Stability and change of genetic and environmental effects on the common liability to alcohol, tobacco, and cannabis DSM-IV dependence symptoms.

This study investigated the stability of genetic and environmental effects on the common liability to alcohol, tobacco, and cannabis dependence across adolescence and young adulthood. DSM-IV symptom counts from 2,361 adolescents were obtained using a structured diagnostic interview. Several sex-limited longitudinal common pathway models were used to examine gender differences in the magnitude of additive genetic (A), shared environment, and non-shared environmental effects over time. Model fitting indicated limited gender differences. Among older adolescents (i.e., age > 14), the heritability of the latent trait was estimated at 0.43 (0.05, 0.94) during the first wave and 0.63 (0.21, 0.83) during the second wave of assessment. A common genetic factor could account for genetic influences at both assessments, as well as the majority of the stability of SAV over time [rA = 1.00 (0.55, 1.00)]. These results suggest that early genetic factors continue to play a key role at later developmental stages.

The heritability of general cognitive ability increases linearly from childhood to young adulthood.

Although common sense suggests that environmental influences increasingly account for individual differences in behavior as experiences accumulate during the course of life, this hypothesis has not previously been tested, in part because of the large sample sizes needed for an adequately powered analysis. Here we show for general cognitive ability that, to the contrary, genetic influence increases with age. The heritability of general cognitive ability increases significantly and linearly from 41% in childhood (9 years) to 55% in adolescence (12 years) and to 66% in young adulthood (17 years) in a sample of 11 000 pairs of twins from four countries, a larger sample than all previous studies combined. In addition to its far-reaching implications for neuroscience and molecular genetics, this finding suggests new ways of thinking about the interface between nature and nurture during the school years. Why, despite life's 'slings and arrows of outrageous fortune', do genetically driven differences increasingly account for differences in general cognitive ability? We suggest that the answer lies with genotype-environment correlation: as children grow up, they increasingly select, modify and even create their own experiences in part based on their genetic propensities.

The Virginia Twin Study of Adolescent Behavioral Development. Influences of age, sex, and impairment on rates of disorder.

BACKGROUND: The Virginia Twin Study of Adolescent Behavioral Development is a cohort-longitudinal epidemiological study that uses the genetic twin design to study the development and maintenance of child psychiatric disorders. We determined the rates of DSM-III-R disorders, disorders with impairment, and age, sex, and comorbidity effects. METHODS: Families of 2762 white twins aged 8 to 16 years participated. Twins and their parents were asked systematically about risk factors and current psychiatric symptoms by means of investigator-based psychiatric interviews and questionnaires. The DSM-III-R diagnoses were made for major depressive disorder, separation anxiety, overanxious disorder, simple phobia, social phobia, agoraphobia, oppositional defiant disorder, conduct disorder, and attention deficit hyperactivity disorder. RESULTS: The 3-month point prevalence for any DSM-III-R disorders was 413 per 1000, and that for disorders with associated impairment was 142 per 1000. Emotional disorders with impairment occurred in 89 per 1000, with girls being more commonly affected; behavioral disorders had a prevalence of 71 per 1000, with boys being more frequently affected. The proportion with disorder who also had functional impairment varied across disorders; anxiety and phobic disorders were particularly likely not to be accompanied by impairment. Rates of emotional and behavioral disorders increased over the age range. There was extensive comorbidity among disorders. CONCLUSIONS: The prevalence rates and patterns of findings from this study of twins are consistent with those of other epidemiological studies, supporting previous findings of few differences in rates of psychiatric disorder between twins and singletons. The importance of including measures of functional impairment is evident by its effect on rates of disorder and patterns of comorbidity.

Analytic power calculation for QTL linkage analysis of small pedigrees.

Power calculation for QTL linkage analysis can be performed via simple algebraic formulas for small pedigrees, but requires intensive computation for large pedigrees, in order to evaluate the expectation of the test statistic over all possible inheritance vectors at the test position. In this report, we show that the non-centrality parameter for an arbitrary pedigree can be approximated by the sum of the variances of the correlations between all pairs of relatives, each variance being weighted by a factor that is determined by the mean correlation of the pair. We show that this approximation is sufficiently accurate for practical purposes in small to moderately large pedigrees, and that large sibships are more efficient than other family structures under a range of genetic models.

