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Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d -1 ) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.

Background: Alcohol dependence and long-term excessive alcohol use may cause liver damage, but only some patients develop cirrhosis. Similarly, high alcohol intake without evident liver disease often but not always produces abnormal enzymatic liver function tests (LFTs), particularly gamma-glutamyl transferase (GGT). We postulate that the factors predisposing to cirrhosis in alcoholics and to liver enzyme abnormality in drinkers are similar, and that biochemical LFTs could therefore be useful as markers of risk of alcoholic liver disease in excessive drinkers., Methods: Data from participants in twin and twin-family studies on alcohol use and dependence were used to identify 1,003 people who had reported excessive alcohol intake (28 drinks or more per week). A total of 962 of these provided blood for biochemical tests at the same time. Body mass index (BMI) and biomarkers of metabolic syndrome, inflammation, and iron stores were used in logistic regression with abnormality in serum GGT, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) as outcomes. We conducted genome-wide association analyses for GGT, ALT, and AST separately in the group reporting excessive alcohol intake (N = 951) and a low-intake group reporting 14 drinks or fewer per week (N = 8,716), and compared results., Results: Abnormal GGT and ALT among excessive drinkers were associated with higher BMI, triglycerides, insulin, uric acid, C-reactive protein, ferritin, and transferrin saturation; and with lower high-density-lipoprotein cholesterol. Abnormal AST was associated with triglycerides, ferritin, and transferrin saturation. ALT was significantly associated with variants at reported genetic loci for alcoholic liver disease (PNPLA3, rs738409, p = 0.0076; TM6SF2, rs10401969, p = 0.0076; HSD17B13, rs10433879, p = 0.0024)., Conclusions: Known risk factors for alcoholic cirrhosis including obesity and markers of metabolic syndrome, iron overload and inflammation are associated with liver enzyme abnormality in excessive drinkers., (© 2018 by the Research Society on Alcoholism.)

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders 1 . They are heritable 2,3 and etiologically related 4,5 behaviors that have been resistant to gene discovery efforts 6-11 . In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

Laboratory cue exposure investigations have demonstrated that, relative to drinkers who report a high sensitivity to the pharmacologic effects of alcohol, low-sensitivity (LS) drinkers show exaggerated neurocognitive and behavioral reactivity to alcohol-related stimuli. The current study extends this line of work by testing whether LS drinkers report stronger cravings for alcohol in daily life. Data were from an ecological momentary assessment study in which participants ( N = 403 frequent drinkers) carried a palmtop computer for 21 days and responded to questions regarding drinking behavior, alcohol craving, mood states, and situational context. Initial analyses identified subjective states (positive and negative mood, cigarette craving) and contextual factors (bar-restaurant location, weekend, time of day, presence of friend, recent smoking) associated with elevated craving states during nondrinking moments. Effects for nearly all these craving correlates were moderated by individual differences in alcohol sensitivity, such that the associations between situational factors and current alcohol craving were larger among LS individuals (as determined by a questionnaire completed at baseline). Complementary idiographic analyses indicated that self-reported craving increased when the constellation of situational factors more closely resembled individuals' observed drinking situations. Again, this effect was moderated by alcohol sensitivity, with greater craving response increases among LS drinkers. The findings align with predictions generated from theory and laboratory cue exposure investigations and should encourage further study of craving and incentive processes in LS drinkers. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Drinking alcohol is a normal behavior in many societies, and prior studies have demonstrated it has both genetic and environmental sources of variation. Using two very large samples of twins and their first-degree relatives (Australia ≈ 20,000 individuals from 8,019 families; Virginia ≈ 23,000 from 6,042 families), we examine whether there are differences: (1) in the genetic and environmental factors that influence four interrelated drinking behaviors (quantity, frequency, age of initiation, and number of drinks in the last week), (2) between the twin-only design and the extended twin design, and (3) the Australian and Virginia samples. We find that while drinking behaviors are interrelated, there are substantial differences in the genetic and environmental architectures across phenotypes. Specifically, drinking quantity, frequency, and number of drinks in the past week have large broad genetic variance components, and smaller but significant environmental variance components, while age of onset is driven exclusively by environmental factors. Further, the twin-only design and the extended twin design come to similar conclusions regarding broad-sense heritability and environmental transmission, but the extended twin models provide a more nuanced perspective. Finally, we find a high level of similarity between the Australian and Virginian samples, especially for the genetic factors. The observed differences, when present, tend to be at the environmental level. Implications for the extended twin model and future directions are discussed.

Background and Aims: Both high alcohol intake and alcohol dependence increase mortality, and both are associated with smoking. We aimed to compare the associations of quantity of alcohol, number of alcohol-related symptoms and smoking history with all-cause mortality, and to assess symptom count and smoking history as confounders or mediators of the effects of high alcohol intake., Design: Survival was analysed by Cox regression with sex, body mass index, alcohol intake (overall and by beverage), maximum drinks on any day, alcohol symptom count and smoking status as potential predictors of age at death., Setting: Australia., Participants: Participants were apparently healthy volunteers consisting of 33 593 Australian adult twins and their relatives who completed questionnaires or interviews between 1979 and 2005., Measurements: Data on alcohol use, smoking and occurrence of symptoms related to alcohol use disorders and death records from the Australian National Death Index., Findings: A total of 3764 participants were matched with deaths occurring within Australia up to July 2014. Individually, alcohol intake [hazard ratio (HR) = 1.0082, 95% confidence interval (CI) = 1.0063-1.0102, per drink per week], beer intake (HR = 1.0159, 95% CI = 1.0123-1.0195, per drink per week), life-time maximum number of drinks in 1 day (HR = 1.0176, 95% CI = 1.0130-1.0221, per drink), symptom count (HR = 1.0867, 95% CI = 1.0633-1.1106, per symptom) and smoking status (HR = 2.82, 95% CI = 2.52-3.16 for smokers of 10+ cigarettes/day versus never-smokers) were each significant predictors of all-cause mortality. After adjustment for the independently significant predictors alcohol symptom count and smoking status, alcohol intake was no longer significant (adjusted HR = 1.0012 per drink per week, 95% CI = 0.9979-1.0145)., Conclusions: Number of symptoms related to high alcohol intake and tobacco smoking appear to account for the positive association between alcohol consumption and premature mortality., (© 2017 Society for the Study of Addiction.)

The current study examined a stage-based alcohol use trajectory model to test for potential causal effects of earlier drinking milestones on later drinking milestones in a combined sample of two cohorts of Australian monozygotic and same-sex dizygotic twins (N = 7,398, age M = 30.46, SD = 2.61, 61% male, 56% monozygotic twins). Ages of drinking, drunkenness, regular drinking, tolerance, first nontolerance alcohol use disorder symptom, and alcohol use disorder symptom onsets were assessed retrospectively. Ages of milestone attainment (i.e., age-of-onset) and time between milestones (i.e., time-to-event) were examined via frailty models within a multilevel discordant twin design. For age-of-onset models, earlier ages of onset of antecedent drinking milestones increased hazards for earlier ages of onset for more proximal subsequent drinking milestones. For the time-to-event models, however, earlier ages of onset for the "starting" milestone decreased risk for a shorter time period between the starting and the "ending" milestone. Earlier age of onset of intermediate milestones between starting and ending drinking milestones had the opposite effect, increasing risk for a shorter time period between the starting and ending milestones. These results are consistent with a causal effect of an earlier age of drinking milestone onset on temporally proximal subsequent drinking milestones.

Background and Objectives: We examined the associations of religious attendance during childhood (C-RA) and adulthood (A-RA) with alcohol involvement (ever drinking, timing of first alcohol use, and alcohol use disorder [AUD]) in White and Black female twins. As genetic and environmental factors influence religious attendance and alcohol involvement, we examined the extent to which they contribute to their association., Methods: Data on 3,234 White and 553 Black female twins (18-29 years) from the Missouri Adolescent Female twin Study. Significant correlations between C-RA or A-RA and alcohol involvement were parsed into their additive genetic, shared environmental, and individual-specific environmental sources., Results: C-RA was associated with ever drinking and timing of first alcohol use in Whites. A-RA was associated with ever drinking and AUD in both Whites and Blacks. Shared environmental influences did not contribute to alcohol or religiosity phenotypes in Blacks. In Whites, the association between C-RA and alcohol was due to shared environmental influences, whereas the association between A-RA and alcohol was attributable to additive genetic, shared environmental, and individual-specific environmental sources. Individual-specific environment and genetics contributed to associations between A-RA and ever drinking and AUD, respectively, in Blacks., Conclusions: Factors other than C-RA contribute to lower rates of alcohol involvement in Blacks. Shared environment does not contribute to links between A-RA and alcohol involvement in Blacks., Scientific Significance: The protective impact of childhood religiosity on alcohol use and misuse is important in Whites and is due to familial factors shared by religiosity and alcohol involvement. (Am J Addict 2017;26:437-445)., (© 2016 American Academy of Addiction Psychiatry.)

