Sex-specific genetic influences on the comorbidity of alcoholism and major depression in a population-based sample of US twins

BACKGROUND: Alcoholism and depression frequently co-occur, but the origins of this comorbidity remain uncertain. Most previous family, twin, and adoption studies of these disorders have used cases ascertained through treatment settings, who may differ from cases in epidemiological samples. We studied the importance of genetic influences on risk for lifetime comorbidity of major depression and alcoholism by means of a population-based twin sample. METHODS: Lifetime major depression (MD), alcohol abuse, and alcohol dependence were assessed by structured interview for both members of 3755 twin pairs from the Mid-Atlantic Twin Registry. Pair resemblance was analyzed by means of structural equation models. RESULTS: Individuals with MD were at significantly increased risk for alcohol dependence and for a combined diagnosis of alcohol abuse and/or dependence. History of MD in a twin significantly increased the risk of cotwin alcohol dependence and alcohol abuse and/or dependence among identical male pairs and for alcohol abuse and/or dependence in identical female pairs, but not among male or female fraternal pairs. Results of structural modeling indicate that comorbidity occurs because the genetic and specific environmental sources of liability to MD overlap with those underlying alcohol dependence and alcohol abuse and/or dependence. This overlap was significant only within sex, not across sexes. CONCLUSIONS: In this population-based twin sample, the familial transmission of MD and alcohol dependence was largely disorder specific. Comorbidity appears to be due to sex-specific genetic and environmental risk factors. The factors underlying depression in women do not appear to arise from the same factors underlying alcoholism in men.     

Sleep spindles in twins

Sleep spindle characteristics and spindle power periodicity were studied in 4 identical and 3 fraternal twin pairs (mean age, 16 years). There were no significant genetic effects such as concordance between the identical twins and discordance between the fraternal twins for mean duration, mean amplitude and mean frequency of spindles. Spindle periodicity, which is correspondent to the sleep cycle, was visually more similar between the identical twins than between the fraternal twins. These observations suggest that the sleep cycle which is expressed by periodic appearance of spindle powers is genetically determined. On the other hand, some spindle characteristics and some physical measures had significant relationships. These relationships may suggest that some spindle characteristics are influenced by the individual development rather than by a genetic trait.     

Sleep spindles and physical parameters

In 4 identical (Nos. 1-4) and 3 fraternal (Nos. 5-7) male twin pairs (mean age, 16 years), sleep spindles were analysed during sleep. The height, body weight, plantar length and chest circumference were measured, and the correlations between sleep spindles and these physical parameters were examined. The physical parameters showed concordance between identical twin pairs except one pair (No. 4) and one fraternal pair (No. 5) but discordance between two fraternal twin pairs (Nos. 6 and 7). Number of sleep spindles and sleep spindle density showed almost concordance between identical twin pairs and one fraternal pair (No. 5), while discordance between two fraternal ones (Nos. 6 and 7). Both number of sleep spindles and sleep spindle density were inversely correlated with body weight (r = -0.61, p less than 0.02; r = -0.62, p less than 0.02). These facts would suggest that sleep spindles rather reflect the individual development than genetic trait.     

Twin relationships and depression

The authors investigated closeness and other variables measuring depression in 22 identical and 13 fraternal twin pairs. Each twin rated him/herself on a two-part questionnaire; part 1 included questions on demographic characteristics and the twin relationship, and part 2, the Zung Self-Rating Depression Scale, measured depressive symptoms. There was a high degree of agreement across all variables for the total sample, and degrees of depression were comparable to that in the general population. Closeness was found to be inversely correlated with depression. The authors suggest that future studies include other groups (siblings, spouses, etc.) and follow-up data.     

