 × 10-6, R2 = 0.023; Yale-Penn: best P = .08, R2 = 0.0013; and NHRVS: best P = .006, R2 = 0.0072). After recalculating MDD PRS using MDD GWAS data sets without comorbid MDD-AD cases, significant evidence was observed for an association between the MDD PRS and AD in the meta-analysis of 3 GWAS AD samples without MDD cases (best P = .007)., Conclusions and Relevance: These results suggest that shared genetic susceptibility contributes modestly to MDD and AD comorbidity. Individuals with elevated polygenic risk for MDD may also be at risk for AD.

Background: Differences in fast beta (20-28Hz) electroencephalogram (EEG) oscillatory activity distinguish some individuals with psychiatric and substance use disorders, suggesting that it may be a useful endophenotype for studying the genetics of disorders characterized by neural hyper-excitability. Despite the high heritability estimates provided by twin and family studies, there have been relatively few genetic studies of beta EEG, and to date only one genetic association finding has replicated (i.e., GABRA2)., Method: In a sample of 1564 individuals from 117 families of European Ancestry (EA) drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a Genome-Wide Association Study (GWAS) on resting-state fronto-central fast beta EEG power, adjusting regression models for family relatedness, age, sex, and ancestry. To further characterize genetic findings, we examined the functional and behavioral significance of GWAS findings., Results: Three intronic variants located within DSE (dermatan sulfate epimerase) on 6q22 were associated with fast beta EEG at a genome wide significant level (p<5×10 -8 ). The most significant SNP was rs2252790 (p<2.6×10 -8 ; MAF=0.36; β=0.135). rs2252790 is an eQTL for ROS1 expressed most robustly in the temporal cortex (p=1.2×10 -6 ) and for DSE/TSPYL4 expressed most robustly in the hippocampus (p=7.3×10 -4 ; β=0.29). Previous studies have indicated that DSE is involved in a network of genes integral to membrane organization; gene-based tests indicated that several variants within this network (i.e., DSE, ZEB2, RND3, MCTP1, and CTBP2) were also associated with beta EEG (empirical p<0.05), and of these genes, ZEB2 and CTBP2 were associated with DSM-V Alcohol Use Disorder (AUD; empirical p<0.05).', Discussion: In this sample of EA families enriched for AUDs, fast beta EEG is associated with variants within DSE on 6q22; the most significant SNP influences the mRNA expression of DSE and ROS1 in hippocampus and temporal cortex, brain regions important for beta EEG activity. Gene-based tests suggest evidence of association with related genes, ZEB2, RND3, MCTP1, CTBP2, and beta EEG. Converging data from GWAS, gene expression, and gene-networks presented in this study provide support for the role of genetic variants within DSE and related genes in neural hyperexcitability, and has highlighted two potential candidate genes for AUD and/or related neurological conditions: ZEB2 and CTBP2. However, results must be replicated in large, independent samples., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The age at onset of alcohol dependence (AD) is a critical moderator of genetic associations for alcohol dependence. The present study evaluated whether single nucleotide polymorphisms (SNPs) can influence the age at onset of AD in large high-risk families from the Collaborative Study on the Genetics of Alcoholism (COGA)., Methods: Genomewide SNP genotyping was performed in 1788 regular drinkers from 118 large European American families densely affected with alcoholism. We used a genome-wide Cox proportional hazards regression model to test for association between age at onset of AD and SNPs., Results: This family-based analysis identified an intergenic SNP, rs2168784 on chromosome 3 that showed strong evidence of association (P=5×10(-9)) with age at onset of AD among regular drinkers. Carriers of the minor allele of rs2168784 had 1.5 times the hazard of AD onset as compared with those homozygous for the major allele. By the age of 20 years, nearly 30% of subjects homozygous for the minor allele were alcohol dependent while only 19% of those homozygous for the major allele were. We also identified intronic SNPs in the ADP-ribosylation factor like 15 (ARL15) gene on chromosome 5 (P=1.11×10(-8)) and the UTP20 small subunit (UTP20) gene on chromosome 12 (P=4.32×10(-8)) that were associated with age at onset of AD., Conclusions: This extended family based genome-wide cox-proportional hazards analysis identified several loci that might be associated with age at onset of AD., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Family-based and genome-wide association studies (GWAS) of alcohol dependence (AD) have reported numerous associated variants. The clinical validity of these variants for predicting AD compared with family history information has not been reported. Using the Collaborative Study on the Genetics of Alcoholism (COGA) and the Study of Addiction: Genes and Environment (SAGE) GWAS samples, we examined the aggregate impact of multiple single nucleotide polymorphisms (SNPs) on risk prediction. We created genetic sum scores by adding risk alleles associated in discovery samples, and then tested the scores for their ability to discriminate between cases and controls in validation samples. Genetic sum scores were assessed separately for SNPs associated with AD in candidate gene studies and SNPs from GWAS analyses that met varying P-value thresholds. Candidate gene sum scores did not exhibit significant predictive accuracy. Family history was a better classifier of case-control status, with a significant area under the receiver operating characteristic curve (AUC) of 0.686 in COGA and 0.614 in SAGE. SNPs that met less stringent P-value thresholds of 0.01-0.50 in GWAS analyses yielded significant AUC estimates, ranging from mean estimates of 0.549 for SNPs with P < 0.01 to 0.565 for SNPs with P < 0.50. This study suggests that SNPs currently have limited clinical utility, but there is potential for enhanced predictive ability with better understanding of the large number of variants that might contribute to risk., (© 2013 The Authors, Addiction Biology © 2013 Society for the Study of Addiction.)