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10 -12 ). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption., Competing Interests: B. Psaty serves on the Data and Safety Monitoring Board for a clinical trial funded by the manufacturer (Zoll LifeCor) and the Steering Committee of the Yale Open Data Access project funded by Johnson & Johnson. D.J.M. serves on the scientific advisory board of Metacrine. The other authors report no competing financial interests.

Background: The aims of this study were to (i) characterize racial differences in alcohol involvement and (ii) examine the risk conferred by specific trauma exposures and posttraumatic stress disorder (PTSD) for different stages of alcohol involvement in European American (EA) and African American (AA) women., Methods: Data are from the Missouri Adolescent Female Twins Study (N = 3,787, 14.6% AA; mean age at most recent interview = 24.5 [SD 2.8]). Trauma exposures (e.g., sexual abuse [SA], physical abuse [PA], witnessing another person being killed or injured, experiencing an accident, and experiencing a disaster) were modeled as time-varying predictors of alcohol initiation, transition to first alcohol use disorder (AUD) symptom, and transition to AUD diagnosis using Cox proportional hazards regression while taking into account other substance involvement, parental characteristics, and commonly co-occurring psychiatric disorders., Results: In EA women only, SA was associated with alcohol initiation prior to the age of 14, PA predicted transition from initiation to first AUD symptom, and PA, witnessing injury or death, and SA predicted transition to AUD diagnosis. No association was discovered between trauma exposures or PTSD for any stage of alcohol involvement in AA women., Conclusions: Results reveal trauma experiences as important contributors to all stages of alcohol involvement in EA women only, with different trauma types conferring risk for each stage of alcohol involvement. PTSD was not revealed as a significant predictor of AUD in EA or AA women, suggesting trauma, independent of PTSD, directly contributes to alcohol involvement. Findings highlight the importance of considering racial differences when developing etiologic models of the association of traumatic experiences with alcohol involvement., Competing Interests: : No conflict declared, (Copyright © 2016 by the Research Society on Alcoholism.)

Rationale: Low sensitivity to alcohol is a well-established risk factor for alcohol use disorder (AUD). However, little is known about how the low sensitivity phenotype is expressed on a fine-grained, momentary level in drinkers' daily experience., Objectives: The objective of the study is to evaluate individual differences in subjective states and appraisals of alcoholic beverages during the ascending limb of real-world drinking episodes., Methods: Social drinkers (N = 398) with varying degrees of alcohol sensitivity as indexed by the Self-Rating of the Effects of Alcohol form (SRE; Schuckit et al. in Addiction 92:979-988, 1997a) recorded diary entries over a 3-week monitoring period (2576 drinking episodes containing 6546 moments). Hierarchical linear modeling was used to evaluate whether individual differences in alcohol sensitivity predicted differing intra-episode estimated blood alcohol concentration (eBAC) trajectories, ratings of subjective states, and drink appraisals., Results: Lower self-reported alcohol sensitivity was associated with consuming "too much, too fast," as indicated by a steeper slope of ascending eBAC. In models adjusted for momentary eBAC level, participants reporting lower alcohol sensitivity at baseline showed blunted subjective intoxication and drink-contingent punishment., Conclusions: The results suggest that low sensitivity to alcohol is associated with a blunting of some forms of subjective feedback (i.e., perceptions of intoxication and punishment) that might typically encourage drinking restraint. This may 'tip the scales' toward excess consumption and could help to explain why a low alcohol sensitivity forecasts AUD.

Objective: Research indicates that low parental monitoring increases the risk for early substance use. Because low parental monitoring tends to co-occur with other familial and neighborhood factors, the specificity of the association is challenging to establish. Using logistic regression and propensity score analyses, we examined associations between low parental monitoring and early substance use in European American (EA) and African American (AA) girls, controlling for risk factors associated with low parental monitoring., Method: Participants were 3,133 EA and 523 AA girls from the Missouri Adolescent Female Twin Study with data on parental monitoring assessed via self-report questionnaire, and with ages at first use of alcohol, tobacco, and cannabis queried in at least one of three diagnostic interviews (median ages = 15, 22, and 24 years)., Results: The rate of early alcohol use was greater in EA than AA girls, whereas the proportion of AA girls reporting low parental monitoring was higher than in EA girls. EA girls who experienced low parental monitoring were at elevated risk for early alcohol, tobacco, and cannabis use, findings supported in both logistic regression and propensity score analyses. Evidence regarding associations between low parental monitoring and risk for early substance use was less definitive for AA girls., Conclusions: Findings highlight the role of parental monitoring in modifying risk for early substance use in EA girls. However, we know little regarding the unique effects, if any, of low parental monitoring on the timing of first substance use in AA girls.

Background: Self-harm has considerable societal and economic costs and has been extensively studied in relation to alcohol involvement. Although early onset alcohol use (EAU) has been causally linked to maladaptive clinical outcomes, its association with self-harm is less well characterized. This study aimed to further examine the link between EAU and both nonsuicidal self-injury (NSSI) and suicide attempt (SA), and elucidate shared familial and causal/individual-specific pathways that explain this co-occurrence., Methods: Using data from 6,082 Australian same-sex twin pairs (1,732 monozygotic [MZ] and 1,309 dizygotic [DZ]), ages 23 to 40, we examined prevalence rates of NSSI and SA among twin pairs concordant and discordant for EAU. Conditional logistic regression, controlling for early clinical covariates and the influence of zygosity on EAU, was used to examine the odds ratio (OR) of self-harm within twin pairs discordant for EAU., Results: Prevalence rates of both NSSI and SA were highest among twin pairs concordant for EAU and for twins who reported EAU within discordant twin pairs. Results from discordant twin analyses revealed nearly 4-fold increased odds of SA for the twin who endorsed EAU, and this OR was equal across MZ and DZ twins. EAU also was associated with elevated odds of NSSI (OR = 7.62), although this was only the case for DZ twins in discordant pairs., Conclusions: The equivalent increase in odds of SA for both MZ and DZ twins suggests that causal or individual-specific influences explain the link between EAU and SA. For NSSI, elevated odds for DZ twins and nonsignificant findings for MZ twins implicate correlated genetic factors in the association between EAU and NSSI. Future studies should test mechanisms through which EAU may causally influence SA, as well as examine whether genetic risk for third variables (e.g., negative urgency, stress reactivity) may explain the genetic overlap between EAU and NSSI., (Copyright © 2015 by the Research Society on Alcoholism.)

Aims: (1) To compare affective changes over drinking and non-drinking days among frequent drinkers and (2) to evaluate whether drinkers' expectations influence affective changes and perceived pleasure and relief from drinking., Design: Observational study involving ecological momentary assessments collected via electronic diaries during the course of 3 weeks., Setting: Drinkers' usual settings in Columbia, MO, USA., Participants: A total of 400 adult, frequent drinkers, aged 18-70 years., Measurements: Ecological assessments included morning reports, pre-drinking random prompts, user-initiated first-drink reports and device-prompted follow-ups over drinking episodes. Participants rated positive (enthusiastic, excited, happy) and negative (distressed, sad) affect and perceived pleasure and relief from drinking in real time. A self-report questionnaire completed at baseline evaluated expectancies for enhanced sociability and tension reduction from drinking., Findings: Relative to affective changes over non-drinking days, positive affect increased prior to drinking [95% confidence interval (CI) = 0.004, 0.023], and at first drink (95% CI = 0.238, 0.317), whereas negative affect decreased prior to drinking (95% CI = - 0.007, 0.000) and at first drink (95% CI = - 0.154, - 0.098). Sociability expectancies augmented increases in positive affect prior to drinking (95% CI = 0.009, 0.027) and at first drink (95% CI = 0.017, 0.169). Sociability expectancies also enhanced perceived pleasure from first drinks (95% CI = 0.046, 0.318). Tension-reduction expectancies attenuated decreases in negative affect at first drink (95% CI = - 0.133, - 0.029), but augmented perceived relief from first drinks (95% CI = 0.001, 0.304)., Conclusions: Although theoretical models tend to focus on negative affective outcomes of drinking, changes in positive affect prior to drinking and early in drinking episodes are important for maintaining drinking behavior. Frequent drinkers' expectations for enhanced sociability or tension reduction from drinking influence their affective experiences over drinking days and perceptions of pleasure and relief from drinking., (© 2015 Society for the Study of Addiction.)

