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

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

Background: Although effective treatments exist, alcohol use disorder (AUD) is undertreated. We used a cascade of care framework to understand gaps in care for persons with AUD., Methods: Using 2015-2019 National Survey on Drug Use and Health data, we evaluated the following steps in the cascade of care: (1) adult prevalence of AUD; (2) proportion of adults with AUD who utilized health care in the past 12 months; (3) proportion with AUD screened about their alcohol use; (4) proportion with AUD who received a brief intervention about their alcohol misuse; (5) proportion with AUD who received information about treatment for alcohol misuse; and (6) proportion with AUD who received treatment. Analyses were stratified by AUD severity., Results: Of the 214,505 persons included in the sample, the weighted prevalence of AUD was 7.8% (95% CI 7.6-8.0%). Cascades of care showed the majority of individuals with AUD utilized health care in the past 12 months [81.4% (95% CI 80.7-82.1%)] and were screened about alcohol use [69.9% (95% CI 68.9-70.8%)]. However, only a minority of individuals received subsequent steps of care, including 11.6% (95% CI 11.0-12.2%) who reported receiving a brief intervention, 5.1% (95% CI 4.6-5.6%) who were referred to treatment, and 5.8% (95% CI 5.4-6.3%) who received treatment. Similar patterns were observed when cascades of care were stratified by AUD severity., Conclusions: Persons with AUD commonly utilize health care and are often screened about alcohol use, but few receive treatment. Healthcare settings-particularly primary care settings-represent a prime opportunity to implement AUD treatment to improve outcomes in this high-risk population., (© 2021 by the Research Society on Alcoholism.)

Background: Although the risks of using central nervous system depressant (CNS-D) medications with alcohol are well documented, little is known about trends in prescribed use of these medications among individuals who regularly consume alcohol (i.e., trends in "concurrent use"). We examined changes in the prevalence of prescribed CNS-D medications among individuals who drank alcohol on 52 or more occasions in the past year ("regular drinking"). CNS-D medications included sedative-hypnotics (subclassified as anxiolytics or sleep medications) and opioids., Methods: We used 8 cross-sectional cycles of the National Health and Nutrition Examination Survey (1999-2000 to 2013-2014) from participants aged 20 and older (n = 37,709). We used log-binomial regression to examine (i) prevalence trends of prescribed CNS-D medication use, (ii) trend differences by drinking status, and (iii) correlates of CNS-D medication use., Results: Among those who drink regularly, the relative annual increase in prevalence of sedative-hypnotic use was 5.3% (95% CI: 2.7 to 7.9): Anxiolytic and sleep medication use increased annually by 3.7% (95% CI: 0.8 to 6.7) and 11.2% (95% CI: 6.5 to 16.0), respectively. Opioid use trends among those who drink regularly were not statistically significant but were nonlinear. Differences in CNS-D medication trends between those who drink regularly and those who drink infrequently/abstain were not statistically significant. Those who drink regularly were less likely than those who drink infrequently/abstain to use opioids (adjusted relative risk [ARR]: 0.69, 95% CI: 0.60 to 0.78) and anxiolytics (ARR: 0.71, 95% CI: 0.61 to 0.81), but not sleep medications (ARR: 1.04, 95% CI: 0.80 to 1.35). Those aged 40 and older were 2 to 5 times as likely as those aged 20 to 29 to use sedative-hypnotics., Conclusions: Among those who drink regularly, the prevalence of prescribed sedative-hypnotic use increased and prescribed opioid use remained common. These trends indicate that a substantial portion of the population is at risk of alcohol-related adverse drug reactions-particularly those aged 40 and older., (© 2019 by the Research Society on Alcoholism.)

