Examining associations between genetic and neural risk for externalizing behaviors in adolescence and early adulthood.

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.

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.

Youth fatal drug overdose and suicide: Trends in Connecticut, 2019-2021.

BACKGROUND AND OBJECTIVES: Increasing rates of fatal drug overdose (FDO) among youth since 2016 have been driven by fentanyl and polysubstance use. Suicide by youth also increased steadily since 2007. The manner of FDO may be accidental (i.e., unintentional) or suicidal (i.e., intentional). This report examines the rate of youth intentional and unintentional FDO as well as specific drug toxicology in Connecticut, between the years 2019 and 2021, compared to a 2016-2018 report. METHODS: We reviewed N = 286 consecutive FDO files of youth, <26 years of age dated for 2019-2021 from the Connecticut Medical Examiner's office. RESULTS: FDO attributed to fentanyl increased significantly from 2016 to 2018 to 2019 to 2021. Xylazine FDO emerged in 2019 and reached 16% in 2021. Intentional FDO rates doubled between these periods from 3.8% to 7.7%. Most FDOs involved individuals aged 20-25 years, whereas 10% were among those aged 15-19. For the first time since 2018, FDO among 10-14 years old was detected. Analysis of gender found no differences. Within each gender, however, FDO attributed to fentanyl increased significantly between these periods. The FDO rate for Hispanics increased significantly, while the rate for Whites decreased significantly. DISCUSSION AND CONCLUSIONS: The availability of high lethality potential drugs leading to youth FDO including an increasing rate of intentional FDO, is a public health concern. It is prudent to identify modifiable acute high-risk circumstances for intentional FDO and prevention-intervention evidence-based approach to reduce FDO. SCIENTIFIC SIGNIFICANCE: This is the first study of FDO among youth examining the manner of death by suicide.

Alcohol use polygenic risk score, social support, and alcohol use among European American and African American adults.

Alcohol use is influenced by genetic and environmental factors. We examined the interactive effects between genome-wide polygenic risk scores for alcohol use (alc-PRS) and social support in relation to alcohol use among European American (EA) and African American (AA) adults across sex and developmental stages (emerging adulthood, young adulthood, and middle adulthood). Data were drawn from 4,011 EA and 1,274 AA adults from the Collaborative Study on the Genetics of Alcoholism who were between ages 18-65 and had ever used alcohol. Participants completed the Semi-Structured Assessment for the Genetics of Alcoholism and provided saliva or blood samples for genotyping. Results indicated that social support from friends, but not family, moderated the association between alc-PRS and alcohol use among EAs and AAs (only in middle adulthood for AAs); alc-PRS was associated with higher levels of alcohol use when friend support was low, but not when friend support was high. Associations were similar across sex but differed across developmental stages. Findings support the important role of social support from friends in buffering genetic risk for alcohol use among EA and AA adults and highlight the need to consider developmental changes in the role of social support in relation to alcohol use.

Principal Component Analysis Reduces Collider Bias in Polygenic Score Effect Size Estimation.

In this study, we test principal component analysis (PCA) of measured confounders as a method to reduce collider bias in polygenic association models. We present results from simulations and application of the method in the Collaborative Study of the Genetics of Alcoholism (COGA) sample with a polygenic score for alcohol problems, DSM-5 alcohol use disorder as the target phenotype, and two collider variables: tobacco use and educational attainment. Simulation results suggest that assumptions regarding the correlation structure and availability of measured confounders are complementary, such that meeting one assumption relaxes the other. Application of the method in COGA shows that PC covariates reduce collider bias when tobacco use is used as the collider variable. Application of this method may improve PRS effect size estimation in some cases by reducing the effect of collider bias, making efficient use of data resources that are available in many studies.

Predicting risk for Alcohol Use Disorder using longitudinal data with multimodal biomarkers and family history: a machine learning study.