Background: Measures of social context, such as marriage and religious participation, are associated with remission from alcohol use disorders (AUDs) in population-based and treatment samples, but whether these associations hold among individuals at high familial risk for AUD is unknown. This study tests associations of measures of social context and treatment with different types of remission from DSM-5 AUD in a high-risk sample., Methods: Subjects were 686 relatives of probands (85.7% first-degree) who participated in a high-risk family study of alcohol dependence. All subjects met criteria for AUD at baseline and were re-interviewed 5 years later. Follow-up status was categorized as persistent AUD, high-risk drinking, remitted low-risk drinking, and abstinence. Social context measures were defined as stable or changing from baseline to follow-up, and their bivariate and multivariate associations with follow-up status were tested., Results: At follow-up, 62.8% of subjects had persistent AUD, 6.4% were high-risk drinkers, 22.2% were remitted low-risk drinkers, and 8.6% were abstinent. Birth of first child during the interval was the only measure of social context associated with remitted low-risk drinking and was significant for women only. Abstinent remission was characterized by being stably separated or divorced for women, new marriage for both sexes, experiencing low levels of family support and high levels of friend support, and receiving treatment. High-risk drinkers were more likely than individuals with persistent AUD to have a stable number of children and to have been recently unemployed., Conclusions: The social contexts accompanying different types of remission in this high-risk sample resemble those found in population-based and clinical samples. Low-risk drinkers resemble natural remitters from population-based samples who change their drinking habits with life transitions. Abstainers resemble clinical samples in marital context, support from friends, and treatment. High-risk drinkers appear to continue to experience negative consequences of heavy drinking., (Copyright © 2014 by the Research Society on Alcoholism.)

Background: Despite the high heritability of alcohol dependence (AD), the genes found to be associated with it account for only a small proportion of its total variability. The goal of this study was to identify and analyze phenotypes based on homogeneous classes of individuals to increase the power to detect genetic risk factors contributing to the risk of AD., Methods: The 7 individual DSM-IV criteria for AD were analyzed using latent class analysis (LCA) to identify classes defined by the pattern of endorsement of the criteria. A genome-wide association study was performed in 118 extended European American families (n = 2,322 individuals) densely affected with AD to identify genes associated with AD, with each of the 7 DSM-IV criteria, and with the probability of belonging to 2 of 3 latent classes., Results: Heritability for DSM-IV AD was 61% and ranged from 17 to 60% for the other phenotypes. A single nucleotide polymorphism (SNP) in the olfactory receptor OR51L1 was significantly associated (7.3 × 10(-8) ) with the DSM-IV criterion of persistent desire to, or inability to, cut down on drinking. LCA revealed a 3-class model: the "low-risk" class (50%) rarely endorsed any criteria and none met criteria for AD; the "moderate-risk" class (33%) endorsed primarily 4 DSM-IV criteria and 48% met criteria for AD; and the "high-risk" class (17%) manifested high endorsement probabilities for most criteria and nearly all (99%) met criteria for AD. One SNP in a sodium leak channel NALCN demonstrated genome-wide significance with the high-risk class (p = 4.1 × 10(-8) ). Analyses in an independent sample did not replicate these associations., Conclusions: We explored the genetic contribution to several phenotypes derived from the DSM-IV AD criteria. The strongest evidence of association was with SNPs in NALCN and OR51L1., (Copyright © 2013 by the Research Society on Alcoholism.)

Aims: To examine whether DSM-IV symptoms of substance dependence are psychometrically equivalent between existing community-sampled and clinically overselected studies., Participants: A total of 2476 adult twins born in Minnesota and 4121 unrelated adult participants from a case-control study of alcohol dependence., Measurements: Life-time DSM-IV alcohol, marijuana and cocaine dependence symptoms and ever use of each substance., Design: We fitted a hierarchical model to the data, in which ever use and dependence symptoms for each substance were indicators of alcohol, marijuana or cocaine dependence which were, in turn, indicators of a multi-substance dependence factor. We then tested the model for measurement invariance across participant groups, defined by study source and participant sex., Findings: The hierarchical model fitted well among males and females within each sample [comparative fit index (CFI) > 0.96, Tucker-Lewis index (TLI) > 0.95 and root mean square error of approximation (RMSEA) < 0.04 for all], and a multi-group model demonstrated that model parameters were equivalent across sample- and sex-defined groups (ΔCFI = 0.002 between constrained and unconstrained models). Differences between groups in symptom endorsement rates could be expressed solely as mean differences in the multi-substance dependence factor., Conclusions: Life-time substance dependence symptoms fitted a dimensional model well. Although clinically overselected participants endorsed more dependence symptoms, on average, than community-sampled participants, the pattern of symptom endorsement was similar across groups. From a measurement perspective, DSM-IV criteria are equally appropriate for describing substance dependence across different sampling methods., (© 2013 The Authors, Addiction © 2013 Society for the Study of Addiction.)

