The Heritability of Alcoholism Symptoms: "Indicators of Genetic and Environmental Influence in Alcohol-Dependent Individuals" Revisited

There is consistent evidence from twin and adoption studies implicating genetic factors in the etiology of alcoholism, yet few studies have examined the role of genetic influences on individual symptoms of alcoholism. In a previous study of 113 male twins, Johnson et al. (1996a) identified 7 alcoholism symptoms that were more "genetic" and 14 that were more "environmental" (that is, non-genetic) in their etiology by examining symptom concordances among monozygotic and dizygotic twin pairs. The present study represents an attempt to replicate the results of this previous study and extend them by estimating the contribution of genetic factors to the variation in liability for different alcoholism symptoms. Subjects were 3356 male twin pairs from the Vietnam Era Twin Registry. Lifetime histories of alcoholism symptoms were assessed by a structured psychiatric telephone interview. The results of the previous study were not replicated. The correlations between symptom classifications as genetic and non-genetic in the present and previous study were nonsignificant and ranged from -0.27 to 0.11. However, within the present study the correlation between symptom classifications as genetic and non-genetic was statistically significant across random split-half subsamples (r = 0.59); nine alcoholism symptoms were consistently classified as genetic and six symptoms as non-genetic in their etiology. Model-fitting analyses applied to different alcoholism symptoms yielded heritability estimates ranging from 0.03 to 0.53 with broad and overlapping confidence intervals around these estimates, ranging from 0.00 to 0.65. The results of this study highlight the difficulty of identifying more or less heritable phenotypes in twin research, and suggest that it may not be possible to identify specific alcoholism symptoms that are more genetic in their etiology than others. Nevertheless, there appears to be potentially important variation in the relative magnitude of genetic influences for individual alcoholism symptoms, and exploring these differences may lead to further insights into the nosology and etiology of alcohol-related problems.     

Common Genetic Contributions to Alcohol and Cannabis Use and Dependence Symptomatology

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.     

Subtypes of Alcohol-Dependent Men: A Typology Based on Relative Genetic and Environmental Loading

Using scales that distinguish between relative genetic and environmental loading, cluster analysis was used to identify three subtypes of alcohol dependence in Caucasian men from the Epidemiologic Catchment Area study (n = 911). Although all subjects met DSM-III criteria for alcohol dependence, only the severe subtype showed evidence of substantial genetic influence. When compared on a range of clinical characteristics, the mild subtype (53% of the sample) was typically least adversely affected and the severe subtype (17%) most affected, with the dyssocial subtype (30%) falling between. Severe subtype subjects had significantly greater comorbid drug dependence and were at least four times more likely than mild subjects to have sought treatment for alcohol problems. Ratio of genetic scale score to total symptom count (genetic ratio) was highest for the severe subtype (mean = 0.37). and negatively correlated with age of first alcohol problem (r_s= -0.16) and years between first intoxication and first problem (r_s= -0.19). No significant correlations were found between these clinical features and genetic ratio for the mild or dyssocial subtypes. Use of these scales and subtypes may improve our ability to detect specific gene effects in genetic linkage studies and to identify environmental influences in behavioral and epidemiological studies.     

Sex Differences in the Sources of Genetic Liability to Alcohol Abuse and Dependence in a Population-Based Sample of U.S. Twins

BACKGROUND: There are substantial sex differences in all levels of alcohol involvement among U.S. adults. The goal of this study was to test whether the magnitude and sources of genetic and environmental influences on liability for alcohol abuse and dependence differ for men and women. METHODS: Structured personal interviews were used to assess DSM-III-R- and DSM-IV-defined alcohol abuse and dependence among 5091 male and 4168 female twins (including 1546 identical, 1128 same-sex fraternal, and 1423 opposite-sex pairs) born in Virginia between 1934 and 1974. Twin correlations were analyzed using structural equation modeling. RESULTS: The magnitude of twin-pair resemblance was similar across several definitions of alcoholism and was substantially higher among identical than fraternal pairs. The proportion of population variation in liability attributed to genetic factors was substantial among both women (55-66%) and men (51-56%), and we found little evidence of a role of environmental factors shared by family members. In all definitions studied, we could reject a model that the genetic sources of liability in the two sexes overlap completely. CONCLUSION: In this first population-based study of alcoholism among male and female twins from the U.S., we found that genetic factors play a major role in the development of alcoholism in both sexes, that the magnitudes of genetic influence were equally high for men and women, and that the genetic sources of vulnerability are partially, but not completely, overlapping in men and women.     