Background: There is evidence that low-level alcohol use, drinking 1 to 2 drinks on occasion, is protective for cardiovascular disease, but increases the risk of cancer. Synthesizing the overall impact of low-level alcohol use on health is therefore complex. The objective of this paper was to examine the association between frequency of low-level drinking and mortality., Methods: Two data sets with self-reported alcohol use and mortality follow-up were analyzed: 340,668 individuals from the National Health Interview Survey (NHIS) and 93,653 individuals from the Veterans Health Administration (VA) outpatient medical records. Survival analyses were conducted to evaluate the association between low-level drinking frequency and mortality., Results: The minimum risk drinking frequency among those who drink 1 to 2 drinks per occasion was found to be 3.2 times weekly in the NHIS data, based on a continuous measure of drinking frequency, and 2 to 3 times weekly in the VA data. Relative to these individuals with minimum risk, individuals who drink 7 times weekly had an adjusted hazard ratio (HR) of all-cause mortality of 1.23 (p < 0.0001) in the NHIS data, and individuals who drink 4 to 7 times weekly in the VA data also had an adjusted HR of 1.23 (p = 0.01). Secondary analyses in the NHIS data showed that the minimum risk was drinking 4 times weekly for cardiovascular mortality, and drinking monthly or less for cancer mortality. The associations were consistent in stratified analyses of men, women, and never smokers., Conclusions: The minimum risk of low-level drinking frequency for all-cause mortality appears to be approximately 3 occasions weekly. The robustness of this finding is highlighted in 2 distinctly different data sets: a large epidemiological data set and a data set of veterans sampled from an outpatient clinic. Daily drinking, even at low levels, is detrimental to one's health., (© 2018 by the Research Society on Alcoholism.)

Background: Recent trends in alcoholic liver disease, alcohol-related emergency room admissions, and alcohol use disorder prevalence as measured by general-population surveys have raised concerns about rising alcohol-related morbidity and mortality in the United States. In contrast, upward trends in per capita alcohol consumption have been comparatively modest., Methods: To resolve these discordant observations, we sought to examine trends in the prevalence of alcohol use and binge drinking from 6 regularly or periodically administered national surveys using a meta-analytic approach. Annual or periodic prevalence estimates for past-12-month or past-30-day alcohol use and binge drinking were estimated for available time points between the years 2000 and 2016. Estimates were combined in a random-effects regression model in which prevalence was modeled as a log-linear function of time to obtain meta-analytic trend estimates for the full population and by sex, race, age, and educational attainment., Results: Meta-analysis-derived estimates of average annual percentage increase in the prevalence of alcohol use and binge drinking were 0.30% per year (95% CI: 0.22%, 0.38%) and 0.72% per year (95% CI: 0.46%, 0.98%), respectively. There was substantial between-survey heterogeneity among trend estimates, although there was notable consistency in the degree to which trends have impacted various demographic groups. For example, most surveys found that the changes in prevalence for alcohol use and binge drinking were large and positive for ages 50 to 64 and 65 and up, and smaller, negative, or nonsignificant for ages 18 to 29., Conclusions: Significant increases in the prevalence of alcohol use and of binge drinking over the past 10 to 15 years were observed, but not for all demographic groups. However, the increase in binge drinking among middle-aged and older adults is substantial and may be driving increasing rates of alcohol-related morbidity and mortality., (© 2018 by the Research Society on Alcoholism.)

Background: The minimum legal drinking age (MLDA) of 21 has been associated with a number of benefits compared to lower MLDAs, including long-term effects, such as reduced risk for alcoholism in adulthood. However, no studies have examined whether MLDA during young adulthood is associated with mortality later in life. We examined whether individuals exposed to permissive MLDA (<21) had higher risk of death from alcohol-related chronic disease compared to those exposed to the 21 MLDA. Because prior work suggests that MLDA affects college students differently, we also conducted conditional analyses based on ever having attended college., Methods: Data from the 1990 through 2010 U.S. Multiple Cause-of-Death files were combined with data on the living population and analyzed. We included individuals who turned 18 during the years 1967 to 1990, the period during which MLDA varied across states. We examined records on death from several alcohol-related chronic diseases, employing a quasi-experimental approach to control for unobserved state characteristics and stable time trends., Results: Individuals who reported any college attendance did not exhibit significant associations between MLDA and mortality for the causes of death we examined. However, permissive MLDA for those who never attended college was associated with 6% higher odds for death from alcoholic liver disease, 8% higher odds for other liver disease, and 7% higher odds for lip/oral/pharynx cancers (odds ratio [OR] = 1.06, 95% confidence interval [CI] [1.02, 1.10]; OR = 1.08, 95% CI [1.03, 1.13]; OR = 1.07, 95% CI [1.03, 1.12], respectively)., Conclusions: The 21 MLDA likely protects against risk of death from alcohol-related chronic disease across the lifespan, at least for those who did not attend college. This is consistent with other work that shows that the long-term association between MLDA and alcohol-related outcomes is specific to those who did not attend college., (Copyright © 2016 by the Research Society on Alcoholism.)