Maximum number of alcoholic drinks consumed in a 24-h period (maxdrinks) is a heritable (>50 %) trait and is strongly correlated with vulnerability to excessive alcohol consumption and subsequent alcohol dependence (AD). Several genome-wide association studies (GWAS) have studied alcohol dependence, but few have concentrated on excessive alcohol consumption. We performed two GWAS using maxdrinks as an excessive alcohol consumption phenotype: one in 118 extended families (N = 2,322) selected from the Collaborative Study on the Genetics of Alcoholism (COGA), and the other in a case-control sample (N = 2,593) derived from the Study of Addiction: Genes and Environment (SAGE). The strongest association in the COGA families was detected with rs9523562 (p = 2.1 × 10(-6)) located in an intergenic region on chromosome 13q31.1; the strongest association in the SAGE dataset was with rs67666182 (p = 7.1 × 10(-7)), located in an intergenic region on chromosome 8. We also performed a meta-analysis with these two GWAS and demonstrated evidence of association in both datasets for the LMO1 (p = 7.2 × 10(-7)) and PLCL1 genes (p = 4.1 × 10(-6)) with maxdrinks. A variant in AUTS2 and variants in INADL, C15orf32 and HIP1 that were associated with measures of alcohol consumption in a meta-analysis of GWAS studies and a GWAS of alcohol consumption factor score also showed nominal association in the current meta-analysis. The present study has identified several loci that warrant further examination in independent samples. Among the top SNPs in each of the dataset (p ≤ 10(-4)) far more showed the same direction of effect in the other dataset than would be expected by chance (p = 2 × 10(-3), 3 × 10(-6)), suggesting that there are true signals among these top SNPs, even though no SNP reached genome-wide levels of significance.

Gender-moderated gene-environment interactions are rarely explored, raising concerns about inaccurate specification of etiological models and inferential errors. The current study examined the influence of gender, negative and positive daily life events, and GABRA2 genotype (SNP rs279871) on alcohol dependence, testing two- and three-way interactions between these variables using multi-level regression models fit to data from 2,281 White participants in the Collaborative Study on the Genetics of Alcoholism. Significant direct effects of variables of interest were identified, as well as gender-specific moderation of genetic risk on this SNP by social experiences. Higher levels of positive life events were protective for men with the high-risk genotype, but not among men with the low-risk genotype or women, regardless of genotype. Our findings support the disinhibition theory of alcohol dependence, suggesting that gender differences in social norms, constraints and opportunities, and behavioral undercontrol may explain men and women's distinct patterns of association.

Introduction: Craving is being considered for inclusion in the Diagnostic and Statistical Manual (DSM) DSM-5. However, little is known of its genetic underpinnings - specifically, whether genetic influences on craving are distinct from those influencing DSM-IV alcohol dependence., Method: Analyses were conducted in a sample of unrelated adults ascertained for alcohol dependence (N=3976). Factor analysis was performed to examine how alcohol craving loaded with the existing DSM-IV alcohol dependence criteria. For genetic analyses, we first examined whether genes in the dopamine pathway, including dopamine receptor genes (DRD1, DRD2, DRD3, DRD4) and the dopamine transporter gene (SLC6A3), which have been implicated in neurobiological studies of craving, as well as alpha-synuclein (SNCA), which has been previously found to be associated with craving, were associated with alcohol craving in this sample. Second, in an effort to identify novel genetic variants associated with craving, we conducted a genomewide association study (GWAS). For variants that were implicated in the primary analysis of craving, we conducted additional comparisons - to determine if these variants were uniquely associated with alcohol craving as compared with alcohol dependence. We contrasted our results to those obtained for DSM-IV alcohol dependence, and also compared alcohol dependent individuals without craving to non-dependent individuals who also did not crave alcohol., Results: Twenty-one percent of the full sample reported craving alcohol. Of those reporting craving, 97.3% met criteria for DSM-IV alcohol dependence with 48% endorsing all 7 dependence criteria. Factor analysis found a high factor loading (0.89) for alcohol craving. When examining genes in the dopamine pathway, single nucleotide polymorphisms (SNPs) in DRD3 and SNCA were associated with craving (p<0.05). There was evidence for association of these SNPs with DSM-IV alcohol dependence (p<0.05) but less evidence for dependence without craving (p>0.05), suggesting that the association was due in part to craving. In the GWAS, the greatest evidence of association with craving was for a SNP in the integrin alpha D (ITGAD) gene on chromosome 7 (rs2454908; p=1.8×10(-6)). The corresponding p-value for this SNP with DSM-IV alcohol dependence was similar (p=4.0×10(-5)) but was far less with dependence without craving (p=0.02), again suggesting the association was due to alcohol craving. Adjusting for dependence severity (number of endorsed criteria) attenuated p-values but did not eliminate association., Conclusions: Craving is frequently reported by those who report multiple other alcohol dependence symptoms. We found that genes providing evidence of association with craving were also associated with alcohol dependence; however, these same SNPs were not associated with alcohol dependence in the absence of alcohol craving. These results suggest that there may be unique genetic factors affecting craving among those with alcohol dependence., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Depression and alcohol dependence (AD) are common psychiatric disorders that often co-occur. Both disorders are genetically influenced, with heritability estimates in the range of 35-60%. In addition, evidence from twin studies suggests that AD and depression are genetically correlated. Herein, we report results from a genome-wide association study of a comorbid phenotype, in which cases meet the Diagnostic and Statistical Manual of Mental Disorders-IV symptom threshold for major depressive symptomatology and the Diagnostic and Statistical Manual of Mental Disorders-IV criteria for AD., Methods: Samples (N=467 cases and N=407 controls) were of European-American descent and were genotyped using the Illumina Human 1M BeadChip array., Results: Although no single-nucleotide polymorphism (SNP) meets genome-wide significance criteria, we identified 10 markers with P values less than 1 × 10(-5), seven of which are located in known genes, which have not been previously implicated in either disorder. Genes harboring SNPs yielding P values less than 1 × 10(-5) are functionally enriched for a number of gene ontology categories, notably several related to glutamatergic function. Investigation of expression localization using online resources suggests that these genes are expressed across a variety of tissues, including behaviorally relevant brain regions. Genes that have been previously associated with depression, AD, or other addiction-related phenotypes - such as CDH13, CSMD2, GRID1, and HTR1B - were implicated by nominally significant SNPs. Finally, the degree of overlap of significant SNPs between a comorbid phenotype and an AD-only phenotype is modest., Conclusion: These results underscore the complex genomic influences on psychiatric phenotypes and suggest that a comorbid phenotype is partially influenced by genetic variants that do not affect AD alone.