Genetic and environmental effects on offspring alcoholism: new insights using an offspring-of-twins design

CONTEXT: Although there is now considerable evidence that genetic effects play a critical role in the development of alcohol dependence (AD), theoretical and methodological limitations of this literature require caution in describing the etiology and development of this disorder. OBJECTIVE: To disentangle genetic and environmental effects on AD by means of the infrequently used, yet potentially powerful, offspring-of-twins design. DESIGN: Offspring of twins. PARTICIPANTS: Male monozygotic and dizygotic twins concordant or discordant for AD and control pairs from the Vietnam Era Twin Registry were assessed, as were the offspring of these twins and the mothers of these offspring. INTERVENTIONS: Structured psychiatric interviews. MAIN OUTCOME MEASURES: Participants' psychiatric, alcohol abuse (AA), and AD histories (DSM-IV). RESULTS: Offspring of monozygotic and dizygotic twins with a history of AD were significantly more likely to exhibit AA or AD than were offspring of nonalcoholic fathers. Offspring of an alcohol-abusing monozygotic twin whose co-twin was AD were also more likely to exhibit AD than were offspring of nonalcoholic twins. In contrast, offspring of an unaffected (ie, no history of abuse or dependence) monozygotic twin whose co-twin was AD were no more likely to exhibit AA or AD than were offspring of nonalcoholic twins. CONCLUSIONS: These findings support the hypothesis that family environmental effects do make a difference in accounting for offspring outcomes, in particular, that a low-risk environment (ie, the absence of parental alcoholism) can moderate the impact of high genetic risk regarding offspring for the development of alcohol-use disorders.     

Sleep characteristics in twins

Polysomnograms were recorded for three consecutive nights on 14 male students (mean age, 16), comprising 4 identical and 3 fraternal twin pairs. The number of body movements and the measures related to the REM cycle, which correlated among the identical twins without reference to the physical parameters, were considered to be determined by a genetic trait. The sleep spindle density was in almost complete concordance between the identical twins and was associated with some physical parameters, which suggests that sleep spindles rather reflect the individual development. %S3, %SREM and the number of SREM showed a relationship to the physical parameters, without heritability. Twitch movements during REM sleep correlated not only between the identical twins but also between the fraternal twins.     

Sleep Characteristics in Twins

Abstract: Polysomnograms were recorded for three consecutive nights on 14 male students (mean age, 16), comprising 4 identical and 3 fraternal twin pairs. The number of body movements and the measures related to the REM cycle, which correlated among the identical twins without reference to the physical parameters, were considered to be determined by a genetic trait. The sleep spindle density was in almost complete concordance between the identicaltwins and was associated with some physical parameters, which suggests that sleep spindles rather reflect the individual development. %S3, %SREM and the number of SREM showed a relationship to the physical parameters without heritability. Twitch movements during REMsleep correlated not only between the identical twins but also between the fraternal twins.     

Illicit psychoactive substance use, heavy use, abuse, and dependence in a US population-based sample of male twins

BACKGROUND: In order to develop informed approaches to prevention and treatment of illicit psychoactive substance use, abuse, and dependence, we need to understand the sources of individual differences in risk. METHODS: In personal interviews with 1198 male-male twin pairs (708 monozygotic and 490 dizygotic) ascertained from a population-based registry, we assessed lifetime use, heavy use, and abuse of and dependence on cannabis, sedatives, stimulants, cocaine, opiates, and hallucinogens. Twin resemblance was assessed by probandwise concordance, odds ratio, tetrachoric correlations, and biometrical model fitting. RESULTS: Twin resemblance for substance use, heavy use, abuse, and dependence was substantial, and consistently greater in monozygotic than in dizygotic twins. For any drug use and for cannabis and hallucinogen use, model fitting suggested that twin resemblance was due to both genetic and familial-environmental factors. Twin resemblance for sedative, stimulant, cocaine, and opiate use, however, was caused solely by genetic factors. With 2 exceptions (cocaine abuse and stimulant dependence), twin resemblance for heavy use, abuse, and dependence resulted from only genetic factors, with heritability of liability usually ranging from 60% to 80%. No consistent evidence was found for violations of the equal environment assumption. CONCLUSIONS: In accord with prior results in studies of women, the family environment plays a role in twin resemblance for some forms of substance use in men. However, twin resemblance for heavy use, abuse, and dependence in men is largely caused by genetic factors, and heritability estimates are high.     

Alcohol dependence in same-sex and opposite-sex twins

Males with a female co-twin are more likely to become alcohol-dependent than males with a male co-twin. According to the twin testosterone transfer model, this finding can be interpreted as indirect evidence for a role of prenatal testosterone in alcohol dependence.     