Background: Effective policies that can reduce alcohol use behaviors and impaired driving among young people at a population level are needed. Graduated driver licensing (GDL) laws increase the driving privileges of young novice drivers as they age and gain more driving experience. In this study, we seek to determine the effects of GDLs on risky driving behaviors of youth and to assess if GDLs have an unintended effect on underage drinking behaviors., Methods: We utilized 2000 to 2013 data on 12th grade students from the Monitoring the Future (MTF) study, an ongoing, annual national survey (since 1975) that studies the substance use behaviors of adolescents, as well as data on GDL laws obtained via the Insurance Institute for Highway Safety (IIHS). We conducted a series of regular logistic regression models that included fixed effects for year and state, and adjusted for demographic characteristics, school characteristics, and other state alcohol policies., Results: Total weighted sample size was 129,289 12th graders. Past month alcohol use and binge drinking (i.e., ≥5 drinks on one occasion) in the past 2 weeks were 45 and 26%, respectively. Seventeen percent of respondents reported riding with a driver who drank alcohol. Nearly 12% reported driving in the past 2 weeks after drinking alcohol, and 7% reported driving after binge drinking. Over half of the students lived in a state with a "good" GDL law. The logistic regression models suggest a link between restrictive GDL policies and a reduction of alcohol use behaviors and risky driving behaviors among youth., Conclusions: Our findings indicate that the effects of GDLs extend beyond driving-related risks and into other drinking-related behaviors that pose immediate or delayed health risks for young people. We speculate that GDLs may dictate social norms and expectations for youth risk behaviors, and should be maximized throughout the United States., (Copyright © 2016 by the Research Society on Alcoholism.)

Background: Increasing state cigarette excise taxes and strengthening smoke-free air (SFA) laws are known to reduce smoking prevalence. Some studies suggest that such policies may also reduce alcohol use, but results for cigarette taxes have been mixed, and associations with smoke-free air policies have been limited to some demographic subgroups. To shed further light on the potential secondary effects of tobacco control policy, we examined whether increases in cigarette taxes and strengthening of SFA laws were associated with reductions of per capita alcohol consumption and whether any reductions were specific to certain beverage types., Methods: State per capita alcohol consumption from 1980 to 2009 was modeled as a function of state price per pack of cigarettes and SFA policy scores while controlling for secular trends and salient state covariates. Both policy measures also accounted for local policies. Total alcohol, beer, wine, and spirits consumption per capita were modeled separately. For each type of beverage, we used a nested models approach to determine whether the 2 policies together were associated with reduced consumption., Results: For total alcohol consumption, and for beer or spirits (but not wine), one or both tobacco policies were associated with reductions in consumption. A 1% increase in cigarette price per pack was associated with a 0.083% decrease in per capita total alcohol consumption (95% confidence interval [CI] 0.0002 to 0.166, p = 0.0495), and a 1-point increase in SFA policy score, measured on a 6-point scale, was associated with a 1.1% decrease in per capita total alcohol consumption (95% CI 0.4 to 1.7, p = 0.001; p < 0.001 for the hypothesis that the 2 policies are jointly associated with reduced alcohol consumption)., Conclusions: The public health benefits of increasing cigarette taxes and smoke-free policies may go beyond the reduction of smoking and extend to alcohol consumption, specifically beer and spirits., (Copyright © 2014 by the Research Society on Alcoholism.)

Background: High average daily consumption of alcohol has been associated with elevated mortality risk, but more moderate consumption, relative to abstinence, has been associated with reduced mortality risk. However, average daily consumption can be complicated to assess, limiting its usefulness in both research and clinical practice. There are also concerns that average consumption fails to capture the risk associated with certain drinking patterns, such as heavy episodic drinking. This study assessed mortality associated with drinking pattern, operationalized as the frequency of both heavy and nonheavy drinking occasions., Methods: Data from the 1997 to 2001 administrations of the National Health Interview Survey (NHIS; n = 111,511) were paired with the current release of the NHIS Linked Mortality Files, which provided mortality follow-up data through the end of 2006. We estimated the impact of drinking pattern on all-cause mortality, operationalized as the frequency of heavy (5+ drinks) and nonheavy (<5 drinks) drinking occasions. Other covariates in the model included survey wave, sex, age, race/ethnicity, ratio of family income to poverty threshold, educational attainment, body mass index, and smoking status., Results: Over a third of past-year drinkers reported heavy drinking. Mortality risk increased steadily as heavy drinking frequency increased; daily heavy drinkers exhibited an almost 2-fold risk of death compared with abstainers (p < 0.001). Regular nonheavy drinking was associated with decreased mortality, similar to the "J-shaped curve" highlighted in past research on alcohol mortality; this potential protective effect peaked around 2 nonheavy occasions per week., Conclusions: Any heavy drinking likely elevates mortality risk, and substantial health benefits could be realized by reducing heavy drinking occasions or limiting overall drinking. Heavy and nonheavy drinking frequencies are valid targets for clinical screening and could be helpful in assessing risk and promoting less harmful drinking behavior., (Copyright © 2013 by the Research Society on Alcoholism.)