Background: A variety of species and experimental designs have been used to study genetic influences on alcohol dependence, ethanol response, and related traits. Integration of these heterogeneous data can be used to produce a ranked target gene list for additional investigation., Results: In this study, we performed a unique multi-species evidence-based data integration using three microarray experiments in mice or humans that generated an initial alcohol dependence (AD) related genes list, human linkage and association results, and gene sets implicated in C. elegans and Drosophila. We then used permutation and false discovery rate (FDR) analyses on the genome-wide association studies (GWAS) dataset from the Collaborative Study on the Genetics of Alcoholism (COGA) to evaluate the ranking results and weighting matrices. We found one weighting score matrix could increase FDR based q-values for a list of 47 genes with a score greater than 2. Our follow up functional enrichment tests revealed these genes were primarily involved in brain responses to ethanol and neural adaptations occurring with alcoholism., Conclusions: These results, along with our experimental validation of specific genes in mice, C. elegans and Drosophila, suggest that a cross-species evidence-based approach is useful to identify candidate genes contributing to alcoholism.

Background: Alcohol dependence is a complex disease, and although linkage and candidate gene studies have identified several genes associated with the risk for alcoholism, these explain only a portion of the risk., Methods: We carried out a genome-wide association study (GWAS) on a case-control sample drawn from the families in the Collaborative Study on the Genetics of Alcoholism. The cases all met diagnostic criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition; controls all consumed alcohol but were not dependent on alcohol or illicit drugs. To prioritize among the strongest candidates, we genotyped most of the top 199 single nucleotide polymorphisms (SNPs) (p < or = 2.1 x 10(-4)) in a sample of alcohol-dependent families and performed pedigree-based association analysis. We also examined whether the genes harboring the top SNPs were expressed in human brain or were differentially expressed in the presence of ethanol in lymphoblastoid cells., Results: Although no single SNP met genome-wide criteria for significance, there were several clusters of SNPs that provided mutual support. Combining evidence from the case-control study, the follow-up in families, and gene expression provided strongest support for the association of a cluster of genes on chromosome 11 (SLC22A18, PHLDA2, NAP1L4, SNORA54, CARS, and OSBPL5) with alcohol dependence. Several SNPs nominated as candidates in earlier GWAS studies replicated in ours, including CPE, DNASE2B, SLC10A2, ARL6IP5, ID4, GATA4, SYNE1, and ADCY3., Conclusions: We have identified several promising associations that warrant further examination in independent samples.

Excessive alcohol consumption is one of the leading causes of preventable death in the United States. Approximately 14% of those who use alcohol meet criteria during their lifetime for alcohol dependence, which is characterized by tolerance, withdrawal, inability to stop drinking, and continued drinking despite serious psychological or physiological problems. We explored genetic influences on alcohol dependence among 1,897 European-American and African-American subjects with alcohol dependence compared with 1,932 unrelated, alcohol-exposed, nondependent controls. Constitutional DNA of each subject was genotyped using the Illumina 1M beadchip. Fifteen SNPs yielded P < 10(-5), but in two independent replication series, no SNP passed a replication threshold of P < 0.05. Candidate gene GABRA2, which encodes the GABA receptor alpha2 subunit, was evaluated independently. Five SNPs at GABRA2 yielded nominal (uncorrected) P < 0.05, with odds ratios between 1.11 and 1.16. Further dissection of the alcoholism phenotype, to disentangle the influence of comorbid substance-use disorders, will be a next step in identifying genetic variants associated with alcohol dependence.