Considerable attention has been paid to the "gateway" pattern of drug use initiation in which individuals progress from tobacco and alcohol use to cannabis and other illicit drugs. The extent to which this sequence reflects a causal impact of licit substance use on illicit substance involvement remains unclear. Clarifying the mechanisms underlying substance use initiation may help inform our understanding of risk for psychopathology, as increasing research is demonstrating associations between initiation patterns and heavier involvement. This study examined patterns of substance use initiation using a discordant twin design. Participants were 3,476 monozygotic twins (37% male) from the Australian Twin Registry who reported on their ages of tobacco, alcohol, and cannabis initiation. Multilevel proportional hazard regression models were used to (a) estimate within-twin-pair and between-twin-pair contributions to associations between the ages of onset of different drugs; and (b) examine whether the magnitude of effects differed as a function of the order of substance use initiation. Finding significant effects within twin pairs would support the hypothesis that the age of initiation of a substance causally influences the age of initiation of a subsequent substance. Finding significant effects between twin pairs would support the operation of familial influences that explain variation in the ages of initiation of multiple drugs. Within-twin-pair effects for typical patterns were modest. When initiation was atypical, however, larger within-twin-pair effects were observed and causal influences were more strongly implicated. Results support the utility of examining the timing and ordering of substance use initiation within sophisticated, genetically informative designs., ((c) 2015 APA, all rights reserved).)

Alcohol use can be understood as a strategic behavior, such that people choose to drink based on the anticipated affective changes produced by drinking relative to those produced by alternative behaviors. This study investigated whether people who report drinking for specific reasons via the Drinking Motives Questionnaire-Revised (DMQ-R; Cooper, 1994) actually experience the alcohol effects they purportedly seek. As a secondary goal, we examined relations between drinking motives and indices of the amount of alcohol consumed. Data were drawn from 3,272 drinking episodes logged by 393 community-recruited drinkers during a 21-day Ecological Momentary Assessment investigation. After accounting for selected covariates, DMQ-R enhancement motives uniquely predicted real-time reports of enhanced drinking pleasure. DMQ-R coping motives were associated with reports of increased drinking-contingent relief and punishment. Enhancement motives uniquely predicted consuming more drinks per episode and higher peak intra-episode estimated blood alcohol concentration. The findings extend the evidence for the validity of the DMQ-R motive scores by demonstrating that internal drinking motives (enhancement and coping) are related to the experienced outcomes of drinking in the manner anticipated by theory.

Background: Measures of hangover are associated with current and future problematic alcohol use. At present, it is not known whether these associations reflect any direct influence of hangover events on near-term drinking behaviors. The current study aimed to determine whether hangover following a drinking episode influences time to next drink (TTND) and, if so, to determine the direction of this effect and identify any moderating personal or contextual factors., Methods: Community-recruited, frequent drinkers oversampled for current smoking (N = 386) carried electronic diaries for 21 days, reporting on drinking behaviors and other experiences. Survival analysis was used to model data from 2,276 drinking episodes, including 463 episodes that were followed by self-reported hangover in morning diary entries., Results: When tested as the sole predictor in a survival model, hangover was associated with increased TTND. The median survival time was approximately 6 hours longer after episodes with hangovers compared to those without. In a multivariate model, hangover was only significant in the presence of interaction effects involving craving at the end of the index drinking episode and the occurrence of financial stressors. Additional predictors of TTND in the final multivariate model included age, lifetime alcohol use disorder diagnosis, typical drinking frequency, day of the week, and morning reports of craving, negative affect, and stressors after the index episode. There was no association between morning reports of hangover and contemporaneous diary ratings of likelihood of drinking later the same day., Conclusions: The findings suggest that hangover has, at best, a modest or inconsistent influence on the timing of subsequent alcohol use among frequent drinkers., (Copyright © 2014 by the Research Society on Alcoholism.)

Aims: To investigate the genetic and environmental contributions to age at first drink (AFD) and age first gambled (AFG), assess their overlap and examine sex differences., Design: Univariate twin models were fitted to decompose the variation in AFD and AFG into additive genetic, shared environmental and unique environmental factors. Bivariate genetic models were fitted to assess the genetic and environmental contributions to the sources of covariation in AFD and AFG., Setting: National Australian Twin Registry., Participants: A total of 4542 same-sex and opposite-sex twins aged 32-43 years, 42% male and 58% female., Measurements: AFD and AFG were assessed via structured psychiatric telephone interviews. Age of onset was treated as both continuous and categorical (early/late onset)., Findings: AFD and AFG were modestly correlated (r = 0.18). Unique environmental influences explained a substantial proportion of the variation in both AFD (0.55, 95% confidence interval [CI] = 0.50-0.61) and AFG (0.66, 95% CI = 0.59-0.72), but these influences were uncorrelated (rE  = 0.01). Additive genetic factors explained a notable proportion of variation in AFG (0.21, 95% CI = 0.003-0.39), while shared environmental factors were important for AFD (0.31, 95% CI = 0.15-0.46). Among men, genetic factors influenced variation in AFG but not in AFD and shared environmental factors influenced variation in AFD but not in AFG. Among women, shared environmental factors influenced variation in both AFD and AFG, but these environmental factors were not significantly correlated (rC  = 0.09)., Conclusions: Among Australian twins, age at first drink and age first gambled are influenced by distinct unique environmental factors, and the genetic and environmental underpinnings of both phenotypes differ in men and women., (© 2013 Society for the Study of Addiction.)

Background: Differences in age at initiation of alcohol use and rates of problem drinking between African Americans and European Americans are well documented, but the association between early and problem use-and distinctions by ethnic group in this association-have yet to be examined in a genetically informative framework., Methods: Data were derived from a longitudinal study of female twins in Missouri. The sample was composed of 3,532 twins (13.6% African-American [AA], 86.4% European-American [EA]), who participated in the fourth wave of data collection and reported consumption of at least 1 alcoholic drink over the lifetime. Mean age at Wave 4 was 21.7 (range = 18 to 29) years. Twin modeling was conducted to estimate the relative contributions of additive genetic (A), shared environmental (C), and unique environmental (E) factors to variation in age at first drink and problem alcohol use and the cross-phenotype overlap in these influences., Results: Early initiation of alcohol use predicted problem use in EA but not AA women. Separate AA and EA twin models produced substantially different estimates (but not statistically different models) of the relative contributions of A and C to problem alcohol use but similar genetic correlations between the phenotypes. Whereas 33% of the variance in the EA model of problem use was attributed to C, no evidence for C was found in the AA model. Heritability estimates for problem alcohol use were 41% in the AA model, 21% in the EA model. Evidence for A and C were found in both AA and EA models of age at first drink, but the A estimate was higher in the EA than AA model (44% vs. 26%)., Conclusions: Findings are suggestive of distinctions between AA versus EA women in the relative contribution of genetic and environmental influences on the development of problem drinking., (Copyright © 2013 by the Research Society on Alcoholism.)

Objective: Previous research has established a connection between early age at drinking initiation and greater alcohol involvement in adulthood, but it has not yet been established whether this is a causal effect. The current study used a multilevel discordant twin design to examine individual and contextual effects, and an interaction between these effects, of the age at drinking initiation on the frequency and quantity of drinking in adulthood., Method: Participants were 4,194 same-sex twins (2,264 monozygotic, 1,924 dizygotic; 2,270 women; Mage = 29.9 years) from the Australian Twin Registry who completed a telephone interview that included assessments of the age at alcohol use initiation and past-year frequency and quantity of alcohol use. Multilevel models were estimated using data from the full sample and using data from only monozygotic twins. Individual (within-twin-pair comparison) and family contextual (between-twin-pair comparison) effects were estimated., Results: The age at first drink was related to the past-year frequency (r = -.16) and quantity of drinking (r = -.12) in young adulthood. Individual (causal) and family context effects of age at drinking onset predicted later adult drinking frequency and quantity. There was also a significant cross-level interaction between individual and family contexts for frequency but not quantity of drinking., Conclusions: Results of this study indicate a potential causal effect of age at drinking onset on adult alcohol involvement as well as the importance of examining both individual and contextual effects in discordant twin studies.