Predictive models have succeeded in distinguishing between individuals with Alcohol use Disorder (AUD) and controls. However, predictive models identifying who is prone to develop AUD and the biomarkers indicating a predisposition to AUD are still unclear. Our sample (n = 656) included offspring and non-offspring of European American (EA) and African American (AA) ancestry from the Collaborative Study of the Genetics of Alcoholism (COGA) who were recruited as early as age 12 and were unaffected at first assessment and reassessed years later as AUD (DSM-5) (n = 328) or unaffected (n = 328). Machine learning analysis was performed for 220 EEG measures, 149 alcohol-related single nucleotide polymorphisms (SNPs) from a recent large Genome-wide Association Study (GWAS) of alcohol use/misuse and two family history (mother DSM-5 AUD and father DSM-5 AUD) features using supervised, Linear Support Vector Machine (SVM) classifier to test which features assessed before developing AUD predict those who go on to develop AUD. Age, gender, and ancestry stratified analyses were performed. Results indicate significant and higher accuracy rates for the AA compared with the EA prediction models and a higher model accuracy trend among females compared with males for both ancestries. Combined EEG and SNP features model outperformed models based on only EEG features or only SNP features for both EA and AA samples. This multidimensional superiority was confirmed in a follow-up analysis in the AA age groups (12-15, 16-19, 20-30) and EA age group (16-19). In both ancestry samples, the youngest age group achieved higher accuracy score than the two other older age groups. Maternal AUD increased the model's accuracy in both ancestries' samples. Several discriminative EEG measures and SNPs features were identified, including lower posterior gamma, higher slow wave connectivity (delta, theta, alpha), higher frontal gamma ratio, higher beta correlation in the parietal area, and 5 SNPs: rs4780836, rs2605140, rs11690265, rs692854, and rs13380649. Results highlight the significance of sampling uniformity followed by stratified (e.g., ancestry, gender, developmental period) analysis, and wider selection of features, to generate better prediction scores allowing a more accurate estimation of AUD development.

A genome-wide association study of interhemispheric theta EEG coherence: implications for neural connectivity and alcohol use behavior.

Aberrant connectivity of large-scale brain networks has been observed among individuals with alcohol use disorders (AUDs) as well as in those at risk, suggesting deficits in neural communication between brain regions in the liability to develop AUD. Electroencephalographical (EEG) coherence, which measures the degree of synchrony between brain regions, may be a useful measure of connectivity patterns in neural networks for studying the genetics of AUD. In 8810 individuals (6644 of European and 2166 of African ancestry) from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a Multi-Trait Analyses of genome-wide association studies (MTAG) on parietal resting-state theta (3-7 Hz) EEG coherence, which previously have been associated with AUD. We also examined developmental effects of GWAS findings on trajectories of neural connectivity in a longitudinal subsample of 2316 adolescent/young adult offspring from COGA families (ages 12-30) and examined the functional and clinical significance of GWAS variants. Six correlated single nucleotide polymorphisms located in a brain-expressed lincRNA (ENSG00000266213) on chromosome 18q23 were associated with posterior interhemispheric low theta EEG coherence (3-5 Hz). These same variants were also associated with alcohol use behavior and posterior corpus callosum volume, both in a subset of COGA and in the UK Biobank. Analyses in the subsample of COGA offspring indicated that the association of rs12954372 with low theta EEG coherence occurred only in females, most prominently between ages 25 and 30 (p < 2 × 10-9). Converging data provide support for the role of genetic variants on chromosome 18q23 in regulating neural connectivity and alcohol use behavior, potentially via dysregulated myelination. While findings were less robust, genome-wide associations were also observed with rs151174000 and parieto-frontal low theta coherence, rs14429078 and parieto-occipital interhemispheric high theta coherence, and rs116445911 with centro-parietal low theta coherence. These novel genetic findings highlight the utility of the endophenotype approach in enhancing our understanding of mechanisms underlying addiction susceptibility.

Evaluating risk for alcohol use disorder: Polygenic risk scores and family history.