Objective: The aim of this study was to examine the abbreviated Desires for Alcohol Questionnaire (DAQ) with respect to component structure and concurrent validity., Method: The DAQ was administered to 2,960 adults participating in the Collaborative Studies on the Genetics of Alcohol. Rotated principal components analysis was conducted on 1,500 subjects with an alcohol-use disorder (AUD) and on 1,460 non-AUD subjects. Total DAQ scores were compared for these two subsamples. In addition, correlations were computed between DAQ scores and the following: (1) a sum of alcohol symptoms, and (2) endorsement of a single interview craving question., Results: Similar solutions emerged in the AUD and non-AUD subsamples, with dimensions characterized by (1) strong desires/intentions to drink, (2) negative reinforcement, and (3) positive reinforcement + ability to control drinking. Each component was significantly correlated with the alcohol symptom scale in both subsamples (r(s) = .25-.64 and .31-.40, respectively, p < .0001) and with the interview craving item in the AUD subsample (r(s) = .22-.55, p < .0001). Total DAQ score was significantly higher for AUD subjects (40.5) than for non-AUD subjects (23.1, p < .0001) and exhibited significant correlations with the alcohol symptom scale in the AUD and non-AUD subsamples (r(s) = .61 and .39, respectively, p < .0001) and with the interview craving item in the AUD subsample (r(s) = .51, p < .0001)., Conclusions: The DAQ is an appropriate measure of alcohol craving, as demonstrated by similar component structures across two samples as well as its concurrent validity.

Objective: The aim of this study was to compare the prevalence of psychiatric diagnoses when the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA-II) interview was administered in person with the prevalence when the SSAGA-II was conducted by telephone., Method: As part of the Collaborative Studies on the Genetics of Alcoholism, SSAGAs were administered either by telephone (n = 1,294) or in person (n = 1,484) to adult relatives of probands (42.3% male). The two modes of interview were compared with respect to reported lifetime prevalence of (1) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) alcohol dependence; (2) other DSM-IV substance-dependence diagnoses (nicotine, marijuana, cocaine, opioid, stimulant, sedative); and (3) DSM-IV nonsubstance diagnoses (i.e., antisocial personality disorder, major depressive disorder, mania, panic, social phobia, obsessive-compulsive disorder, and generalized anxiety disorder). These analyses took into account the potential confounds of gender, age, race, education, income, marital status, and potential within-family correlation., Results: Diagnostic prevalence rates for alcohol dependence and major depressive disorder were lower for telephone interviews than for in-person interviews (7% and 2%, respectively); there were no other significant differences., Conclusions: When circumstances dictate (e.g., subject out of area, subject preference), telephone administration of the SSAGA should be considered.

Background: Several lines of evidence in both human and animal studies suggest that variation in neuropeptide Y (NPY) or its receptor genes (NPY1R, NPY2R and NPY5R) is associated with alcohol dependence as well as alcohol withdrawal symptoms. Additional studies suggest that cocaine may affect NPY expression., Methods: A total of 39 single nucleotide polymorphisms (SNPs) were genotyped across NPY and its 3 receptor genes in a sample of 1,923 subjects from 219 multiplex alcoholic families of European American descent recruited as part of the Collaborative Studies on the Genetics of Alcoholism (COGA) study. Family-based association analysis was performed to test the primary hypothesis that variation in these genes is associated with alcohol dependence. Secondary analyses evaluated whether there was an association of these SNPs with symptoms of alcohol withdrawal, cocaine dependence, or comorbid alcohol and cocaine dependence., Results: Although variations in NPY itself were not associated with these phenotypes, variations in 2 NPY-receptor genes were. SNPs in NPY2R provided significant evidence of association with alcohol dependence, alcohol withdrawal symptoms, comorbid alcohol and cocaine dependence, and cocaine dependence (all p < 0.03). Haplotype analyses strengthened the evidence for these phenotypes (global 0.0004 < p < 0.005). SNPs in NPY5R demonstrated significant association with alcohol withdrawal characterized by seizures (p < 0.05)., Conclusion: These results indicate that sequence variations in NPY receptor genes are associated with alcohol dependence, particularly a severe subtype of alcohol dependence characterized by withdrawal symptoms, comorbid alcohol and cocaine dependence, and cocaine dependence.

Variations in OPRK1, which encodes the kappa-opioid receptor, are associated with the risk for alcohol dependence. Sequencing DNAs with higher and lower risk haplotypes revealed an insertion/deletion (indel) with a net addition of 830 bp located 1986 bp upstream of the translation start site (1389 bp upstream of the transcription start site). We demonstrated that the upstream region extending from -1647 to -10 bp or from -2312 to -10 bp (relative to the translation start site) could function as a promoter in transient transfection assays. We then determined that the presence of the indel reduced transcriptional activity by half. We used a PCR assay to genotype individuals in 219 multiplex alcohol-dependent families of European American descent for the presence or absence of this indel. Family-based association analyses detected significant evidence of association of this insertion with alcoholism; the longer allele (with the indel), which had lower expression, is associated with higher risk for alcoholism. This indel is, therefore, a functional regulatory variation likely to explain at least part of the association of OPRK1 with alcohol dependence.