Background: Exposure to permissive minimum legal drinking age (MLDA) laws not only affects young adults in the short term, but also later in life; for example, individuals who could legally purchase alcohol before the age of 21 are more likely to suffer from drinking problems as older adults, long after the laws had been changed. However, it is not known how permissive MLDA exposure affects specific drinking behavior. This present study uses changes in MLDA laws during the 1970s and 1980s as a natural experiment to investigate the potential impact of permissive MLDA exposure on average alcohol consumption, frequency of drinking, and patterns of binging and more moderate, nonheavy drinking., Methods: Policy exposure data were paired with alcohol use data from the 1991 to 1992 National Longitudinal Alcohol Epidemiologic Survey and the 2001 to 2002 National Epidemiologic Survey on Alcohol and Related Conditions. Past-year drinkers born between 1949 and 1972 (n = 24,088) were included. Average daily intake, overall drinking frequency, and frequency of both binge episodes (5+ drinks) and days without a binge episode (nonheavy drinking) for the previous year at the time of interview were tracked for each respondent., Results: Exposure to permissive MLDAs was associated with higher odds to report frequent binging and lower odds to report any moderate drinking; these associations were largely driven by men and those who did not attend college. Overall drinking frequency and average alcohol consumption were not affected by MLDA exposure., Conclusions: The ability to legally purchase alcohol before the age of 21 does not seem to increase overall drinking frequency, but our findings suggest that it is associated with certain types of problematic drinking behaviors that persist into later adulthood: more frequent binge episodes and less frequent nonheavy drinking. We also propose that policymakers and critics should not focus on college drinking when evaluating the effectiveness of MLDAs., (Copyright © 2013 by the Research Society on Alcoholism.)

Background: Excessive alcohol use is the third leading cause of preventable death and is highly correlated with alcohol dependence, a heritable phenotype. Many genetic factors for alcohol dependence have been found, but many remain unknown. In search of additional genetic factors, we examined the association between Diagnostic and StatisticalManual of Mental Disorders, Fourth Edition (DSM-IV) alcohol dependence and all common copy number variations (CNVs) with good reliability in the Study of Addiction: Genetics and Environment (SAGE)., Methods: All participants in SAGE were interviewed using the Semi-Structured Assessment for the Genetics of Alcoholism, as a part of 3 contributing studies. A total of 2,610 non-Hispanic European American samples were genotyped on the Illumina Human 1M array. We performed CNV calling by CNVPartition, PennCNV, and QuantiSNP, and only CNVs identified by all 3 software programs were examined. Association was conducted with the CNV (as a deletion/duplication) as well as with probes in the CNV region. Quantitative polymerase chain reaction (qPCR) was used to validate the CNVs in the laboratory., Results: CNVs in 6q14.1 (p = 1.04 × 10(-6)) and 5q13.2 (p = 3.37 × 10(-4)) were significantly associated with alcohol dependence after adjusting multiple tests. On chromosome 5q13.2, there were multiple candidate genes previously associated with various neurological disorders. The region on chromosome 6q14.1 is a gene desert that has been associated with mental retardation and language delay. The CNV in 5q13.2 was validated, whereas only a component of the CNV on 6q14.1 was validated by qPCR. Thus, the CNV on 6q14.1 should be viewed with caution., Conclusions: This is the first study to show an association between DSM-IV alcohol dependence and CNVs. CNVs in regions previously associated with neurological disorders may be associated with alcohol dependence., (Copyright © 2012 by the Research Society on Alcoholism.)