BACKGROUND: Early identification of individuals at high risk for alcohol use disorder (AUD) coupled with prompt interventions could reduce the incidence of AUD. In this study, we investigated whether Polygenic Risk Scores (PRS) can be used to evaluate the risk for AUD and AUD severity (as measured by the number of DSM-5 AUD diagnostic criteria met) and compared their performance with a measure of family history of AUD. METHODS: We studied individuals of European ancestry from the Collaborative Study on the Genetics of Alcoholism (COGA). DSM-5 diagnostic criteria were available for 7203 individuals, of whom 3451 met criteria for DSM-IV alcohol dependence or DSM-5 AUD and 1616 were alcohol-exposed controls aged ≥21 years with no history of AUD or drug dependence. Further, 4842 individuals had a positive first-degree family history of AUD (FH+), 2722 had an unknown family history (FH?), and 336 had a negative family history (FH-). PRS were derived from a meta-analysis of a genome-wide association study of AUD from the Million Veteran Program and scores from the problem subscale of the Alcohol Use Disorders Identification Test in the UK Biobank. We used mixed models to test the association between PRS and risk for AUD and AUD severity. RESULTS: AUD cases had higher PRS than controls with PRS increasing as the number of DSM-5 diagnostic criteria increased (p-values ≤ 1.85E-05 ) in the full COGA sample, the FH+ subsample, and the FH? subsample. Individuals in the top decile of PRS had odds ratios (OR) for developing AUD of 1.96 (95% CI: 1.54 to 2.51, p-value = 7.57E-08 ) and 1.86 (95% CI: 1.35 to 2.56, p-value = 1.32E-04 ) in the full sample and the FH+ subsample, respectively. These values are comparable to previously reported ORs for a first-degree family history (1.91 to 2.38) estimated from national surveys. PRS were also significantly associated with the DSM-5 AUD diagnostic criterion count in the full sample, the FH+ subsample, and the FH? subsample (p-values ≤6.7E-11 ). PRS remained significantly associated with AUD and AUD severity after accounting for a family history of AUD (p-values ≤6.8E-10 ). CONCLUSIONS: Both PRS and family history were associated with AUD and AUD severity, indicating that these risk measures assess distinct aspects of liability to AUD traits.

Polygenic contributions to alcohol use and alcohol use disorders across population-based and clinically ascertained samples.

BACKGROUND: Studies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds. METHODS: We examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes. RESULTS: In COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47-0.68%, p = 2.0 × 10-8-1.0 × 10-10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10-8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10-6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10-11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10-7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10-16). CONCLUSIONS: AUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.

Mapping Pathways by Which Genetic Risk Influences Adolescent Externalizing Behavior: The Interplay Between Externalizing Polygenic Risk Scores, Parental Knowledge, and Peer Substance Use.

Genetic predispositions and environmental influences both play an important role in adolescent externalizing behavior; however, they are not always independent. To elucidate gene-environment interplay, we examined the interrelationships between externalizing polygenic risk scores, parental knowledge, and peer substance use in impacting adolescent externalizing behavior across two time-points in a high-risk longitudinal sample of 1,200 adolescents (764 European and 436 African ancestry; Mage = 12.99) from the Collaborative Study on the Genetics of Alcoholism. Results from multivariate path analysis indicated that externalizing polygenic scores were directly associated with adolescent externalizing behavior but also indirectly via peer substance use, in the European ancestry sample. No significant polygenic association nor indirect effects of genetic risk were observed in the African ancestry group, likely due to more limited power. Our findings underscore the importance of gene-environment interplay and suggest peer substance use may be a mechanism through which genetic risk influences adolescent externalizing behavior.

Using a developmental perspective to examine the moderating effects of marriage on heavy episodic drinking in a young adult sample enriched for risk.

Many studies demonstrate that marriage protects against risky alcohol use and moderates genetic influences on alcohol outcomes; however, previous work has not considered these effects from a developmental perspective or in high-risk individuals. These represent important gaps, as it cannot be assumed that marriage has uniform effects across development or in high-risk samples. We took a longitudinal developmental approach to examine whether marital status was associated with heavy episodic drinking (HED), and whether marital status moderated polygenic influences on HED. Our sample included 937 individuals (53.25% female) from the Collaborative Study on the Genetics of Alcoholism who reported their HED and marital status biennially between the ages of 21 and 25. Polygenic risk scores (PRS) were derived from a genome-wide association study of alcohol consumption. Marital status was not associated with HED; however, we observed pathogenic gene-by-environment effects that changed across young adulthood. Among those who married young (age 21), individuals with higher PRS reported more HED; however, these effects decayed over time. The same pattern was found in supplementary analyses using parental history of alcohol use disorder as the index of genetic liability. Our findings indicate that early marriage may exacerbate risk for those with higher polygenic load.