Univariate genetic analysis of blood pressure in children (the Medical College of Virginia Twin Study).

The relative contributions of genetic, individual environmental and shared environmental effects on resting blood pressure (BP) and heart rate (HR) were studied in prepubescent twins. The study population consisted of 251 caucasian 11-year-old twin pairs. Correlations were higher for all variables in monozygotic twins compared to dizygotic twins; this is consistent with a significant genetic effect. Path analysis revealed that the model of additive genetic and individual environmental effects fit systolic BP, diastolic BP and HR. In boys and girls, sex-specific genetic effects controlled systolic BP. The magnitudes of the sex-specific genetic effects on systolic BP were similar in both boys and girls and accounted for 66% of the variance. In boys, for diastolic BP, genetic effects accounted for 64% of the variance while in girls they accounted for 51%. These results provide no evidence for different genetic effects on HR in boys or girls. No shared environmental effects were detected. The large sample size and design, using different-sex dizygotic twins of the same age, establish that genes play an important role in the influence of resting BP and HR and that there are sex-specific genetic contributions in early pubertal children.

Bivariate genetic analysis of left ventricular mass and weight in pubertal twins (the Medical College of Virginia twin study).

Left ventricular (LV) hypertrophy in adults is a recognized risk factor for the subsequent development of cardiovascular morbidity. To make informed preventive health decisions it is important to understand the interaction of genes and environment on LV mass. In both children and adults, weight is a strong correlate of LV mass. We hypothesized that genetic influences common to both of these variables could in part explain the strong relation between weight and LV mass in children. In a population of 341 twins (11 years old), these questions were asked: (1) How much of the total variance of LV mass is under genetic control? (2) After accounting for weight and weight adjusted for sexual maturity, how much of the remaining variance is genetic? (3) Of the total genetic variance, what proportion is specific for LV mass and what proportion is common to both weight and LV mass? (4) How much of the correlation between these 2 variables is explained by genes common to both LV mass and weight? Univariate genetic analyses documented that genes operating at different magnitudes in boys (63%) and girls (71%) explain a significant proportion of the variance of LV mass. After removing the effect of weight and sexual maturity by regression methods, genes remain an important influence. Bivariate genetic analyses confirmed that genes common to LV mass and weight significantly influence the covariation of these variables and that greater than 90% of the correlation of LV mass and weight is due to common genes.

Genetic and environmental influences on behavioral disinhibition.

Comorbidity among childhood disruptive behavioral disorders is commonly reported in both epidemiologic and clinical studies. These problems are also associated with early substance use and other markers of behavioral disinhibition. Previous twin research has suggested that much of the covariation between antisocial behavior and alcohol dependence is due to common genetic influences. Similar results have been reported for conduct problems and hyperactivity. For the present study, an adolescent sample consisting of 172 MZ and 162 DZ twin pairs, recruited through the Colorado Twin Registry and the Colorado Longitudinal Twin Study were assessed using standardized psychiatric interviews and personality assessments. DSM-IV symptom counts for conduct disorder and attention deficit hyperactivity disorder, along with a measure of substance experimentation and novelty seeking, were used as indices of a latent behavioral disinhibition trait. A confirmatory factor model fit to individual-level data showed a strong common factor accounting for 16-42% of the observed variance in each measure. A common pathway model evaluating the genetic and environmental architecture of the latent phenotype suggested that behavioral disinhibition is highly heritable (a(2) = 0.84), and is not influenced significantly by shared environmental factors. A residual correlation between conduct disorder and substance experimentation was explained by shared environmental effects, and a residual correlation between attention deficit hyperactivity disorder and novelty seeking was accounted for by genetic dominance. These results suggest that a variety of adolescent problem behaviors may share a common underlying genetic risk.

Familial association between allergic disorders and depression in adult Finnish twins.