Background: A broad region on chromosome 4q was previously linked to the phenotype of alcohol dependence in the Collaborative Study on the Genetics of Alcoholism sample. A strong positional candidate gene was identified within this region: tachykinin receptor 3 gene (TACR3), which encodes tachykinin receptor 3 (NK3R), the receptor for the tachykinin 3 (neurokinin B) peptide. Pharmacological studies have provided evidence that the administration of NK3R agonists attenuates the intake of alcohol and NK3R can also mediate the acute and chronic behavioral effects of cocaine., Methods: Thirty SNPs were genotyped throughout TACR3. Family based association analysis was performed in 219 European American families to detect an association with alcohol dependence. Subsequent analyses were performed to evaluate the evidence of association with other definitions of alcohol dependence as well as cocaine dependence., Results: Seven of the 9 SNPs in the 3' region of TACR3 provided significant evidence of association with alcohol dependence (p

Recent studies in animal models have shown that the nociceptin system, comprising nociceptin (or OFQ/N, encoded by PNOC) and the nociceptin receptor (an opioid receptor-like protein encoded by OPRL1), may be involved in alcohol and other drug reward pathways. To determine whether the nociceptin system is associated with alcohol or illicit drug dependence in humans, we analyzed 10 single nucleotide polymorphisms (SNPs) in OPRL1 and 15 SNPs in PNOC in a sample of 1923 European Americans from 219 multiplex alcohol dependent families ascertained by the Collaborative Study on the Genetics of Alcoholism. The SNPs spanned both genes and several kb of their flanking sequences, and were in high linkage disequilibrium. Neither gene was associated with alcohol or illicit drug dependence, although two SNPs in PNOC showed marginal association with alcoholism and one with illicit drug dependence (P = 0.04-0.05). Secondary analyses suggested that two adjacent SNPs in intron 1 of OPRL1 were marginally associated with opioid dependence (P = 0.05); none of the SNPs in PNOC were associated with opioid dependence.

This article describes both sociological and genetic theories of illness causation and derives propositions expected under each and under a transdisciplinary theoretical frame. The authors draw propositions from three theories -- fundamental causes, social stress processes, and social safety net theories -- and tailor hypotheses to the case of alcohol dependence. Analyses of a later wave of the Collaborative Study on the Genetics of Alcoholism reveal a complex interplay of the GABRA2 gene with social structural factors to produce cases meeting DSM/ICD diagnoses. Only modest evidence suggests that genetic influence works through social conditions and experiences. Further, women are largely unaffected in their risk for alcohol dependence by allele status at this candidate gene; family support attenuates genetic influence; and childhood deprivation exacerbates genetic predispositions. These findings highlight the essential intradisciplinary tension in the role of proximal and distal influences in social processes and point to the promise of focusing directly on dynamic, networked sequences that produce different pathways to health and illness.

Objective: To test whether variation in the gene encoding the enzyme catechol-O-methyltransferase (COMT), which catalyzes the breakdown of dopamine and other catecholamine neurotransmitters, is associated with the risk for alcohol dependence and habitual smoking., Methods: Single nucleotide polymophisms (SNPs) were genotyped in a sample of 219 multiplex alcohol-dependent families of European American descent from the Collaborative Study on the Genetics of Alcoholism (COGA). Family-based tests of association were performed to evaluate the evidence of association between the 18 SNPs distributed throughout COMT, including the functional Val158Met polymorphism, and the phenotypes of alcohol dependence, early onset alcohol dependence, habitual smoking, and comorbid alcohol dependence and habitual smoking., Results: No significant, consistent evidence of association was found with alcohol dependence, early onset alcohol dependence, habitual smoking or the comorbid phenotype. There was no evidence that the functional Val158Met polymorphism, previously reported to be associated with these phenotypes, was associated with any of them., Conclusion: Despite the substantial size of this study, we did not find evidence to support an association between alcohol dependence or habitual smoking and variation in COMT.

Objective: This article expands on the results from a 1997 report from the Collaborative Study on the Genetics of Alcoholism (COGA), using a new phase of the protocol to evaluate the prevalence and characteristics of substance-induced and independent major depressive episodes (MDEs) in a population of alcoholics and nonalcoholics., Method: Data were evaluated from Phase II of the six-center-wide COGA investigation using information gathered beginning in January 1997. Data were generated through face-to-face evaluations using the updated version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA-II) interview, with distinctions between substanceinduced and independent MDEs based on the chronology of development of full depressive syndromes. The analyses focused on the 2,548 men and women who were divided into 351 individuals who had only an independent MDE (Group 1), 238 subjects who experienced only substance-induced MDEs, and 1,959 individuals with no MDE history., Results: The two MDE groups were similar in age, marital status, and religion; but those with substance-induced depressions (Group 2) were more likely to be original alcoholic probands, be males, be nonwhite, and have less education. They were also more likely to have alcohol, drug, or antisocial personality diagnoses and to report higher maximum drinks. In addition, only Group 2 subjects reported an elevated family history of alcohol diagnoses compared with the nondepressed Group 3. Subjects with independent MDEs were different from the comparison Group 3 regarding the family histories of independent MDEs. However, symptoms during the worst depressive episode were quite similar across Groups 1 and 2., Conclusions: This study corroborates a high rate of substance-induced MDEs among alcoholics, with these disorders explaining about half of the lifetime depressive episodes. The results also support the validity of the distinction between substance-induced and independent depressions regarding external validators of gender, substance-use patterns, and family histories of independent MDEs.