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.

Density and Dichotomous Family History Measures of Alcohol Use Disorder as Predictors of Behavioral and Neural Phenotypes: A Comparative Study Across Gender and Race/Ethnicity.

BACKGROUND: Family history (FH) is an important risk factor for the development of alcohol use disorder (AUD). A variety of dichotomous and density measures of FH have been used to predict alcohol outcomes; yet, a systematic comparison of these FH measures is lacking. We compared 4 density and 4 commonly used dichotomous FH measures and examined variations by gender and race/ethnicity in their associations with age of onset of regular drinking, parietal P3 amplitude to visual target, and likelihood of developing AUD. METHODS: Data from the Collaborative Study on the Genetics of Alcoholism (COGA) were utilized to compute the density and dichotomous measures. Only subjects and their family members with DSM-5 AUD diagnostic information obtained through direct interviews using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) were included in the study. Area under receiver operating characteristic curves were used to compare the diagnostic accuracy of FH measures at classifying DSM-5 AUD diagnosis. Logistic and linear regression models were used to examine associations of FH measures with alcohol outcomes. RESULTS: Density measures had greater diagnostic accuracy at classifying AUD diagnosis, whereas dichotomous measures presented diagnostic accuracy closer to random chance. Both dichotomous and density measures were significantly associated with likelihood of AUD, early onset of regular drinking, and low parietal P3 amplitude, but density measures presented consistently more robust associations. Further, variations in these associations were observed such that among males (vs. females) and Whites (vs. Blacks), associations of alcohol outcomes with density (vs. dichotomous) measures were greater in magnitude. CONCLUSIONS: Density (vs. dichotomous) measures seem to present more robust associations with alcohol outcomes. However, associations of dichotomous and density FH measures with different alcohol outcomes (behavioral vs. neural) varied across gender and race/ethnicity. These findings have great applicability for alcohol research examining FH of AUD.

Genome-wide association studies of the self-rating of effects of ethanol (SRE).

The level of response (LR) to alcohol as measured with the Self-Report of the Effects of Alcohol Retrospective Questionnaire (SRE) evaluates the number of standard drinks usually required for up to four effects. The need for a higher number of drinks for effects is genetically influenced and predicts higher risks for heavy drinking and alcohol problems. We conducted genome-wide association study (GWAS) in the African-American (COGA-AA, N = 1527 from 309 families) and European-American (COGA-EA, N = 4723 from 956 families) subsamples of the Collaborative Studies on the Genetics of Alcoholism (COGA) for two SRE scores: SRE-T (average of first five times of drinking, the period of heaviest drinking, and the most recent 3 months of consumption) and SRE-5 (the first five times of drinking). We then meta-analyzed the two COGA subsamples (COGA-AA + EA). Both SRE-T and SRE-5 were modestly heritable (h2 : 21%-31%) and genetically correlated with alcohol dependence (AD) and DSM-IV AD criterion count (rg : 0.35-0.76). Genome-wide significant associations were observed (SRE-T: chromosomes 6, rs140154945, COGA-EA P = 3.30E-08 and 11, rs10647170, COGA-AA+EA P = 3.53E-09; SRE-5: chromosome13, rs4770359, COGA-AA P = 2.92E-08). Chromosome 11 was replicated in an EA dataset from the National Institute on Alcohol Abuse and Alcoholism intramural program. In silico functional analyses and RNA expression analyses suggest that the chromosome 6 locus is an eQTL for KIF25. Polygenic risk scores derived using the COGA SRE-T and SRE-5 GWAS predicted 0.47% to 2.48% of variances in AD and DSM-IV AD criterion count in independent datasets. This study highlights the genetic contribution of alcohol response phenotypes to the etiology of alcohol use disorders.

Multivariate Analyses Reveal Biological Components Related to Neuronal Signaling and Immunity Mediating Electroencephalograms Abnormalities in Alcohol-Dependent Individuals from the Collaborative Study on the Genetics of Alcoholism Cohort.