A twin study of febrile convulsions in the general population

Seven monozygotic (MZ) and six dizygotic (DZ) twin pairs with febrile convulsions (FC) in the general population were studied. The pairwise concordance rate for FC in MZ 85.7% (6/7) was higher than that in DZ 16.7% (1/6). In a discordant MZ pair, the unaffected co-twin was attacked by epileptic seizures later. Between the concordant DZ twins, the clinical symptoms and EEGs differed in quality. According to the ratio of concordance rate in MZ to that in DZ 5.1, a multifactorial mode of inheritance for FC was suspected.     

Increased tardive dyskinesia in alcohol-abusing schizophrenic patients.

Many schizophrenics have a diagnosis of substance abuse or dependence. We evaluated whether drug or alcohol abuse is an independent risk factor for tardive dyskinesia (TD) in schizophrenia. In a consecutive admission, clinical study of 75 hospitalized schizophrenics, drug or alcohol abusers had significantly higher TD scores than nonabusers. The association of alcohol abuse or dependence with TD seemed independent from other risk factors for TD.     

A Twin Study of Febrile Convulsions in the General Population

Seven monozygotic (MZ) and six dizygotic (DZ) twin pairs with febrile convulsions (FC) in the general population were studied. The pairwise concordance rate for FC in MZ 85.7% (6/7) was higher than that in DZ 16.7% (1/6). In a discordant MZ pair, the unaffected co-twin was attacked by epi leptic seizures later. Between the concordant DZ twins, the clinical symptoms and EEGs differed in quality. According to the ratio of concordance rate in MZ to that in DZ 5.1, a multifactorial mode of inheritance for FC was suspected.     

A genetic study of platelet phenolsulphotransferase activity in normal and schizophrenic twins

In a series of 19 identical and 16 fraternal twin pairs, the activities of the two forms of the enzyme, phenolsulphotransferase, denominated M and P, were investigated in blood platelets. Both were shown to be under a high degree of genetic control. No differences were found between 11 schizophrenic patients from discordant twin pairs, compared with their well cotwins and 12 male and female volunteer twin pairs, for either form of the enzyme.     

Frontal lobe GABA levels in cocaine dependence: a two-dimensional, J-resolved magnetic resonance spectroscopy study

Non-invasive measures of brain gamma-aminobutyric acid (GABA) concentrations may be especially useful in the identification of cocaine-related changes in brain chemistry that can be used to guide the development of future treatments for cocaine-dependent persons. This study assessed whether brain GABA levels in cocaine-dependent subjects with and without an alcohol disorder differ from GABA levels in healthy comparison subjects. Two-dimensional, proton magnetic resonance spectroscopy was used to determine GABA levels in the left prefrontal lobe of cocaine-dependent subjects (N=35) recruited from a National Institute on Drug Abuse (NIDA)-sponsored treatment trial of cocaine dependence and a comparison group (N=20). At treatment baseline, mean GABA concentrations were 0.93±0.27 mM/kg in cocaine-dependent subjects and 1.32±0.44 mM/kg in the comparison sample (t [d.f.=53]=3.65, P<0.001). Cocaine-dependent subjects with a history of a co-morbid alcohol disorder (N=23) had significantly lower baseline GABA levels (0.87 mM/kg) (t [d.f.=41]=4.31, P<0.001) than the comparison group. However, cocaine-dependent subjects without an alcohol disorder (N=12) also had lower GABA levels (1.04 mM/kg) than the comparison subjects (t [d.f.=30]=2.09, P=0.045), suggesting that cocaine dependence alone can decrease GABA levels.     

A prospective twin study of birth weight discordance and child problem behavior.