Mood-Related Drinking Motives Mediate the Familial Association Between Major Depression and Alcohol Dependence

Background:  Major depression and alcohol dependence co-occur within individuals and families to a higher than expected degree. This study investigated whether mood-related drinking motives mediate the association between major depression and alcohol dependence, and what the genetic and environmental bases are for this relationship.
Methods:  The sample included 5,181 individuals from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders, aged 30 and older. Participants completed a clinical interview which assessed lifetime major depression, alcohol dependence, and mood-related drinking motives.
Results:  Mood-related drinking motives significantly explained the depression-alcohol dependence relationship at both the phenotypic and familial levels. Results from twin analyses indicated that for both males and females, the familial factors underlying mood-related drinking motives accounted for virtually all of the familial variance that overlaps between depression and alcohol dependence.
Conclusions:  The results are consistent with an indirect role for mood-related drinking motives in the etiology of depression and alcohol dependence, and suggest that mood-related drinking motives may be a useful index of vulnerability for these conditions.     

Operant Behavior and Alcohol Levels in Blood and Brain of Alcohol-Dependent Rats

Background:  The purpose of the present investigation was to more clearly define blood-alcohol parameters associated with alcohol dependence produced by alcohol vapor inhalation and alcohol-containing liquid diet.
Methods:  Alcohol levels in blood and brain were compared during and after 4 hours of acute alcohol vapor exposure; also, brain-alcohol levels were assessed in alcohol-exposed (14-day alcohol vapor) and alcohol-naïve rats during and after 4 hours of acute alcohol vapor exposure. A separate group of rats were implanted with i.v. catheters, made dependent on alcohol via vapor inhalation, and tested for operant alcohol responding; blood-alcohol levels (BALs) were measured throughout operant alcohol drinking sessions during alcohol withdrawal. A final group of rats consumed an alcohol-liquid diet until they were dependent, and those rats were then tested for operant behavior at various withdrawal time points; BALs were measured at different withdrawal time points and after operant sessions.
Results:  Blood- and brain-alcohol levels responded similarly to vapor, but brain-alcohol levels peaked at a higher point and more slowly returned to zero in alcohol-naïve rats relative to alcohol-exposed rats. Alcohol vapor exposure also produced an upward shift in subsequent operant alcohol responding and resultant BALs. Rats consumed large quantities of alcohol-liquid diet, most of it during the dark cycle, sufficient to produce high blood-alcohol levels and elevated operant alcohol responding when tested during withdrawal from liquid diet.
Conclusions:  These results emphasize that the key determinants of excessive alcohol drinking behavior are the BAL range and pattern of chronic high-dose alcohol exposure.     

Immune Changes in Alcohol-Dependent Patients Without Medical Disorders

INTRODUCTION: We examined a battery of in vitro immune measures in inner city alcohol-dependent (as determined by the Structured Clinical Interview for DSM-III-R (SCID) persons who were without liver or other medical disorders and free of other substance abuse. These subjects were seeking treatment at an ambulatory alcohol treatment center. METHODS: Alcohol-dependent subjects (n = 44) were compared with healthy, nonabusing community subjects (n = 34). Subjects, both male and female, had a mean age of 41 years and were primarily African American. Many were homeless. An extended battery of enumerative and functional immune measures was obtained, as well as information about alcohol consumption. RESULTS: CONTROLLING for age and gender, ANCOVA revealed no differences (p > 0.1) between alcohol-dependent and control subjects in leukocyte and lymphocyte subsets or in circulating CD56+ (natural killer) cells. There were also no significant differences in responses to the mitogens phytohemagglutinin, concanavalin A, or pokeweed mitogen ( > 0.1) or in natural killer cell activity (p > 0.1). There was, however, altered granulocyte function in the alcohol-dependent sample, with decreased phagocytic activity in the alcohol-dependent males (p < 0.04) and gender and age dependent differences in the number of circulating granulocytes (p < 0.01). Granulocyte killing of Staphylococcus aureus, however, did not differ between the groups. CONCLUSIONS: The findings suggest that although males with chronic alcohol dependence have compromised phagocytic function, chronic alcohol-dependent subjects who are free of medical disorders do not have substantial abnormalities in many immune system functions.     

Genetic and environmental influences on the rate of progression to alcohol dependence in young women

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.     