Background: Prior to the establishment of the uniform drinking age of 21 in the United States, many states permitted legal purchase of alcohol at younger ages. Lower drinking ages were associated with several adverse outcomes, including elevated rates of suicide and homicide among youth. The objective of this study is to examine whether individuals who were legally permitted to drink prior to age 21 remained at elevated risk in adulthood., Methods: Analysis of data from the U.S. Multiple Cause of Death files, 1990 to 2004, combined with data on the living population from the U.S. Census and American Community Survey. The assembled data contained records on over 200,000 suicides and 130,000 homicides for individuals born between 1949 and 1972, the years during which the drinking age was in flux. Logistic regression models were used to evaluate whether adults who were legally permitted to drink prior to age 21 were at elevated risk for death by these causes. A quasi-experimental analytical approach was employed, which incorporated state and birth-year fixed effects to account for unobserved covariates associated with policy exposure., Results: In the population as a whole, we found no association between minimum drinking age and homicide or suicide. However, significant policy-by-sex interactions were observed for both outcomes, such that women exposed to permissive drinking age laws were at higher risk for both suicide (OR = 1.12, 95% CI: 1.05, 1.18, p = 0.0003) and homicide (OR = 1.15, 95% CI: 1.04, 1.25, p = 0.0028). Effect sizes were stronger for the portion of the cohort born after 1960, whereas no significant effects were observed for women born prior to 1960., Conclusions: Lower drinking ages may result in persistent elevated risk for suicide and homicide among women born after 1960. The national drinking age of 21 may be preventing about 600 suicides and 600 homicides annually., (Copyright © 2011 by the Research Society on Alcoholism.)

Background: Endophenotypes reflect more proximal effects of genes than diagnostic categories, hence providing a more powerful strategy in searching for genes involved in complex psychiatric disorders. There is strong evidence suggesting the P3 amplitude of the event-related potential (ERP) as an endophenotype for the risk of alcoholism and other disinhibitory disorders. Recent studies demonstrated a crucial role of corticotropin releasing hormone receptor 1 (CRHR1) in the environmental stress response and ethanol self-administration in animal models. The aim of the present study was to test the potential associations between single-nucleotide polymorphisms (SNPs) in the CRHR1 gene and the quantitative trait, P3 amplitude during the processing of visual target signals in an oddball paradigm, as well as alcohol dependence diagnosis., Methods: We analyzed a sample from the Collaborative Study on the Genetics of Alcoholism (COGA) comprising 1049 Caucasian subjects from 209 families (including 472 alcohol-dependent individuals). Quantitative transmission disequilibrium test (QTDT) and family-based association test (FBAT) were used to test the association, and false discovery rate (FDR) was applied to correct for multiple comparisons., Results: Significant associations (p < 0.05) were found between the P3 amplitude and alcohol dependence with multiple SNPs in the CRHR1 gene., Conclusions: Our results suggest that CRHR1 may be involved in modulating the P3 component of the ERP during information processing and in vulnerability to alcoholism. These findings underscore the utility of electrophysiology and the endophenotype approach in the genetic study of psychiatric disorders.

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.

Background: Many studies have found that earlier drinking initiation predicts higher risk of later alcohol and substance use problems, but the causal relationship between age of initiation and later risk of substance use disorder remains unknown., Method: We use a "natural experiment" study design to compare the 12-month prevalence of Diagnostic and Statistical Manual, Fourth Edition, alcohol and substance use disorders among adult subjects exposed to different minimum legal drinking age laws minimum legal drinking age in the 1970s and 1980s. The sample pools 33,869 respondents born in the United States 1948 to 1970, drawn from 2 nationally representative cross-sectional surveys: the 1991 National Longitudinal Alcohol Epidemiological Survey (NLAES) and the 2001 National Epidemiological Study of Alcohol and Related Conditions. Analyses control for state and birth year fixed effects, age at assessment, alcohol taxes, and other demographic and social background factors., Results: Adults who had been legally allowed to purchase alcohol before age 21 were more likely to meet criteria for an alcohol use disorder [odds ratio (OR) 1.31, 95% confidence intervals (95% CI) 1.15 to 1.46, p < 0.0001] or another drug use disorder (OR 1.70, 95% CI 1.19 to 2.44, p = 0.003) within the past-year, even among subjects in their 40s and 50s. There were no significant differences in effect estimates by respondent gender, black or Hispanic ethnicity, age, birth cohort, or self-reported age of initiation of regular drinking; furthermore, the effect estimates were little changed by inclusion of age of initiation as a potential mediating variable in the multiple regression models., Conclusion: Exposure to a lower minimum legal purchase age was associated with a significantly higher risk of a past-year alcohol or other substance use disorder, even among respondents in their 40s or 50s. However, this association does not seem to be explained by age of initiation of drinking, per se. Instead, it seems plausible that frequency or intensity of drinking in late adolescence may have long-term effects on adult substance use patterns.