BACKGROUND: We investigated whether low birth weight constitutes a causal risk factor for child problem behavior, using a variation of the co-twin control method. METHODS: In a representative sample of 745 twin pairs (monozygotic: 324 pairs), birth weight was recorded at birth and child problem behavior at mean age 10 years was measured with the Child Behaviour Checklist (CBCL). RESULTS: Lower birth weight was a continuous risk factor for later child problem behavior (adjusted regression coefficient over units of 500 g: beta = -.15, p =.046), and greater levels of within-pair CBCL discordance did not result in a reduced effect size. Greater within-pair birth weight discordance was associated with greater within-pair CBCL score discordance (beta =.35, p <.001). This latter effect was similar in monozygotic (beta =.34, p =.005) and dizygotic twins (beta =.37, p =.003). CONCLUSIONS: The fact that (1) the effect size of the association between low birth weight and child problem behavior was not reduced in pairs with greater levels of CBCL discordance, and (2) similar effect sizes were found in monozygotic and dizygotic twins for the within-pair association between birth weight discordance and CBCL score discordance, suggests that the observed relationship between low birth weight and child problem behavior is not due to a shared environmental or genetic variable that influences both characteristics. Lower birth weight is a causal risk factor for child problem behavior, the effects of which may well extend into adulthood.     

The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women

BACKGROUND: Patterns of comorbidity suggest that the common psychiatric and substance use syndromes may be divisible into 2 broad groups of internalizing and externalizing disorders. We do not know how genetic and environmental risk factors contribute to this pattern of comorbidity or whether the etiologic structure of these groups differ in men and women. METHODS: Lifetime diagnoses for 10 psychiatric syndromes were obtained at a personal interview in more than 5600 members of male-male and female-female twin pairs ascertained from a population-based registry. Multivariate twin modeling was performed using the program Mx. RESULTS: We first fit models to the following 7 syndromes: major depression, generalized anxiety disorder, phobia, alcohol dependence, drug abuse/dependence, adult antisocial behavior, and conduct disorder. The full model, which could be constrained to equality in male and female subjects, identified 2 genetic factors. The first had strongest loadings on alcohol dependence, drug abuse/dependence, adult antisocial behavior, and conduct disorder; the second, on major depression, generalized anxiety disorder, and phobia. Alcohol dependence and drug abuse/dependence had substantial disorder-specific genetic risk factors. Shared environmental factors were most pronounced for conduct disorder and adult antisocial behavior. No clear internalizing/externalizing structure was seen for the unique environmental common factors. We then fit models to 5 internalizing syndromes. The full model, which could also be constrained to equality in men and women, revealed one genetic factor loading most heavily on major depression and generalized anxiety disorder and another loading most strongly on animal and situational phobia. CONCLUSIONS: The underlying structure of the genetic and environmental risk factors for the common psychiatric and drug abuse disorders in men and women is very similar. Genetic risk factors predispose to 2 broad groups of internalizing and externalizing disorders. Within the internalizing disorders, 2 genetic factors are seen that predispose to disorders dominated by anxious-misery and fear. Substance use disorders have disorder-specific genetic risks. The externalizing disorders of conduct disorder and adult antisocial behavior are significantly influenced by the shared environment. The pattern of lifetime comorbidity of common psychiatric and substance use disorders results largely from the effects of genetic risk factors.     

The impact of alcohol and illicit drugs on people with psychosis: The second Australian national survey of psychosis

Objective: To provide the most up-to-date prevalence estimates of alcohol and illicit drug use among individuals with psychosis in Australia, and explore correlates associated with a lifetime diagnosis of both alcohol abuse/dependence and cannabis abuse/dependence. Method: This paper uses data from the Survey of High Impact Psychosis (SHIP), conducted as a follow-up to the first Australian National Low Prevalence (Psychotic) Disorders Study (1997-1998). The SHIP was a national study, carried out across five states, in which a sample of 1825 individuals was recruited through a two-phase sampling framework. Results: Alcohol and illicit drug use was highly prevalent for the entire sample. There were few significant differences in the prevalence or frequency of use across the diagnostic categories examined. Substantial increases in substance abuse/dependence were noted since the 1997-1998 survey (51% diagnosed with alcohol abuse/dependence, 51% with cannabis abuse/dependence and 32% with other illicit drug abuse/dependence, compared to 28%, 23% and 12% respectively, in the 1997-1998 survey by Kavanagh et al., 2004). Factors significantly associated with both lifetime alcohol and cannabis dependence included male gender, younger age, single marital status, lower educational attainment, shorter duration of illness, lifetime presence of hallucinations, higher negative syndrome score and lower body mass index (BMI). A number of other factors were found to be differentially associated with either lifetime alcohol or cannabis dependence. Conclusions: The use of alcohol and illicit substances is common among people with a psychotic illness, with a concerning upward trend in rates of substance abuse/dependence since the 1997-1998 survey. Clinicians should be aware of the potential impact of concurrent substance use and provide integrated treatment for individuals presenting with psychotic illnesses. More research and investment in new intervention programs is required.     