Background: The effects of sibship size and structure on delinquency are well established. Specifically, having a large family and many brothers has been shown to predict offending. However, despite strong links between delinquency and alcohol use, the contribution of sibship factors to drinking behaviors remains largely unexplored. The current study investigated the impact of sibship size and composition on younger brothers' and sisters' ages of drinking and intoxication onset., Methods: We employed a sample of 4,281 same-sex twins from the Australian Twin Register to examine whether (i) large sibship size facilitates earlier age at first drink (AFD) and age at first intoxication (AFI) in males and females, (ii) having many older brothers predicts earlier ages of AFD and AFI in males, and (iii) having many older brothers results in later AFD and AFI in females. We tested whether effects were moderated by parental divorce and alcohol misuse and mediated by familial religion., Results: Sibling effects were minimal before accounting for family context. However, when parental divorce and excessive parental drinking were included as moderators, sibling effects were significantly amplified among individuals from homes of divorce, and effects were strongest when siblings were close in age., Conclusions: Strong close in age older sibling effects indicate that proximal sibling attitudes and behaviors about alcohol likely interact with structural factors to influence younger siblings' drinking. Sibship factors were much more influential in one population (individuals from homes of divorce) than another (respondents with a parental history of excessive drinking), suggesting that sibling effects vary depending on the type of co-occurring familial risk. Prevention efforts performed at the family level, and introduced before first use of alcohol, are likely to delay drinking initiation and help prevent future alcohol problems., (Copyright © 2012 by the Research Society on Alcoholism.)

Background: Alcohol consumption has multiple biochemical consequences. Only a few of these are useful as diagnostic markers, but many reflect potentially harmful or beneficial effects of alcohol. Average consumption of 2 to 4 drinks per day is associated with lower overall or cardiovascular mortality risk than either lower or higher intake. We have analyzed the dose-response relationships between reported alcohol consumption and 17 biomarkers, with emphasis on intake of up to 3 drinks per day., Methods: Biochemical tests were performed on serum from 8,396 study participants (3,750 men and 4,646 women, aged 51 ± 13 years, range 18 to 93) who had provided information on alcohol consumption in the week preceding blood collection., Results: Gamma glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, carbohydrate-deficient transferrin, urate, ferritin, and bilirubin showed little or no change with alcohol consumption below 2 to 3 drinks per day, but increased with higher intake. High-density lipoprotein cholesterol and albumin showed increasing results, and insulin showed decreasing results, across the entire range of alcohol use. Biphasic responses, where subjects reporting 1 to 2 drinks per day had lower results than those reporting either more or less alcohol use, occurred for triglycerides, glucose, C-reactive protein, alkaline phosphatase, and butyrylcholinesterase. Increasing alcohol use was associated with decreasing low-density lipoprotein cholesterol (LDL-C) in younger women, but higher LDL-C in older men., Conclusions: Some markers show threshold relationships with alcohol, others show continuous ones, and a third group show biphasic or U-shaped relationships. Overall, the biochemical sequelae of low-to-moderate alcohol use are consistent with the epidemiological evidence on morbidity and mortality., (Copyright © 2012 by the Research Society on Alcoholism.)

Objective: The current investigation tested whether low sensitivity to alcohol, as measured by the Self-Rating of the Effects of Alcohol (SRE) form, is associated with hangover occurrence or resistance, two potentially important predictors of later problematic drinking outcomes., Method: Drinkers who reported using alcohol at least four times in the past month (N = 402) completed the SRE at baseline and used ecological momentary assessment methods with an electronic diary to record drinking behaviors and related experiences over 21 days. Each morning, the diary assessed prior-night drinking behaviors and the presence of current hangover., Results: After adjustments for sex, body weight, age, and smoking status, higher SRE scores (indicating lower alcohol sensitivity) predicted hangover occurrence on postdrinking mornings (odds ratio [OR] = 1.24 per interquartile range [IQR], p = .003). However, when the number of drinks consumed in the drinking episode was covaried, SRE scores were negatively associated with hangover (OR = 0.67 per IQR, p <.001). An interaction between SRE scores and the number of drinks consumed indicated that low-sensitivity drinkers tend to be differentially resistant to hangover at a given number of drinks. Higher SRE scores were associated with consuming more drinks on average (generalized estimating equations coefficient = 2.20 per IQR, p <.001)., Conclusions: Individuals lower in alcohol sensitivity appear to be more resistant to hangovers per unit of alcohol. However, they are also more likely to engage in excessive drinking, and this may account for their increased odds of experiencing hangover during an arbitrary monitoring period. Heavy consumption, hangover resistance, and hangover frequency may each be manifestations of low sensitivity to alcohol, an established risk factor for alcohol use disorder.

Rationale: Tobacco and alcohol are frequently used together, and this may be partly explained by a distinct profile of subjective effects associated with co-administration. Ecological momentary assessment studies have examined effects of naturally occurring co-use, but, to date, have not assessed differing effects as alcohol levels rise and fall., Objectives: The objective of the study was to describe subjective states and appraisals of cigarette and alcohol effects reported during the entirety of real-world drinking episodes., Methods: Currently-smoking frequent drinkers (N = 255) carried electronic diaries for 21 days. Analyses focused on reports made during 2,046 drinking episodes. Signaled prompts intensively oversampled moments in the hours following consumption of the first drink in an episode. Multilevel regression analyses were used to predict ratings of buzz, dizziness, excitement, and sluggishness as a function of person-level and contextual covariates, estimated blood alcohol concentration (eBAC) level, ascending vs. descending eBAC, smoking, and their interactions. Appraisals of cigarette and alcohol effects were also examined within this framework., Results: Buzz, excitement, and pleasure from alcohol and cigarettes were prominent features of real-world drinking episodes. Smoking was associated with enhanced buzz and excitement when eBAC was high and descending. Smoking slightly accentuated the relation between eBAC and ratings of drinking pleasure among women, but this relation was somewhat weakened by smoking among men., Conclusions: Smoking during drinking episodes may be partly explained by a persistence of stimulant alcohol effects beyond the blood alcohol concentration peak. Acute effects of nicotine and tobacco use on the descending limb deserve further scrutiny in experimental alcohol challenge research.

Background: Although substance use is associated with reduced educational attainment, this association may be owing to common risk factors such as socioeconomic disadvantage. We tested whether alcohol, nicotine, and illicit drug use and dependence were associated with lifetime educational attainment after controlling for familial background characteristics., Methods: Data were from a 1987 questionnaire and a 1992 telephone diagnostic interview of 6,242 male twins (n = 3,121 pairs; mean age = 41.9 years in 1992) who served in the U.S. military during the Vietnam era and therefore, were eligible for educational benefits after military service. Reduced educational attainment (<16 years) was examined in twin pairs discordant for substance use history. Substance use and dependence risk factors assessed were early alcohol and cannabis use, daily nicotine use, lifetime cannabis use, and alcohol, nicotine, cannabis, and any illicit drug dependence., Results: Three significant differences were observed between at-risk twins and their cotwins: Compared to their low-risk cotwins, likelihood of completing <16 years of education was significantly increased for the following: (i) twins who used alcohol before age 18 (adjusted OR = 1.44; 95% CI: 1.02 to 2.05), (ii) twins with a lifetime alcohol dependence diagnosis (adjusted OR = 1.76; 95% CI: 1.27 to 2.44), and (iii) twins who had used nicotine daily for 30 or more days (adjusted OR = 2.54, 95% CI: 1.55 to 4.17). However, no differences in education were observed among twin pairs discordant for cannabis initiation, early cannabis use, or cannabis, nicotine, or any illicit drug dependence., Conclusions: Even in a veteran population with access to military educational benefits, early alcohol use, alcohol dependence, and daily nicotine use remained significantly associated with years of education after controlling for shared familial contributions to educational attainment. The association between other substances and educational attainment was explained by familial factors common to these substance use phenotypes and adult educational attainment., (Copyright © 2012 by the Research Society on Alcoholism.)