BACKGROUND: The underlying molecular mechanisms associated with alcohol use disorder (AUD) risk have only been partially revealed using traditional approaches such as univariate genomewide association and linkage-based analyses. We therefore aimed to identify gene clusters related to Electroencephalograms (EEG) neurobiological phenotypes distinctive to individuals with AUD using a multivariate approach. METHODS: The current project adopted a bimultivariate data-driven approach, parallel independent component analysis (para-ICA), to derive and explore significant genotype-phenotype associations in a case-control subset of the Collaborative Study on the Genetics of Alcoholism (COGA) dataset. Para-ICA subjects comprised N = 799 self-reported European Americans (367 controls and 432 AUD cases), recruited from COGA, who had undergone resting EEG and genotyping. Both EEG and genomewide single nucleotide polymorphism (SNP) data were preprocessed prior to being subjected to para-ICA in order to derive genotype-phenotype relationships. RESULTS: From the data, 4 EEG frequency and 4 SNP components were estimated, with 2 significantly correlated EEG-genetic relationship pairs. The first such pair primarily represented theta activity, negatively correlated with a genetic cluster enriched for (but not limited to) ontologies/disease processes representing cell signaling, neurogenesis, transmembrane drug transportation, alcoholism, and lipid/cholesterol metabolism. The second component pair represented mainly alpha activity, positively correlated with a genetic cluster with ontologies similarly enriched as the first component. Disease-related enrichments for this component revealed heart and autoimmune disorders as top hits. Loading coefficients for both the alpha and theta components were significantly reduced in cases compared to controls. CONCLUSIONS: Our data suggest plausible multifactorial genetic components, primarily enriched for neuronal/synaptic signaling/transmission, immunity, and neurogenesis, mediating low-frequency alpha and theta abnormalities in alcohol addiction.

A Pilot Follow-Up Study of Older Alcohol-Dependent COGA Adults.

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.

Reliability and validity of an internalizing symptom scale based on the adolescent and adult Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA).

BACKGROUND: The Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) is an interview that assesses psychiatric symptoms and diagnoses, including substance use disorders and anxiety and mood (i.e., internalizing) disorders. Although the SSAGA is widely used, there exists no overall internalizing characteristics scale based on items drawn from SSAGA's mood and anxiety disorder sections. OBJECTIVES: To design and assess a SSAGA-based measurement instrument capturing the overall internalizing dimension that underlies more specific internalizing conditions. METHODS: We developed, assessed, and characterized a new scale for measuring internalizing problematic characteristics derived from the SSAGA interview. All samples were drawn from the Collaborative Studies on the Genetics of Alcoholism, a prospective multi-site genetic study of families at high risk for alcohol use disorders. All participants taking part in the study between September 2005 and September 2017 were eligible (n = 904, 52.2% female). RESULTS: The scale had adequate internal consistency (ordinal α = 0.85, 95% CI = [0.81, 0.89]). Construct validity was supported by its association with other measures of internalizing characteristics (Internalizing Scale from Achenbach Self Reports; Neuroticism Scale from the Neuroticism-Extraversion-Openness Five-Factor Personality Inventory). Several indices of alcohol, marijuana, and nicotine misuse were also positively associated with Internalizing Scale scores. CONCLUSIONS: The Internalizing Scale has very good psychometric properties and can be used in studies that incorporate the SSAGA interview to study the association between internalizing characteristics and problematic alcohol and other substance use. These associations can potentially be utilized to identify individuals at risk for substance problems and to design treatments targeting such individuals.

A Brief Critique of the TATES Procedure.

The Trait-based test that uses the Extended Simes procedure (TATES) was developed as a method for conducting multivariate GWAS for correlated phenotypes whose underlying genetic architecture is complex. In this paper, we provide a brief methodological critique of the TATES method using simulated examples and a mathematical proof. Our simulated examples using correlated phenotypes show that the Type I error rate is higher than expected, and that more TATES p values fall outside of the confidence interval relative to expectation. Thus the method may result in systematic inflation when used with correlated phenotypes. In a mathematical proof we further demonstrate that the distribution of TATES p values deviates from expectation in a manner indicative of inflation. Our findings indicate the need for caution when using TATES for multivariate GWAS of correlated phenotypes.