Lifetime and 6-month prevalence of abuse and dependence of alcohol in the Munich follow-up study

Summary This paper reports lifetime and 6-month prevalence rates of alcohol abuse and dependence in West Germany. Assessment instruments are a modified German version of the Diagnostic Interview Schedule (DIS), a fully standardized interview for the assessment of selected DSM-III diagnoses and the Munich Alcoholism Test (MALT). According to the DIS/DSM-III criteria, 13.0% of the adult general population (aged 25–64 years) were found to fulfill the lifetime criteria for alcohol abuse, alcohol dependence, or both; however, only 1.3% of all men and 0.9% of the women interviewed received a current DSM-III diagnosis of alcohol abuse or dependence. There was good consensus between current DSM-III diagnoses with current clinical ICD-diagnoses, but poor concordance with lifetime diagnoses. Symptoms of alcoholism, onset and severity, comorbidity with other DIS/DSM-III disorders as well as some selected risk factors are reported. The results are primarily compared with the results of the US-Epidemiological Catchment Area Program (ECA).     

Genetic and environmental influences on substance initiation, use, and problem use in adolescents

BACKGROUND: We conducted a sibling/twin/adoption study of substance initiation, use, and problem use, estimating the relative contribution of genetic and environmental influences on these phenotypes in adolescents. METHODS: The participants were 345 monozygotic twin pairs, 337 dizygotic twin pairs, 306 biological sibling pairs, and 74 adoptive sibling pairs assessed by the Colorado Center for the Genetics and Treatment of Antisocial Drug Dependence, Denver and Boulder. The initiation, use, and problem use of tobacco, alcohol, marijuana, and other illicit drugs were assessed. Tetrachoric correlations were computed for each group, and univariate model-fitting analyses were conducted. RESULTS: There were moderate to substantial genetic influences, with the exception of alcohol use and any drug use, and modest to moderate shared environmental influences on substance initiation, use, and problem use. For alcohol and any drug, heritability was higher and the magnitude of shared environmental influences was lower for problem use than for initiation or use. Environmental influences shared only by twin pairs had a significant effect on tobacco initiation, alcohol use, and any drug use. For tobacco use, tobacco problem use, and marijuana initiation, heritability was higher and the magnitude of shared environmental influences was lower in female than in male adolescents. There was no evidence for sex-specific genetic or shared environmental influences on any variable. CONCLUSIONS: The moderate to substantial heritabilities found for adolescents in the present study are comparable to those found in twin studies of adult substance use and substance use disorders. The finding that problem use is more heritable than initiation and use is also consistent with the results of adult twin studies. The significance of environmental influences shared only by twin pairs on tobacco initiation, alcohol use, and any drug use suggests the influences of peers, accessibility of substances, and sibling interaction.     

Traits of ADHD and autism in girls with a twin brother: a Mendelian randomization study

It has been hypothesized that prenatal exposure to testosterone may be associated with traits of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD). We conducted a population-based study of dizygotic female twins to elucidate this hypothesis, assuming that the sex of the co-twin influences the level of prenatal exposure to testosterone. We invited parents of 24,552 3- to 15-year-old twins to answer questionnaires on traits of ADHD and ASD. We analysed the data using a proportional odds model with sex of the co-twin as an instrumental variable for prenatal exposure to testosterone of female twins. We received responses for 6,339 girls from dizygotic twin pairs. Odds ratios for male versus female co-twin were 0.71 (95?% confidence interval 0.61-0.81) for ADHD traits and 0.74 (0.66-0.83) for ASD traits, indicating that a twin brother reduces traits of ADHD and ASD in females. In conclusion, we found that female twins with a twin brother scored significantly lower in parent-reported traits of ADHD and ASD than those with a twin sister. The reason for this may be parental reporting bias, or confounding by unmeasured variables, or a causal effect of an intrauterine environment modified by the sex of the co-twin in the opposite direction of what we expected.