Background: Alcohol dependence is a major cause of morbidity and mortality worldwide and has a strong familial component. Several linkage and association studies have identified chromosomal regions and/or genes that affect alcohol consumption, notably in genes involved in the 2-stage pathway of alcohol metabolism., Methods: Here, we use multiple regression models to test for associations and interactions between 2 alcohol-related phenotypes and SNPs in 17 genes involved in alcohol metabolism in a sample of 1,588 European American subjects., Results: The strongest evidence for association after correcting for multiple testing was between rs1229984, a nonsynonymous coding SNP in ADH1B, and DSM-IV symptom count (p = 0.0003). This SNP was also associated with maximum number of drinks in 24 hours (p = 0.0004). Each minor allele at this SNP predicts 45% fewer DSM-IV symptoms and 18% fewer max drinks. Another SNP in a splice site in ALDH1A1 (rs8187974) showed evidence for association with both phenotypes as well (p = 0.02 and 0.004, respectively), but neither association was significant after accounting for multiple testing. Minor alleles at this SNP predict greater alcohol consumption. In addition, pairwise interactions were observed between SNPs in several genes (p = 0.00002)., Conclusions: We replicated the large effect of rs1229984 on alcohol behavior, and although not common (MAF = 4%), this polymorphism may be highly relevant from a public health perspective in European Americans. Another SNP, rs8187974, may also affect alcohol behavior but requires replication. Also, interactions between polymorphisms in genes involved in alcohol metabolism are likely determinants of the parameters that ultimately affect alcohol consumption.

Background: Several lines of evidence suggest that the lifetime prevalence of alcohol dependence among women has increased in recent decades, but has not risen significantly for men. Early age at onset of drinking (AOD) is strongly correlated with risk for alcohol dependence and there is evidence that mean AOD has also decreased, particularly for women. The present report sought to confirm the trends in AOD and to determine the extent to which they might account for secular trends in alcohol dependence., Methods: Repeated cross-sectional analyses of data from 2 large, national epidemiological surveys were conducted to enable estimates of cross-cohort differences while controlling for age-related factors. Regression analyses were used to compute risk for alcohol dependence associated with birth cohort membership, before and after inclusion of AOD as a covariate., Results: Both men and women born between 1944 and 1963 had earlier ages of onset for drinking than did the earliest birth cohort analyzed (1934-43). However, the net decrease in AOD was twice as large for women (3.2 years) than that for men (1.6 years). After adjusting for AOD, differences in lifetime prevalence between different birth cohorts of women were rendered nonsignificant, indicating that AOD accounts for a substantial portion of change in the lifetime prevalence of alcohol dependence., Conclusions: These results suggest that a decrease in AOD accounts for much of the increase in lifetime alcohol dependence among women. AOD is likely to be an indicator of dynamic, and therefore modifiable risk behaviors impacting risk for alcohol dependence.

Background: U.S. epidemiologic surveys have consistently found higher lifetime prevalence of alcohol dependence among younger subjects than among older groups. Because lifetime prevalence is cumulative, such patterns are suggestive of strong secular trends; i.e., more-recently born subjects have developed more disease in a shorter period of time than their elders. However, it remains unclear whether such patterns truly reflect secular trends or are confounded by age-dependent factors such as differential recall, differential mortality, and other effects., Methods: Using data from 2 large, national epidemiological surveys, a repeated cross-sectional analysis was conducted to compare lifetime prevalence of alcohol dependence across temporally adjacent birth cohorts surveyed at the same age, thus enabling estimates of cross-cohort differences while controlling for age-related factors., Results: In contrast with results from single cross-sectional analyses, there were few significant cross-cohort differences among groups of men compared at similar ages. On the other hand, women born between 1954 and 1963 were at 1.2-fold higher odds for lifetime drinking, and those who drank were at 1.5-fold higher odds for lifetime alcohol dependence, compared with the immediately preceding birth cohort (1944 to 1953). The 1944 to 1953 cohort was also at elevated odds for lifetime drinking compared with their predecessors (1934 to 1943). These results were largely due to changes among White and Hispanic women., Conclusions: These results suggest that there have been substantial secular increases in drinking and alcohol dependence among women, but not men. Analyses of single cross-sectional studies may tend to over-estimate secular trends by failing to account for age-dependent effects. Nonetheless, secular increases in drinking and alcohol dependence among women are evident after taking age-related factors into account.