A 22-Year Follow-Up (Range 16 to 23) of Original Subjects with Baseline Alcohol Use Disorders from the Collaborative Study on Genetics of Alcoholism.

BACKGROUND: Recent reports indicate higher-than-expected problematic drinking in older populations. However, few data describe how to predict which older individuals are most likely to demonstrate alcohol-related problems, including those with earlier alcohol use disorders (AUDs). These analyses evaluate predictors of alcohol outcomes in individuals with earlier AUDs in the Collaborative Study on Genetics of Alcoholism (COGA). METHODS: Original COGA participants with baseline AUDs at about age 40 were interviewed 13 to 26 years later and placed into clinically derived outcome categories. Chi-square and analysis of variance evaluated baseline differences across 4 outcome groups, with significant items entered into binary logistic regression backwards elimination analyses predicting outcomes. RESULTS: Low-Risk Drinkers (N = 100) at follow-up were predicted by baseline higher levels of response to alcohol (high LRs), lower histories of alcohol treatment, experience with fewer types of illicit drugs, and were more likely to have been widowed. At follow-up, Problem Drinkers (N = 192) differed from High-Risk Drinkers (N = 93) who denied multiple alcohol problems by exhibiting baseline lower LRs, higher Sensation Seeking, and a higher proportion who were widowed. Abstinent (N = 278) outcomes were predicted by a history of higher baseline AUD treatments, higher alcohol problems, lower usual drinks, as well as older age and European American heritage. Thirty-four subjects (4.9%) could not be classified and were not included in these analyses. CONCLUSIONS: These results generated from AUD individuals from both treatment and nontreatment settings reinforce low probabilities of recent Low-Risk Drinking in individuals with AUDs, but also suggest many individuals with AUDs demonstrate good outcomes 2 decades later.

Polygenic Risk Score Prediction of Alcohol Dependence Symptoms Across Population-Based and Clinically Ascertained Samples.

BACKGROUND: Despite consistent evidence of the heritability of alcohol use disorders (AUDs), few specific genes with an etiological role have been identified. It is likely that AUDs are highly polygenic; however, the etiological pathways and genetic variants involved may differ between populations. The aim of this study was thus to evaluate whether aggregate genetic risk for AUDs differed between clinically ascertained and population-based epidemiological samples. METHODS: Four independent samples were obtained: 2 from unselected birth cohorts (Avon Longitudinal Study of Parents and Children [ALSPAC], N = 4,304; FinnTwin12 [FT12], N = 1,135) and 2 from families densely affected with AUDs, identified from treatment-seeking patients (Collaborative Study on the Genetics of Alcoholism, N = 2,097; Irish Affected Sib Pair Study of Alcohol Dependence, N = 706). AUD symptoms were assessed with clinical interviews, and participants of European ancestry were genotyped. Genomewide association was conducted separately in each sample, and the resulting association weights were used to create polygenic risk scores in each of the other samples (12 total discovery-validation pairs), and from meta-analyses within sample type. We then tested how well these aggregate genetic scores predicted AUD outcomes within and across sample types. RESULTS: Polygenic scores derived from 1 population-based sample (ALSPAC) significantly predicted AUD symptoms in another population-based sample (FT12), but not in either clinically ascertained sample. Trend-level associations (uncorrected p < 0.05) were found for polygenic score predictions within sample types but no or negative predictions across sample types. Polygenic scores accounted for 0 to 1% of the variance in AUD symptoms. CONCLUSIONS: Though preliminary, these results provide suggestive evidence of differences in the genetic etiology of AUDs based on sample characteristics such as treatment-seeking status, which may index other important clinical or demographic factors that moderate genetic influences. Although the variance accounted for by genomewide polygenic scores remains low, future studies could improve gene identification efforts by amassing very large samples, or reducing genetic heterogeneity by informing analyses with other phenotypic information such as sample characteristics. Multiple complementary approaches may be needed to make progress in gene identification for this complex disorder.