Background: Motivational models of alcohol use propose that the motivation to consume alcohol is the final common pathway to its use. Both alcohol consumption and drinking motives are influenced by latent genetic factors that partially overlap. This study investigated whether drinking motives mediate the associations between alcohol consumption and 2 single-nucleotide polymorphisms (SNPs) from genes involved in serotonin (TPH2; rs1386496) and dopamine synthesis (DDC; rs3779084). Based on earlier work showing that enhancement and coping motives were heritable in regular smokers but not in nonregular smokers, we hypothesized these motives would mediate the relationships between alcohol consumption and these SNPs in regular smokers., Methods: Drinking motives data were available from 830 young adult female twins (n = 344 regular smokers and n = 486 never/nonregular smokers). We used confirmatory factor analyses to model enhancement, coping, and alcohol consumption factors and to conduct mediation analyses in the regular smoker and never/nonregular smoker groups., Results: Our hypothesis was partially supported. The relationship between alcohol consumption and rs1386496 was not mediated by drinking motives in either group. However, in the regular smokers, the relationship between alcohol consumption and rs3779084 was mediated by enhancement and coping motives. Carriers of the rs3779084 minor allele who were regular smokers reported more motivation to consume alcohol. Given this pattern of results was absent in the never/nonregular smokers, our results are consistent with a gene × smoking status interaction., Conclusions: In regular smokers, variability at the locus marked by rs3779084 in the DDC gene appears to index biologically based individual differences in the motivation to consume alcohol to attain or improve a positive affective state or to relieve a negative one. These results could be because of increased sensitivity to the reinforcing effects of alcohol among minor allele carriers who smoke, which might be due to structural or functional differences in mesorticolimic dopamine "reward" circuitry., (Copyright © 2011 by the Research Society on Alcoholism.)

Background: The Hangover Symptoms Scale (HSS) assesses the frequency of 13 symptoms experienced after drinking in the past year. Cross-sectional analyses in college drinkers showed preliminary evidence for the validity of the HSS (Slutske et al., 2003). The current investigation extended this work by examining the construct validity of the HSS in an ecological momentary assessment investigation., Methods: Frequent drinkers (N = 404) carried electronic diaries to track their daily experiences over 3 weeks. Each morning, the diary assessed prior-night drinking behaviors, the presence of current hangover, and intensity of current headache and nausea., Results: Adjusting for sex and body mass, the HSS significantly predicted diary endorsement of hangover (OR = 2.11, 95% CI = 1.78 to 2.49, p < 0.001). Participants who endorsed the HSS headache and nausea items were especially likely to report the elevations of corresponding symptoms in diary records made the morning after drinking. HSS scores incrementally predicted hangover when the number of drinks consumed in the episode was covaried but did not moderate the relationship between the number of drinks and diary hangover reports., Conclusions: The HSS appears to be a valid tool for hangover research. Higher HSS scores identify individuals who complain of "real world" hangovers and who may be especially likely to display particular symptoms after a night of drinking. Past hangovers predicted future hangovers, suggesting hangovers do not necessarily discourage or inhibit future drinking, at least across the several-week time interval studied here. There is a need to develop and evaluate complementary measures that can more directly index individual differences in hangover susceptibility in survey designs., (Copyright © 2011 by the Research Society on Alcoholism.)

Background: Genetic risk for alcohol dependence has been shown to overlap with genetic factors contributing to variation in dimensions of personality. Although drinking motives have been posited as important mediators of the alcohol-personality relation, the extent to which the genetic covariance between alcohol use disorder (AUD) symptoms (i.e., abuse and dependence criteria) and personality is explained by genetic factors contributing to variation in drinking motives remains unclear., Methods: Using data from 2,904 young adult female twins, the phenotypic and genetic associations between personality dimensions (constraint [measured by the Multidimensional Personality Questionnaire; Tellegen A, 1982 unpublished data], conscientiousness, neuroticism, and agreeableness [measured by the NEO-PI; Costa and McCrae, 1985]), internal drinking motives (enhancement and coping motives [measured by the Drinking Motive Questionnaire; Cooper, 1994]), and AUD symptoms were tested., Results: Significant genetic associations were found between all personality measures and AUD symptoms. Coping motives showed significant genetic overlap with AUD symptoms and most personality measures, whereas enhancement motives were not significantly heritable. Adjusting for coping motives, genetic correlations between AUD symptoms and traits of neuroticism and agreeableness were no longer statistically significant., Conclusions: Findings suggest that genetic variation in drinking to cope might account for a considerable proportion of the genetic covariance between specific personality dimensions and AUD symptoms., (Copyright © 2011 by the Research Society on Alcoholism.)

Polysaccharide sidechains attached to proteins play important roles in cell-cell and receptor-ligand interactions. Variation in the carbohydrate component has been extensively studied for the iron transport protein transferrin, because serum levels of the transferrin isoforms asialotransferrin + disialotransferrin (carbohydrate-deficient transferrin, CDT) are used as biomarkers of excessive alcohol intake. We conducted a genome-wide association study to assess whether genetic factors affect CDT concentration in serum. CDT was measured in three population-based studies: one in Switzerland (CoLaus study, n = 5181) and two in Australia (n = 1509, n = 775). The first cohort was used as the discovery panel and the latter ones served as replication. Genome-wide single-nucleotide polymorphism (SNP) typing data were used to identify loci with significant associations with CDT as a percentage of total transferrin (CDT%). The top three SNPs in the discovery panel (rs2749097 near PGM1 on chromosome 1, and missense polymorphisms rs1049296, rs1799899 in TF on chromosome 3) were successfully replicated , yielding genome-wide significant combined association with CDT% (P = 1.9 × 10(-9), 4 × 10(-39), 5.5 × 10(-43), respectively) and explain 5.8% of the variation in CDT%. These allelic effects are postulated to be caused by variation in availability of glucose-1-phosphate as a precursor of the glycan (PGM1), and variation in transferrin (TF) structure.

Background: Given moderately strong genetic contributions to variation in alcoholism and heaviness of drinking (50% to 60% heritability) with high correlation of genetic influences, we have conducted a quantitative trait genome-wide association study (GWAS) for phenotypes related to alcohol use and dependence., Methods: Diagnostic interview and blood/buccal samples were obtained from sibships ascertained through the Australian Twin Registry. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed with 8754 individuals (2062 alcohol-dependent cases) selected for informativeness for alcohol use disorder and associated quantitative traits. Family-based association tests were performed for alcohol dependence, dependence factor score, and heaviness of drinking factor score, with confirmatory case-population control comparisons using an unassessed population control series of 3393 Australians with genome-wide SNP data., Results: No findings reached genome-wide significance (p = 8.4 × 10(-8) for this study), with lowest p value for primary phenotypes of 1.2 × 10(-7). Convergent findings for quantitative consumption and diagnostic and quantitative dependence measures suggest possible roles for a transmembrane protein gene (TMEM108) and for ANKS1A. The major finding, however, was small effect sizes estimated for individual SNPs, suggesting that hundreds of genetic variants make modest contributions (1/4% of variance or less) to alcohol dependence risk., Conclusions: We conclude that 1) meta-analyses of consumption data may contribute usefully to gene discovery; 2) translation of human alcoholism GWAS results to drug discovery or clinically useful prediction of risk will be challenging; and 3) through accumulation across studies, GWAS data may become valuable for improved genetic risk differentiation in research in biological psychiatry (e.g., prospective high-risk or resilience studies)., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Alcohol and tobacco use covary at multiple levels of analysis, and co-use of the 2 substances may have profound health consequences. To characterize the motivationally relevant processes contributing to co-use, the current study used ecological momentary assessment (EMA) to examine the subjective consequences of naturally occurring simultaneous use of alcohol and tobacco. Current smokers who reported frequently drinking alcohol (N=259) used electronic diaries to monitor their daily experiences for 21 days. Participants responded to prompted assessments and also initiated recordings when they smoked a cigarette or completed the first drink in a drinking episode. Momentary reports of smoking and alcohol consumption were associated with one another, and these effects remained after adjustment for occasion- and person-level covariates. When participants consumed alcohol, they reported increased pleasure and decreased punishment from the last cigarette. Smoking was associated with small increases in pleasure from the last drink. Ratings of buzzed and dizzy were synergistically affected by co-use of alcohol and tobacco. Co-use was also followed by higher levels of craving for both alcohol and tobacco. Results point to the importance of reward and incentive processes in ongoing drug use and suggest that alcohol intensifies real-time reports of the motivational consequences of smoking more strongly than smoking affects corresponding appraisals of alcohol effects., (© 2011 American Psychological Association)

Background: Given the weight placed on retrospective reports of age at first drink in studies of later drinking-related outcomes, it is critical that its reliability be established and possible sources of systematic bias be identified. The overall aim of the current study is to explore the possibility that the estimated magnitude of association between early age at first drink and problem alcohol use may be inflated in studies using retrospectively reported age at alcohol use onset., Methods: The sample was comprised of 1,716 participants in the Missouri Adolescent Female Twin Study who reported an age at first drink in at least 2 waves of data collection (an average of 4 years apart). Difference in reported age at first drink at Time 2 versus Time 1 was categorized as 2 or more years younger, within 1 year (consistent), or 2 or more years older. The strength of the association between age at first drink and peak frequency of heavy episodic drinking (HED) at Time 1 was compared with that at Time 2. The association between reporting pattern and peak frequency of HED was also examined., Results: A strong association between age at first drink and HED was found for both reports, but it was significantly greater at Time 2. Just over one-third of participants had a 2 year or greater difference in reported age at first drink. The majority of inconsistent reporters gave an older age at Time 2 and individuals with this pattern of reporting engaged in HED less frequently than consistent reporters., Conclusions: The low rate of HED in individuals reporting an older age at first drink at Time 2 suggests that the upward shift in reported age at first drink among early initiates is most pronounced for light drinkers. Heavy drinkers may therefore be overrepresented among early onset users in retrospective studies, leading to inflated estimates of the association between early age at initiation and alcohol misuse., (Copyright © 2011 by the Research Society on Alcoholism.)