Genetic and environmental effects on conduct disorder and alcohol dependence symptoms and their covariation at age 14

Background: Alcohol misuse and conduct disorder (CD) are strongly associated in adolescents. Is their association due to shared genetic and environmental liabilities? We addressed that question with data obtained from structured interviews of 14‐year‐old Finnish twins. Methods: A total of 1854 twins completed face‐to‐face interviews. Univariate models, allowing for sex limitation, were fit to symptom counts for Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised diagnoses of CD and alcoholism to examine their genetic and environmental influences. Then, bivariate models evaluated the extent to which genetic and environmental influences contributed to the covariation between symptom counts for the two disorders. Results: A total of 822 twins (44% of the sample) reported one or more symptoms of CD; alcohol dependence symptoms were much less common, reported by only 12%. The correlation between the two symptom counts was 0.50. Models fit to the twin data demonstrated that CD symptoms were under significant genetic influence in both boys and girls, although those influences were predominantly sex specific. In contrast, alcohol dependence symptoms were, at this age, under sex‐specific effects of common environments, with no evidence of genetic influences. Accordingly, the substantial covariation between alcohol dependence symptoms and those of CD was attributed entirely to shared environmental effects. Conclusions: At age 14, genetic influences on alcohol dependence symptoms are negligible, and the correlated liabilities between these symptoms and those of CD are to be found in environmental factors that are common to both.     

Alcohol dependence in men: reliability and heritability

Background: The assessment of a Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM‐IV) life‐time history of alcohol dependence (LTH‐AD) has been found to be moderately reliable and substantially heritable. However, in studies of the heritability of LTH‐AD, measurement error could not be discriminated from the true unique environmental effects. The aims of this study were to: (i) estimate the reliability of LTH‐AD in a population based sample, (ii) identify characteristics of LTH‐AD predicting a reliable diagnosis, (iii) investigate the heritability of LTH‐AD as a function of diagnostic confidence, and (iv) to estimate the genetic and environmental influences on LTH‐AD correcting for measurement error. Methods: An unselected sample of 4,203 male twins was interviewed twice approximately 1‐year apart assessing DSM‐IV LTH‐AD over the same period of life. Logistic regression was used to identify clinical features that predict a reliable diagnosis LTH‐AD. Genetic and environmental influences on reliable LTH‐AD were examined using structural equation models. Results: Reliability of the diagnosis of LTH‐AD was moderate (κ = 0.54) and was predicted by the number of AD symptoms, treatment seeking, duration of most severe episode, and a great deal of time spent to obtain, use, or recover from alcohol use (DSM‐IV AD criterion #5). Using an index of caseness, heritability of LTH‐AD increased as a function of diagnostic confidence. Accounting for errors of measurement in a multivariate twin model, the heritability of LTH‐AD increased from 55 to 71%. Conclusions: Reliably diagnosed LTH‐AD can be predicted by characteristics relevant to the disorder. LTH‐AD appears to be a moderately reliable disorder of high heritability.     

Age at first drink and risk for alcoholism: a noncausal association

Prior research indicates risk for alcoholism is increased among individuals who begin to drink at an early age. We replicate and extend these findings, addressing causal and noncausal explanations for this association. Structured psychiatric interviews, including assessment of lifetime DSM-IV alcohol abuse and alcohol dependence (AD), were conducted with 8746 adult twins ascertained through a population-based twin registry. We found strong evidence for an association between early drinking onset and risk for AD, but less evidence for an association with alcohol abuse. The results of twin-pair analyses suggest that all of the association between early drinking and later AD is due to familial sources, which probably reflect both shared environmental and genetic factors. These results suggest the association between drinking onset and diagnosis is noncausal, and attempts to prevent the development of AD by delaying drinking onset are unlikely to be successful.     

Effect of Extended-Release Naltrexone (XR-NTX) on Quality of Life in Alcohol-Dependent Patients

Background: Extended‐release naltrexone (XR‐NTX) is a once‐a‐month injectable formulation for the treatment of alcohol dependence previously shown to reduce drinking and heavy drinking relative to placebo ( Garbutt et al., 2005 ). A 24‐week, randomized, double‐blind, placebo‐controlled study established the efficacy and safety of XR‐NTX in this patient population. In this report, the effect of XR‐NTX on quality of life (QOL) was examined. Methods: Alcohol‐dependent patients were randomly assigned to receive XR‐NTX 380 mg (N = 205), XR‐NTX 190 mg (N = 210), or placebo (N = 209), combined with a standardized psychosocial intervention. QOL was assessed using the Medical Outcomes Study 36‐item short‐form health survey, administered at baseline and at 4‐week intervals during 24 weeks of treatment. Results: Compared with U.S. population norms, patients showed initial impairment in the health‐related QOL domains of mental health, social functioning, and problems with work or other daily activities due to emotional problems. Adherence to all 6 injections was 65% for XR‐NTX 190 mg, 63% for XR‐NTX 380 mg, and 64% for placebo. Generalized estimating equations analyses using an intention‐to‐treat sample revealed that XR‐NTX 380 mg was associated with significantly greater improvements from baseline in mental health (p = 0.0496), social functioning (p = 0.010), general health (p = 0.048), and physical functioning (p = 0.028), compared with placebo. Linear regression analyses revealed that reductions from baseline in drinking (percentage of drinking days and percentage of heavy drinking days in the last 30 days) were significantly (p < 0.05) correlated with improvements in quality of life. Conclusion: Extended‐release naltrexone 380 mg in combination with psychosocial intervention was associated with improvements in QOL, specifically in the domains of mental health, social functioning, general health, and physical functioning.     