Background: Electroencephalographic (EEG) measures of hemispheric asymmetry in anterior brain activity have been related to a variety of indices of psychopathology and emotionality. However, little is known about patterns of frontal asymmetry in alcohol-dependent (AD) samples. It is also unclear whether psychiatric comorbidity in AD subjects accounts for additional variance in frontal asymmetry, beyond a diagnosis of AD alone., Methods: We compared 193 AD subjects with 108 control subjects on resting brain activity in anterior and posterior regions, as indexed by asymmetries in alpha band power in the left and right hemispheres. Within the AD group alone, we examined whether comorbid major depressive disorder (MDD) or antisocial personality disorder (ASPD) had effects on regional asymmetry., Results: Compared with control subjects, AD subjects exhibited lower left, relative to right, cortical activation in anterior regions. Evidence that comorbidity in AD subjects accounted for further variance in EEG asymmetry was mixed; AD subjects with comorbid ASPD were not significantly different from those without ASPD, while AD subjects with a lifetime history of MDD showed less asymmetry in anterior regions than those without MDD., Conclusions: Our findings indicate that AD subjects exhibit a pattern of frontal asymmetry similar to that found in other psychiatric groups. Results examining the effects of comorbidity in AD on EEG asymmetry were inconclusive. The implications of our findings for future work are described.

Results from twin studies suggest that overlapping genetic factors influence alcohol dependence and illicit drug dependence. Using data from the Collaborative Study on the Genetics of Alcoholism (COGA), we examined the association between 69 SNPs in the GABAA receptor gene cluster on chromosome 4 and marijuana and illicit drug dependence, individually, and as co-occurring phenotypes with alcohol dependence. Results suggested association between marijuana dependence and illicit drug dependence with SNPs in the GABRA2 gene. Interestingly, the evidence for association previously observed with alcohol dependence came only from individuals with comorbid illicit drug dependence. There was no association with other genes in the GABAA cluster on chromosome 4 with illicit drug dependence.

Objective: The gene GABRA2 has been associated with the risk for alcohol dependence in independent samples. This article explores how this genetic risk factor interacts with marital status, another factor previously shown to be associated with the risk for alcohol dependence., Method: Data from more than 1,900 male and female subjects from the Collaborative Study of the Genetics of Alcoholism (COGA) sample were analyzed. Subjects were recruited based on membership in a family with multiple individuals with alcoholism. A series of analyses was performed to evaluate the relationship between the following: (1) GABRA2 and alcohol dependence, (2) marital status and alcohol dependence, (3) GABRA2 and marital status, and (4) interactions between GABRA2 and marital status on the development of alcohol dependence in the high-risk COGA sample. Additional analyses were carried out in a sample of approximately 900 individuals from control families to test the generalizability of results., Results: Both GABRA2 and marital status contributed independently to the development of alcohol dependence in the COGA sample. The high-risk genotype at GABRA2 was also related to a decreased likelihood of marrying and an increased likelihood of divorce, which appeared to be mediated in part by personality characteristics. There was also differential risk associated with the GABRA2 genotype according to marital status., Conclusions: These analyses provide evidence of both gene-environment correlation and gene-environment interaction associated with GABRA2, marital status, and alcohol dependence. They illustrate the complex pathways by which genotype and environmental risk factors act and interact to influence alcohol dependence and challenge traditional conceptualizations of "environmental" risk factors.

Objective: The aim of this study was to compare psychiatric diagnoses based on interview information with those based on best-estimate procedures, to evaluate information used in such procedures, and to use 5-year follow-up data to determine whether the best-estimate diagnosis is an improvement over the interview-based diagnosis., Method: Psychiatric diagnoses were based on interview reports from 373 probands and 2615 relatives participating in a high-risk family study of alcoholism. The diagnosis also included clinician ratings in a best-estimate procedure of this study., Results: For most diagnoses, both sensitivity and specificity, using the best-estimate diagnosis (BED) as the gold standard, were excellent, in both relatives and probands. Substance abuse was an exception, with very low sensitivity, although specificity rates were excellent. For nonsubstance diagnoses, specificity was high, but sensitivity ranged from 59% to 84% across relatives and probands. In general, BED procedures led to higher prevalence estimates than those from the interview only. In the BED process, family history data were especially useful for conduct and antisocial personality disorders. Follow-up interview data supported the fact that BED procedures led to both enhancements of, as well as errors in, diagnosis., Conclusions: Our data attest to the utility of family history information, particularly for antisocial personality disorder and conduct disorder, and indicate that, for the phenotype of substance-dependence disorder, an interview-based diagnosis alone is adequate in classifying individuals with a minimum of error. These results should be reassuring for research studies in which costs and resources required for best-estimate procedures are not affordable.

Context: A major criterion to validate diagnoses is stability over time., Objective: To examine the stability of several classification systems for lifetime diagnosis of alcohol dependence, to identify characteristics predicting stability of alcoholism, and to study stability of lifetime assessments of habitual smoking (1 pack per day for at least 6 months) and other drug dependence., Design: Participants in the Collaborative Study on the Genetics of Alcoholism were interviewed using the Semi-Structured Assessment for the Genetics of Alcoholism and reevaluated 5 years later. Initial and follow-up interviews were available for 1728 individuals (641 index cases, 800 siblings, 287 controls) with lifetime diagnoses of alcohol dependence, other substance dependence (marijuana, cocaine, other stimulants, sedatives, opioids), or habitual smoking at first interview. The likelihood that an individual with a lifetime history of substance dependence or habitual smoking at the first interview retained this classification after 5 years was examined to assess stability of diagnosis., Results: Stability of a lifetime diagnosis of alcohol dependence varied among the subject groups of index cases, siblings, and community-based controls. Alcohol dependence as defined by DSM-III-R criteria was highly stable in the index cases (90.5% women, 94.7% men) but much less stable in the community-based controls (27.5% women, 64.7% men). The most important characteristic associated with stability of diagnosis of alcohol dependence was severity, defined by the number of alcohol-related symptoms. Other DSM-III-R substance dependence disorders varied in the stability of diagnosis over a 5-year period. Lifetime history of habitual smoking was highly stable in all subject groups (96.0% overall)., Conclusions: Stability of lifetime assessment of alcohol dependence varies depending on severity of illness. Severe cases of alcohol dependence are more likely to be stable, whereas general population cases of alcohol dependence are less likely to have stable diagnoses. The stability of diagnosis for other substance dependence varies from substance to substance.