The objective of this study was to examine the underlying factorial architecture of lifetime DSM-IV alcohol use disorder (AUD) criteria in a population-based sample of adolescent and emerging adult female twins who had ever used alcohol (n=2832; aged 18-25 years), and to determine whether thresholds and factor loadings differed by age. Item response modeling was applied to DSM-IV AUD criteria. Compound criteria (e.g., persistent desire or unsuccessful attempts to quit or cut down) were included as separate items. Of the remaining 16 items, tolerance and use despite physical problems were the most and least commonly endorsed items, respectively. Underlying the items was a single factor representing liability to AUDs. Factor loadings ranged from 0.67 for blackouts to 0.90 for time spent using/recovering from effects. Some items assessing different DSM-IV criteria had very similar measurement characteristics, while others assessing the same criterion showed markedly different thresholds and factor loadings. Compared to that of women aged 21-25 years, the threshold for hazardous use was higher in women aged 18-20 years, but lower for used longer than intended and persistent desire to cut down. After accounting for threshold differences, no variations in discrimination across age groups were observed. In agreement with the extant literature, our findings indicate that the factorial structure of AUD is unidimensional, with no support for the abuse/dependence distinction. Individual components of compound criteria may differ in measurement properties; therefore pooling information from such divergent items will reduce information about the AUD construct., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: The goal of this study was to develop a factor score derived from measures of past-12-month alcohol consumption., Method: Data were drawn from two studies-the Adult and Family Development Project (N = 734) and the Missouri Adolescent Female Twin Study (N = 3,787). Data on four indices of alcohol consumption (quantity, frequency, frequency of drinking to intoxication, and frequency of five or more drinks/day) were factor analyzed, and differences in factor loadings across gender, race/ethnicity, and study were tested. Correlations between these factors were computed across three assessments and between parent and offspring self-reports. Finally, using the classical twin design, variance in the past-12-month alcohol consumption factor was decomposed into additive genetic (A), shared environmental (C), and nonshared environmental (E) influences, and the extent to which these factors overlap with those influencing lifetime heaviest drinking were examined., Results: Factor loadings across all groups were high (.69-.95), with some evidence for differing factor loadings across gender, race/ethnicity, and study. The across-wave correlations for the factor ranged from .22 to .62. The within-wave correlation between parental and offspring drinking was .25, suggesting the importance of familial influences, which genetic analyses attributed to both additive genetic (31%) and shared environmental (17%) factors. The overlap between genetic influences on past-12-month and lifetime heaviest drinking was 0.97., Conclusions: A factor score derived from past-12-month drinking measures is heritable and is largely influenced by those genetic factors that influence heaviest drinking, at least in young adults. It also shows moderate across-wave stability. This will allow for large- and small-scale genomic studies to use past-12-month drinking measures in data analysis of similar cohorts.

Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 × 10(-8) to P = 4 × 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

Background: Although associations between drinking behavior and marital status are well documented, timing of marital transitions as a function of alcohol use or disorder has received limited empirical attention., Methods: We examine the relationship between lifetime history of alcohol dependence (AD) and timing and survival of first marriages in a sample of 3,575 female and 1,845 male adult Australian twins born mostly between 1940 and 1964. Survival analyses were conducted using Cox proportional hazards regression models., Results: Results indicate moderate delays in marriage associated with AD for both women and men. Among ever-married respondents, AD was strongly predictive of early separation, with similar effects observed for women and men. Heritable sources of covariation were also documented. For women, genetic influences shared between early-onset AD and marital timing were found. Genetic influences shared between AD and marital survival were observed for women without regard to onset and for men with later-onset AD., Conclusions: Results confirm the importance of AD as a predictor of both timing and survival of first marriages, with genetic influences contributing to observed associations., (Copyright © 2011 by the Research Society on Alcoholism.)

Background: Excessive alcohol consumption contributes to significant morbidity and mortality. Heritable influences contribute to 50% of the variation in alcohol consumption, suggesting the important role of genes. We used data on a previously defined alcohol consumption factor score in a sample of 827 young women to investigate association with 1,014 single-nucleotide polymorphisms in genes related to addiction., Methods: Data were drawn from the Missouri Adolescent Female Twin Study (MOAFTS) with replication in the college drinking sample (CDS). Genotypic and phenotypic data were available on 827 MOAFTS and 100 CDS women of European-American ancestry. Data on 1,014 single-nucleotide polymorphisms (SNPs) across 130 genes related to addiction were utilized. Association was conducted in QTDT, which allows for identity-by-descent information to account accurately for twin status in the analysis. The total association variance components model was used, with specification of variance components for relatedness in MOAFTS., Results: The top signals included clusters of SNPs in tryptophan hydroxylase 2 (TPH2) (e.g., rs1386496, p = 0.0003) and dopa decarboxylase (DDC) (e.g., rs3779084, p = 0.0008), genes that encode proteins responsible for serotonin synthesis. Additional polymorphisms in ADH1B, ADH1C, ADH7, and ADH1A1 were also associated at p < 0.05. The false discovery rate for the top signal (p = 0.0003) was 0.15, suggesting nominal significance only. Replication was limited and noted for 2 SNPs in ADH1C., Conclusions: While no results survive the burden of multiple testing, nominal findings in TPH2 and DDC suggest the potential role of the serotonin synthesis pathway in alcohol consumption., (Copyright © 2010 by the Research Society on Alcoholism.)

Background: Alcohol and tobacco use often co-occur. Human and animal studies indicate that nicotine increases alcohol's rewarding effects and the motivation to consume it. The aims of this study were to examine whether the factorial architecture of self-reported motivations to consume alcohol differed between regular and nonregular cigarette smokers while taking into account the lifetime history of alcohol dependence and psychopathology, and to estimate the genetic and environmental influences on the motivations., Methods: Using data on 2,189 monozygotic and dizygotic female twins, we examined the factorial structure (item thresholds and factor loadings, means, and variances) of the items from the Drinking Motives Questionnaire (DMQ) in regular and nonregular smokers. Post hoc tests examined the association between the latent drinking motives factors and alcohol dependence in both groups. Twin models were fitted to the latent drinking motives factors, testing for variations in the magnitude of additive genetic, shared, and nonshared environmental influences between the groups., Results: The 4 DMQ factors (social, conformity, coping, and enhancement) were recovered in both groups, and their measurement structure was consistent across the groups. Regular smokers reported higher levels of coping, enhancement, and social motives while nonregular smokers reported higher conformity motives. Alcohol dependence was associated with higher scores on all motives in both groups; however, in a regression analysis that included all of the motives as predictor variables, only coping was significantly related to alcohol dependence. While twin models revealed evidence for substantially greater genetic influences on enhancement (h² = 0.40), coping (h² = 0.35) and social (h² = 0.37) drinking motives in regular compared to nonregular smokers, the power to statistically distinguish the 2 groups was low., Conclusions: While the measurement structure of the drinking motive factors appears to be similar across regular and nonregular smokers, regular smokers report more motivation to drink for internal affect-related reasons and to obtain social reward. Of all the motives, coping was the most robust predictor of alcohol dependence in both the regular and the nonregular smokers. Further, genetic influences might play a larger role in drinking motives among regular smokers, which provides tentative evidence for latent genetic × smoking status interactions., (Copyright © 2010 by the Research Society on Alcoholism.)