Factor Structure and Concurrent Validity of the Obsessive Compulsive Drinking Scale in a Group of Alcohol-Dependent Subjects of Mexico City

Background:  Obsessive thoughts and compulsive drinking behaviors have been proposed as key factors associated with the loss of control over alcohol consumption experienced by alcohol-dependent patients. The self-report 14-item Obsessive Compulsive Drinking Scale (OCDS; Anton et al., 1995 ) was designed in order to rate these features.
Methods:  A Spanish-translated version of the OCDS was applied to a group of 159 alcohol-dependent subjects while in abstinence, and data were analyzed in order to evaluate the factor structure and concurrent validity of the scale.
Results:  Several solutions were explored after applying the principal factor analysis to the data. The most plausible result was obtained after excluding the items on quantity and frequency of drinking. This model explaining 56.9% of the variance included 2 factors: obsessive thoughts related to drinking and interference/behaviors related to drinking. Additionally, OCDS scores were significantly correlated with measures for the Alcohol Dependence Scale, number of DSM-IV criteria met for alcohol dependence as well as the number of days in a week engaged in heavy drinking, indicating concurrent validity.
Conclusions:  Our results support the use of OCDS as a valid self-rated instrument that can be broadly applied in research and treatment settings. However, its current version includes questions that may not represent the core concept of craving. The abridged 12-item version of the scale (excluding the items on drinking habits) maintains good psychometrics features and seems to be adequate when different cognitive and behavioral dimensions are explored.     

Age-Related Gray Matter Shrinkage in a Treatment Naïve Actively Drinking Alcohol-Dependent Sample

Background:  We previously demonstrated, in a small sample, steeper age-related gray matter shrinkage in treatment naïve alcohol-dependent (TxN) men compared to nonalcoholic controls, but could not separate out the contributions of age and lifetime duration of alcohol use (which were highly correlated) to this effect. In the current study, we have quadrupled the sample size and expanded it to include both men and women to try to replicate and extend the previous findings and to separate the contributions of age and alcohol use to the phenomenon.
Methods:  In the current study, we examine cortical gray matter volumes in 18- to 50-year-old TxN ( n  = 84) versus age and gender comparable controls ( n  = 67). We used a new Region of Interest Analysis method which accounts for differences in sulcal and gyral enfolding between individuals ( Fein et al., 2009a ).
Results:  We found greater age-related gray matter shrinkage in TxN than in controls. Partial correlation analysis showed that the effect was a function of age and not lifetime alcohol burden.
Conclusions:  Implications of the findings are discussed in terms of their contribution toward our knowledge of differences between different subpopulations of alcoholics and in terms of their implications for the morbidity of alcohol dependence in an aging national population.     

A joint genomewide linkage analysis of symptoms of alcohol dependence and conduct disorder

Background: A large linkage peak for alcohol dependence (AD) was detected on chromosome 4q in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD). Are the susceptibility genes underlying this peak specific for AD or do they increase risk for externalizing disorders more generally? Can we, in the IASPSAD, replicate prior evidence for linkage to conduct disorder (CD)? Methods: The 733 all possible sibling pairs in IASPSAD were typed for 1,020 short‐tandem‐repeat genetic markers. Univariate and bivariate linkage analyses were conducted by the program sequential oligogenic linkage analysis routines (SOLAR), for both the raw and the transformed number of symptoms of AD (ADsx) and number of symptoms of CD (CDsx). In the bivariate analyses, specificity was assessed by the ratio of the variance accounted for in ADsx and CDsx by the quantitative trait locus. Results: In the univariate linkage analyses, no evidence for linkage to CDsx was found under the 4q peak for ADsx and the largest peaks for CDsx were seen on chromosomes 1q (LOD=3.16) and 14p (LOD=2.36). In the bivariate linkage analysis, the 4q peak had high specificity for AD (AD/CD ratio of 39.9). Several smaller peaks, on chromosomes 1, 7, and 10, had moderate specificity for CD but also impacted on risk for AD, with AD/CD ratios of 0.18 to 0.32. Conclusions: Genes under the 4q linkage peak for AD in the IASPSAD impact specifically on risk for AD rather than more broadly on risk for externalizing syndromes. Suggestive linkages were found in several locations for CD, 2 of which broadly replicate prior findings. The bivariate analyses identified genomic locations containing susceptibility loci that impacted on risk for both CDsx and ADsx.