Objective: In 1994 DSM-IV presented new criteria for substance abuse as repetitive problems in any one of four areas reflecting social, interpersonal, and legal difficulties. The authors systematically evaluate the performance of each of the four diagnostic criteria for alcohol abuse (problems in role functioning, alcohol use in hazardous situations, alcohol-related legal problems, and social or interpersonal problems) and determine the prognosis associated with a threshold of one versus two or more criterion endorsements., Method: Baseline and 5-year follow-up data were analyzed for 2,596 men and women from the Collaborative Study on the Genetics of Alcoholism, including 1,881 individuals with no alcohol-related diagnosis, and 715 with alcohol abuse, after excluding subjects with alcohol dependence. Performance of each criterion was analyzed for the entire group and for the 565 individuals who endorsed only one criterion at baseline., Results: One alcohol abuse criterion was endorsed by 79% of subjects with alcohol abuse, 18.5% endorsed two, and 2.5% endorsed three. Compared with subjects who endorsed no criteria, individuals who reported any of the four diagnostic criteria at baseline had higher rates of alcohol and drug intake and related problems and higher rates of future difficulties. Diagnostic thresholds of one versus two abuse criteria at baseline performed equally well regarding most outcomes, although endorsement of two criteria predicted a higher risk for progression to dependence. The criterion most frequently endorsed--hazardous use--was associated with baseline substance use characteristics and problematic outcomes similar to those for the other criteria., Conclusions: The four DSM-IV alcohol abuse criteria performed well regarding both cross-sectional characteristics and the prediction of future problems, but no single diagnostic criterion was superior to any other. The similarity of outcomes for subjects with diagnostic thresholds of one versus two or more criteria may favor the continued use of a threshold of one criterion in the diagnosis of alcohol abuse.

Background: Alcohol dependence tends to aggregate within families. We analyzed data from the family collection of the Collaborative Study on the Genetics of Alcoholism to quantify familial aggregation using several different criterion sets. We also assessed the aggregation of other psychiatric disorders in the same sample to identify areas of possible shared genetic vulnerability., Design: Age-corrected lifetime morbid risk was estimated in adult first-degree relatives of affected probands and control subjects for selected disorders. Diagnostic data were gathered by semistructured interview (the Semi-Structured Assessment for the Genetics of Alcoholism), family history, and medical records. Rates of illness were corrected by validating interview and family history reports against senior clinicians' all sources best estimate diagnoses. Sex, ethnicity, comorbidity, cohort effects, and site of ascertainment were also taken into account., Results: Including data from 8296 relatives of alcoholic probands and 1654 controls, we report lifetime risk rates of 28.8% and 14.4% for DSM-IV alcohol dependence in relatives of probands and controls, respectively; respective rates were 37.0% and 20.5% for the less stringent DSM-III-R alcohol dependence, 20.9% and 9.7% for any DSM-III-R diagnosis of nonalcohol nonnicotine substance dependence, and 8.1% and 5.2% for antisocial personality disorder. Rates of specific substance dependence were markedly increased in relatives of alcohol-dependent probands for cocaine, marijuana, opiates, sedatives, stimulants, and tobacco. Aggregation was also seen for panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, and major depression., Conclusions: The risk of alcohol dependence in relatives of probands compared with controls is increased about 2-fold. The aggregation of antisocial personality disorder, drug dependence, anxiety disorders, and mood disorders suggests common mechanisms for these disorders and alcohol dependence within some families. These data suggest new phenotypes for molecular genetic studies and alternative strategies for studying the heterogeneity of alcohol dependence.

The relationship between parental alcohol dependence (with and without comorbid psychopathology) and adolescent psychopathology was examined in a sample of 665 13-17 year-old adolescents and their parents. Results indicated that adolescents who had parents diagnosed with alcohol dependence only did not significantly differ from adolescents who had parents with no psychopathology in regard to any of the measures of psychological symptomatology (substance use, conduct disorder, and depression) or clinical diagnoses (alcohol dependence, marijuana dependence, conduct disorder, or depression) assessed. In contrast, adolescents who had parents diagnosed with alcohol dependence and either comorbid drug dependence or depression were more likely to exhibit higher levels of psychological symptomatology. In addition, adolescents who had parents diagnosed with alcohol dependence, depression, and drug dependence were most likely to exhibit psychological problems. These findings underscore the importance of considering parental comorbid psychopathology when examining the relationship between parental alcoholism and offspring adjustment.