Aims: Peer substance involvement (PSI) is a robust correlate of adolescent substance use. A small number of genetically informative studies suggest that shared genetic and environmental factors contribute to this association. We examine mechanisms by which PSI influences the etiology of regular substance involvement (RSI), particularly in women., Design: Population-based cohort study of twin women from the US Midwest., Participants: 2176 twin women., Measurements: To examine the relationship between self-reported PSI during adolescence and a composite RSI representing regular tobacco, alcohol and cannabis use during young adulthood, using genetically informative correlation, moderation and joint correlation-moderation models., Findings: There was evidence for a significant additive genetic X environment interaction. PSI was moderately heritable (h(2) = 0.25). Genetic, shared and non-shared influences on RSI overlapped with influences on PSI (genetic correlation of 0.43). Even after controlling for these shared genetic influences, RSI was more heritable in those reporting greater PSI., Conclusions: While young women may select peers based on certain dispositional traits (e.g. permissiveness towards substance use), the social milieu constructed by PSI does modify the architecture of increased RSI in those individuals with increasing levels of PSI being associated with stronger expression of heritable influences., (© 2010 The Authors, Addiction © 2010 Society for the Study of Addiction.)

Background: Despite mounting evidence that use of and dependence on alcohol and cannabis are influenced by heritable factors, the extent to which heritable influences on these phenotypes overlap across the 2 substances has only rarely been explored. In the current study, we quantified cross-substance overlap in sources of variance and estimated the degree to which within-substance associations between use and dependence measures are attributable to common genetic and environmental factors for alcohol and cannabis., Methods: The sample was comprised of 6,257 individuals (2,761 complete twin pairs and 735 singletons) from the Australian Twin Registry, aged 24 to 36 years. Alcohol and cannabis use histories were collected via telephone diagnostic interviews and used to derive an alcohol consumption factor, a frequency measure for cannabis use, and DSM-IV alcohol and cannabis dependence symptom counts. Standard genetic analyses were conducted to produce a quadrivariate model that provided estimates of overlap in genetic and environmental influences across the 4 phenotypes., Results: Over 60% of variance in alcohol consumption, cannabis use, and cannabis dependence symptoms, and just under 50% of variance in alcohol dependence (AD) symptoms were attributable to genetic sources. Shared environmental factors did not contribute significantly to the 4 phenotypes. Nearly complete overlap in heritable influences was observed for within-substance measures of use and dependence symptoms. Genetic correlations across substances were 0.68 and 0.62 for use and dependence symptoms, respectively., Conclusions: Common heritable influences were evident for alcohol and cannabis use and for AD and cannabis dependence symptomatology, but findings indicate that substance-specific influences account for the majority of the genetic variance in the cannabis use and dependence phenotypes. By contrast, the substantial correlations between alcohol use and AD symptoms and between cannabis use and cannabis dependence symptoms suggest that measures of heaviness of use capture much of the same genetic liability to alcohol- and cannabis-related problems as dependence symptomatology.

Background: We have previously identified suggestive linkage for alcohol consumption in a community-based sample of Australian adults. In this companion paper, we explore the strength of genetic linkage signals for alcohol dependence symptoms., Methods: An alcohol dependence symptom score, based on DSM-IIIR and DSM-IV criteria, was examined. Twins and their nontwin siblings (1,654 males, 2,518 females), aged 21 to 81 years, were interviewed, with 803 individuals interviewed on 2 occasions, approximately 10 years apart. Linkage analyses were conducted on datasets compiled to maximize data collected at either the younger or the older age. In addition, linkage was compared between full samples and truncated samples that excluded the lightest drinkers (approximately 10% of the sample)., Results: Suggestive peaks on chromosome 5p (LODs >2.2) were found in a region previously identified in alcohol linkage studies using clinical populations. Linkage signal strength was found to vary between full and truncated samples and when samples differed only on the collection age for a sample subset., Conclusions: The results support the finding that large community samples can be informative in the study of alcohol-related traits.

Background: Research suggests that individuals who start drinking at an early age are more likely to subsequently develop alcohol dependence. Twin studies have demonstrated that the liability to age at first drink and to alcohol dependence are influenced by common genetic and environmental factors, however, age at first drink may also environmentally mediate increased risk for alcohol dependence. In this study, we examine whether age at first drink moderates genetic and environmental influences, via gene x environment interactions, on DSM-IV alcohol dependence symptoms., Methods: Using data on 6,257 adult monozygotic and dizygotic male and female twins from Australia, we examined the extent to which age at first drink (i) increased mean alcohol dependence symptoms and (ii) whether the magnitude of additive genetic, shared, and nonshared environmental influences on alcohol dependence symptoms varied as a function of decreasing age. Twin models were fitted in Mx., Results: Risk for alcohol dependence symptoms increased with decreasing age at first drink. Heritable influences on alcohol dependence symptoms were considerably larger in those who reported an age at first drink prior to 13 years of age. In those with later onset of alcohol use, variance in alcohol dependence was largely attributable to nonshared environmental variance (and measurement error). This evidence for unmeasured gene x measured environment interaction persisted even when controlling for the genetic influences that overlapped between age at first drink and alcohol dependence symptoms., Conclusions: Early age at first drink may facilitate the expression of genes associated with vulnerability to alcohol dependence symptoms. This is important to consider, not only from a public health standpoint, but also in future genomic studies of alcohol dependence.

Background: Previous research has reported a significant genetic correlation between heaviness of alcohol consumption and alcohol dependence (AD), but this association might be driven by the influence of AD on consumption rather than the reverse. We test the genetic overlap between AD symptoms and a heaviness of consumption measure among individuals who do not have AD. A high genetic correlation between these measures would suggest that a continuous measure of consumption may have a useful role in the discovery of genes contributing to dependence risk., Methods: Factor analysis of five alcohol use measures was used to create a measure of heaviness of alcohol consumption. Quantitative genetic analyses of interview data from the 1989 Australian Twin Panel (n = 6257 individuals; M = 29.9 years) assessed the genetic overlap between heaviness of consumption, DSM-IV AD symptoms, DSM-IV AD symptom clustering, and DSM-IV alcohol abuse., Results: Genetic influences accounted for 30%-51% of the variance in the alcohol measures and genetic correlations were .90 or higher for all measures, with the correlation between consumption and dependence symptoms among nondependent individuals estimated at .97 (95% confidence interval: .80-1.00)., Conclusions: Heaviness of consumption and AD symptoms have a high degree of genetic overlap even among nondependent individuals in the general population, implying that genetic influences on dependence risk in the general population are acting to a considerable degree through heaviness of use and that quantitative measures of consumption will likely have a useful role in the identification of genes contributing to AD.

The risks associated with early age at initiation for alcohol, cigarette, and cannabis use are well documented, yet the timing of first use has rarely been studied in genetically informative frameworks, leaving the relative contributions of genetic and environmental factors to age at initiation largely unknown. The current study assessed overlap in heritable and environmental influences on the timing of initiation across these three substances in African-American women, using a sample of 462 female twins (100 monozygotic and 131 dizygotic pairs) from the Missouri Adolescent Female Twin Study. Mean age at the time of interview was 25.1 years. Ages at first use of alcohol, cigarettes, and cannabis were gathered in diagnostic interviews administered over the telephone. Standard genetic analyses were conducted with substance use initiation variables categorized as never, late, and early onset. Variance in the timing of first use was attributable in large part to genetic sources: 44% for alcohol, 62% for cigarettes, and 77% for cannabis. Genetic correlations across substances ranged from 0.25 to 0.70. Shared environmental influences were modest for alcohol (10%) and absent for cigarettes and cannabis. Findings contrast with reports from earlier studies based on primarily Caucasian samples, which have suggested a substantial role for shared environment on substance use initiation when measured as lifetime use. By characterizing onset as timing of first use, we may be tapping a separate construct. Differences in findings may also reflect a distinct etiological pathway for substance use initiation in African-American women that could not be detected in previous studies.