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.

Background: A novel family of G protein-coupled receptors, TAS2Rs, has recently been characterized and linked to sensitivity to bitter taste compounds. We have previously reported that a missense mutation in the TAS2R16 gene reduces the sensitivity of the receptor to bitter-taste stimuli and that it is associated with risk for alcohol dependence. Other family-based studies on the genetic transmittance of taste perception have previously demonstrated a correlation between genetic variation in TAS2R38 and sensitivity to bitter-taste compounds such as phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP). Haplotypes resulting from 3 common nonsynonymous coding single-nucleotide polymorphisms in the TAS2R38 gene have been shown to alter receptor functions and taste sensitivity to PTC and PROP. The perceived bitterness of PROP has also been associated with oral sensation and drinking behaviors., Methods: We used family-based association methods to test for association between TAS2R38 haplotypes and alcohol dependence as well as a measure of alcohol consumption (Maxdrinks) and age of onset of drinking behaviors in a sample of families densely affected with alcoholism. We have also extended our analysis of TAS2R16 to include the Maxdrinks phenotype., Results: A positive correlation was observed between TAS2R38 haplotypes and Maxdrinks in Collaborative Study on the Genetics of Alcoholism (COGA) high-risk women of African-American origin. The common taster haplotype is significantly associated with a lower mean Maxdrinks compared with the other haplotypes. Similarly, the allele of TAS2R16 that is associated with a lower risk for alcohol dependence is also associated with lower mean Maxdrinks scores in African-American families. In contrast to the previously reported significant association between TAS2R16 and alcohol dependence, we found no evidence that TAS2R38 haplotypes influence alcohol dependence in the COGA dataset., Conclusion: Functional variants in both TAS2R16 and TAS2R38 correlate with alcohol consumption in African-American families.

Background: Cigarette smoking and alcohol use disorders (AUDs) are closely linked, but it is not clear whether higher rates of AUD among smokers are solely attributable to heavier drinking or, alternatively, whether smokers are more vulnerable to alcohol abuse and dependence than nonsmokers who drink comparable quantities. We sought to address this issue using data from a nationally representative U.S. sample of adolescents and young adults. Specifically, we analyzed the relationship between cigarette smoking, drinking, and AUDs., Methods: Data were from the aggregated 2002 through 2004 U.S. National Survey on Drug Use and Health. Participants were randomly selected, household-dwelling adolescents and young adults (ages 12-20) from the noninstitutionalized, civilian population of the United States (N=74,836). Measurements included current DSM-IV alcohol abuse or dependence, number of drinks in the past 30 days, and past-year cigarette smoking, defined as having smoked more than 100 cigarettes across the lifetime and having smoked during the past year., Results: Past-year smokers (prevalence=16.0%) drank in higher quantities than never-smokers, but were also at elevated risk for AUD when compared with never-smokers who drank equivalent quantities. The effect was observed across age groups, but was more prominent among younger adolescents. After adjusting for drinking quantity and sociodemographic variables, smokers had 4.5-fold higher odds of AUD than never-smokers [95% confidence interval (95% CI), 3.1-6.6]. Youths who reported smoking but did not cross the 100-cigarette threshold were at intermediate risk [odds ratio (OR), 2.3; 95% CI, 1.7-3.3]. Differences in AUD between smokers and never-smokers were most pronounced at lower levels of drinking., Conclusions: The results are consistent with a higher vulnerability to AUDs among smokers, compared with nonsmokers who drink equivalent quantities.

Background: Previous studies have shown that when assessing child psychopathology, parents tend to report more symptoms than children for externalizing disorders such as attention deficit hyperactivity disorder (ADHD), whereas children tend to report more symptoms for internalizing disorders such as major depression. Whether for clinical or research purposes, parents are also frequently asked to report on their children's experiences with alcohol and drugs. The purpose of this study was to analyze correspondence between adolescent and parent reports of adolescent substance use and abuse or dependence., Methods: In the current study, 591 subjects 12 to 17 years old were interviewed using the child version of the Semi-Structured Assessment for the Genetics of Alcoholism (C-SSAGA) as part of the Collaborative Study on the Genetics of Alcoholism (COGA). One parent was also interviewed about each adolescent using the parent version of the C-SSAGA. Sensitivities, specificities, and kappa coefficients were calculated to assess parental agreement with adolescent reports of lifetime substance use and Diagnostic and Statistical Manual of Mental Disorders-Third Revision substance abuse or dependence., Results: The results indicate that parents are somewhat knowledgeable about their children's use of substances, particularly those that are used most commonly. For example, 55% of adolescents who had smoked cigarettes, 50% who had used alcohol, and 47% who had used marijuana had a parent who knew that they used. However, parents were less aware of substance-related problems experienced by their offspring, agreeing with adolescent reports only 27% of the time for diagnoses of alcohol abuse or dependence and 26% of the time for diagnoses of marijuana abuse or dependence. Parent reports added few cases of substance use for 12- to 13 year-olds and essentially no cases for 16- to 17-year-olds. Parent reports added a nominal number of diagnoses of substance abuse or dependence for older adolescents., Conclusions: Whether for clinical or research purposes, the results emphasize the importance of directly assessing adolescents regarding alcohol and other substance use disorders. Furthermore, investigators should consider the specific disorder(s) being investigated and the ages of the children being studied when determining whether to include parent reports as part of study design.

Background: Disinhibitory personality traits such as high novelty seeking (NS) are moderately heritable, and individuals with substance use disorders (SUDs) frequently exhibit such traits. However, recent studies have cast doubt on the supposition that such traits are true familial risk factors for SUD and particularly for alcohol dependence. Another possibility is that familial risk interacts with personality-associated risk, in which case the association between personality and familial risk might depend on sample composition, accounting for the lack of consensus among studies to date. We examined this possibility by analyzing the association between NS and alcohol dependence in individuals at intermediate and high levels of familial risk for alcohol dependence., Methods: Data from the Collaborative Study on the Genetics of Alcoholism, a multisite family study, were examined. Subjects were 1,111 adult siblings of alcohol-dependent index cases. Parental diagnoses of alcohol dependence and personality scores of NS from the Tridimensional Personality Questionnaire were used to predict alcohol dependence., Results: A significant interaction between NS and familial risk for alcoholism was seen, such that NS was a significantly stronger predictor of alcohol dependence in subjects with one or more parents with alcohol dependence than in subjects without alcohol-dependent parents., Conclusions: Novelty seeking and familial risk interact so that the risk associated with high NS is magnified in families with parental alcohol dependence and NS is a moderator of familial risk. Accordingly, high NS is strongly associated with alcohol dependence in subjects with a parent diagnosed with alcohol dependence, but low NS may protect against the risk associated with familial alcoholism. This interaction may account for conflicting findings from studies that have examined this question previously.

Background: Monoamine oxidase B (MAO-B) degrades catecholamines in presynaptic nerve endings and is also active in platelets. There is evidence to suggest that platelet MAO-B activity level is controlled by a major genetic locus distinct from the structural gene on the X chromosome. To expand on a prior report, new linkage analyses for platelet MAO-B activity have been performed on the previously analyzed sample (designated the initial sample), on a new sample of families (the replication sample), and on the combined sample. These families were recruited as part of the Collaborative Study on the Genetics of Alcoholism (COGA)., Methods: The initial sample consists of 105 extended families providing 1002 nonindependent (412 independent) sib pairs that have been phenotyped for MAO activity and genotyped. The replication sample of 157 extended families contains 608 nonindependent (309 independent) phenotyped and genotyped sib pairs. Analyses were conducted using Haseman-Elston based regression on sib pairs and variance component analysis on extended pedigrees, and the importance of cigarette smoking and gender as covariates of platelet MAO-B activity was taken into account., Results: Regions on chromosomes 2, 9, and 12 indicated consistent evidence for linkage across the two distinct datasets by at least one analysis method. Under Haseman-Elston regression of independent sib pairs, only the chromosome 2 region gave lod scores above 1 in both the initial and replication samples. Using all possible pairs, unweighted, for the regression, chromosome 12 gave lod scores above 1 in both samples. For variance component analysis, only the chromosome 9 region gave lod scores above 1 in both samples., Conclusions: The consistency across datasets of these findings is encouraging. In particular, variance component analysis of extended pedigrees supports a potential linkage of MAO-B activity to chromosome 9, with a lod over 3 at 115 cM near D9S261 in the combined sample. Sib-pair regression supports this finding with modest lod scores in the region. Suggestive linkage to chromosomes 2 and 12 from sib-pair analysis is only weakly supported by variance component analysis.