Objective: The aim of this study was to examine the relationships between body mass index (BMI) and alcohol use and misuse in young adulthood in a sample of black and white female twins., Method: Cox proportional hazards and logistic regression models were used to examine the relationships between BMI category and first alcohol use, current weekly alcohol use, and current weekly heavy episodic drinking in 3,514 (14.06% black) young adult female twins. Analyses were conducted separately in black and white women., Results: After adjusting for relevant covariates, in white women obesity was protective against alcohol use (hazard ratio = 0.83; 95% confidence interval [CI]: 0.73-0.93) and against weekly drinking (odds ratio [OR] = 0.36; 95% CI: 0.24-0.53) and weekly heavy episodic drinking (OR = 0.51; 95% CI: 0.31-0.82) among ever drinkers compared with women of ideal weight. Overweight women living with their parents were less likely to be weekly drinkers (OR = 0.31; 95% CI: 0.16-0.61), whereas overweight women who were not living with their parents were less likely to be weekly heavy episodic drinkers (OR = 0.51; 95% CI: 0.31-0.82). Among black women, obesity was not associated with any of the drinking outcomes; however, black women who were overweight and who reported that the majority of their friends were not weekly drinkers had greater odds of reporting weekly drinking than those of ideal weight (OR = 2.91; 95% CI: 1.33-6.39)., Conclusions: Obese white women were less likely to ever use alcohol, be weekly drinkers, or be weekly heavy episodic drinkers than their ideal-weight peers. Body weight may affect drinking behavior in young women, and this effect may differ by race. Future research is needed to identify mediators and moderators of this relationship as well as to explore racial differences in the effect of body weight on drinking behavior.

Background: Previous studies have identified evidence of genetic influence on alcohol use in samples selected to be informative for alcoholism research. However, there are a growing number of genome-wide association studies (GWAS) using samples unselected for alcohol consumption (i.e., selected on other traits and forms of psychopathology), which nevertheless assess consumption as a risk factor. Is it reasonable to expect that genes contributing to variation in alcohol consumption can be identified in such samples?, Methods: An exploratory approach was taken to determine whether linkage analyses for heaviness of alcohol consumption, using a sample collected for heterogeneous purposes, could replicate previous findings. Quantity and frequency measures of consumption were collected in telephone interviews from community samples. These measures, and genotyping, were available for 5,441 individuals (5,067 quasi-independent sibling pairs). For 1,533 of these individuals, data were collected on 2 occasions, about 8.2 years apart, providing 2 datasets that maximize data collected at either a younger or an older age. Analyses were conducted to address the question of whether age and heavier levels of alcohol consumption effects outcome. Linkage results were compared in the younger and older full samples, and with samples in which approximately 10, 20, and 40 of drinkers from the lower end of the distribution of alcohol consumption were dropped., Results: Linkage peaks varied for the age differentiated samples and for percentage of light drinkers retained. Larger peaks (LOD scores >2.0) were typically found in regions previously identified in linkage studies and/or containing proposed candidate genes for alcoholism including AGT, CARTPT, OPRD1, PIK3R1, and PDYN., Conclusions: The results suggest that GWAS assessing alcohol consumption as a covariate for other conditions will have some success in identifying genes contributing to consumption-related variation. However, sample characteristics, such as participant age, and trait distribution, may have substantial effects on the strength of the genetic signal. These results can inform forthcoming GWAS where the same restrictions apply.

Objective: The purpose of this study was to develop a quantitative measure of alcohol consumption for gene-mapping studies., Method: Using a sample of 3,787 young-adult twin women and an independent sample of 489 men and women from a college drinking study, we developed an alcohol-consumption factor score indexed by (1) maximum typical consumption (log-transformed quantity frequency [LQNTFRQ]), (2) maximum drinks in a 24-hours period (LMAXALC), (3) frequency of drinking five or more drinks per day (FIVE), and (4) frequency of drinking to intoxication (INTOX). We tested (1) for factorial and psychometric equivalence across samples and genders; (2) for construct validity and its equivalence, across samples and genders, using measures of tobacco and cannabis use and family history of alcoholism; and (3) to determine the heritability of the alcohol-consumption factor score using a genetic psychometric model., Results: A single-factor model fit well with factor loadings ranging from .60 to .90. With rare exception, we found support for measurement invariance across the two samples and across genders. Measures of nicotine and cannabis use as well as family history of alcoholism were associated, to a similar extent across samples and genders, with the underlying alcohol-consumption factor. Psychometric twin modeling revealed that each of the alcohol-consumption measures (h2=34%-47%) and the underlying factor score (h2=50%) were heritable, with the remainder of the variance attributable to individual-specific environmental factors. This moderately heritable alcohol-consumption factor also accounted for a majority of the genetic variance in LQNTFRQ, LMAXALC, FIVE, and INTOX., Conclusions: Quantitative measures of alcohol consumption with the favorable attributes of measurement invariance, construct validity, and moderate heritability can greatly enhance future gene-mapping efforts, supplementing information afforded by conventional diagnostic measures of alcohol abuse/dependence.

Alcohol dependence symptoms and consumption measures were examined for stability and heritability. Data were collected from 12,045 individuals (5376 twin pairs, 1293 single twins) aged 19 to 90 years in telephone interviews conducted in three collection phases. Phases 1 and 2 were independent samples, but Phase 3 targeted families of smokers and drinkers from the Phase 1 and 2 samples. The stability of dependence symptoms and consumption was examined for 1158 individuals interviewed in both Phases 1 and 3 (mean interval = 11.0 years). For 1818 individuals interviewed in Phases 2 and 3 (mean interval = 5.5 years) the stability of consumption was examined. Heritability was examined for each collection phase and retest samples from the selected Phase 3 collection. The measures examined were a dependence score, based on DSM-IIIR and DSM-IV criteria for substance dependence, and a quantity x frequency measure. Measures were moderately stable, with test-retest correlations ranging from .58 to .61 for dependence and from .55 to .64 for consumption. However, the pattern of changes over time for dependence suggested that the measure may more strongly reflect recent than lifetime experience. Similar to previous findings, heritabilities ranged from .42 to .51 for dependence and from .31 to .51 for consumption. Consumption was significantly less heritable in the younger Phase 2 cohort (23-39 years) compared to the older Phase 1 cohort (28-90 years).

Background: The development of alcohol dependence (AD) involves transitions through multiple stages of drinking behaviors and is shaped by both heritable and environmental influences. We attempted to capture this dynamic process by characterizing genetic and environmental contributions to the rate at which women progressed through 3 significant transitions along the pathway to AD: nonuse to initiation, initiation to onset of first alcohol-related problem, and first problem to onset of AD., Methods: The sample consisted of 3,546 female twins from the Missouri Adolescent Female Twin Study. Participants ranged in age from 18 to 29 years. Retrospective reports of alcohol use histories were collected by telephone diagnostic interview and transition times between drinking milestones were coded ordinally. Standard genetic analyses were conducted in Mx to derive a trivariate model that provided estimates of genetic and environmental influences that were common as well as specific to the 3 transition times., Results: Heritable influences were found for rate of progression across all 3 transitions, accounting for 30 to 47% of the variance in transition times. Shared environmental contributions were evident only in rate of progression from nonuse to initiation (i.e., age at first drink). Heritable contributions to the rate of movement through successive drinking milestones were attributable to a common factor, whereas environmental influences were transition-specific., Conclusions: The current study is unique in its use of a genetically informative design to document the rate of movement between drinking milestones in a female sample and to examine genetic contributions to multiple transition times over the course of AD development. Results indicate that an earlier report of heritability for males in rate of progression from regular drinking to AD generalizes to women and to other alcohol stage transitions. Findings also suggest the need to consider stage-specific environmental contributions to alcohol outcomes in developing interventions.

Background: Constructs such as drinking expectancies (beliefs regarding the effects of alcohol) and motives (drinking alcohol to achieve a valued end) have been shown to be associated with various stages of alcohol use behaviors. However, little is known of the extent to which genetic and environmental influences contribute to individual differences in expectancies and motives., Methods: Using data from 3,656 young adult same-sex female twins, we examined the association between measures of drinking expectancies and motives and drinking behaviors. Using twin models, we estimated the extent to which genetic, shared and non-shared environmental factors influenced individual differences in expectancies and motives and also tested whether the extent of the genetic and environmental contributions on expectancies varied across abstainers and users of alcohol., Results: Expectancies predicted initiation of alcohol use. Both motives and expectancies were associated with frequency and quantity of alcohol consumption and drinks-to-intoxication. There was no evidence for heritable influences on expectancies and enhancement motives, with familial similarity for these traits being due to shared environment. Heritable influences on social, coping and conformity motives ranged from 11% to 33%. When expectancies were stratified by alcohol use, significant heritable influences (31-39%) were found for cognitive-behavioral impairment and risk-taking/negative self-perception (RT/NSP) in abstainers only, while environmental influences contributed to familial variance for other measures of expectancies in alcohol users., Conclusions: Environmental influences (both familial and individual-specific) shape alcohol expectancies, while heritable influences may predispose to motives for drinking. Individual differences in expectancies are moderated by alcohol use, suggesting that sources of individual differences in expectancies may vary in drinkers versus abstainers.