Clinical studies have shown a relationship between allergic disorders and depression, panic disorder, attention deficit/hyperactivity disorder, and social anxiety for a significant subset of patients with these disorders. The nature of the relationship, whether due to shared environmental or biologic vulnerabilities or as a result of the stress of chronic illness, has been less clear. By examining the covariance of atopic disorders and depressive symptoms in a community sample of monozygotic (MZ) and dizygotic (DZ) twins, the contribution of genetic and/or shared environmental etiological factors can be established. A Finnish sample of 1337 MZ and 2506 DZ twin pairs, ages 33-60 years, was sent questionnaires inquiring about history of asthma, eczema, and atopic rhinitis, as well as the Beck Depression Inventory (BDI). The nature of the covariation between twins of these symptoms was investigated by fitting competing genetic and environmental models. Within-person correlation between atopic symptoms and BDI was 0.103 (P < 0.001) for the total sample. Using the Mx statistical modeling program to fit the data to competing quantitative genetic models, the best fitting model estimated that 64% of the association between atopy and BDI was due to shared familial vulnerability, primarily additive genetic influences. Although the measures for allergic disorders and depression are crude, this study supports the hypothesis that there is a small shared genetic risk for atopic and depressive symptoms, and if replicated, may open research for common mechanisms between allergic and depressive disorders. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:146-153, 2000.

The familial aggregation of depressive symptoms, antisocial behavior, and alcohol abuse.

This study describes results from an ongoing family study of adolescent boys and their families designed to investigate potential risk factors for substance abuse. The adolescent treatment probands have severe drug and alcohol related problems and were recruited through a residential rehabilitation program. To date, the sample includes 251 individuals: 39 male probands and their families and 34 control families matched for age and geographic location (zip code). Probands and participating family members are given a structured interview which assesses alcohol and drug problems, and various psychiatric symptoms. The purpose of the present study was to examine the coaggregation of depressive symptoms, antisocial behavior, and alcohol misuse. Multivariate pedigree analyses were performed using a model that allowed for the estimation of vertical familial transmission, residual sibling resemblance, and assortative mating. Spouse correlations were estimated at .57, .21, and .31 for antisocial behavior, depressive symptoms, and alcohol abuse, respectively. Residual sibling environment (i.e., sibling resemblance unaccounted for by parent-offspring transmission) was not found for alcohol problem symptoms, but did contribute to resemblance for antisocial behavior and depressive symptoms. The proportion of variance accounted for by vertical familial transmission was estimated at approximately 30 to 40%. More important, correlations among the transmissible family factors for these psychiatric syndromes ranged from .58 to .73, suggesting substantial overlap among the underlying familial antecedents for these disorders.

Are vaginal and rectal pressures equivalent approximations of one another for the purpose of performing subtracted cystometry?

OBJECTIVE: To determine if rectal and vaginal pressures are clinically equivalent to one another for the purpose of calculating subtracted detrusor pressure during routine filling cystometry and pressure-flow voiding studies. METHODS: A total of 140 consecutive filling and voiding cystometrograms were performed at separate sessions on 127 female patients undergoing routine clinical cystometry for a variety of clinical indications, usually urinary incontinence. In all cases, intravaginal as well as intrarectal pressures were measured simultaneously using microtip transducer pressure catheters, and two subtracted detrusor pressures were calculated throughout each study. Rectal and vaginal pressure measurements from the same patient were compared with the patient in the supine position with an empty bladder, in the erect position with a full bladder, and in the sitting position during voiding at the point of maximum urinary flow. RESULTS: The mean pressures were similar in all cases. Although there was no statistical difference in the mean differences between the rectal and vaginal pressures in the supine-empty position (P = .5528), significant differences were noted between them in the erect-full and sitting-voiding positions (P = .0016 and P = .0033, respectively). Linear regression analysis of the data obtained in each position was carried out, plotting vaginal pressure on the x axis and rectal pressure on the y axis. The corresponding r values for each position were 0.431 for the supine-empty position, 0.547 for the erect-full position, and 0.478 for the sitting-voiding position, indicating poor correlation between pressures in individual patients. In nine patients (6.5%) with significant vaginal relaxation and large cystoceles, a steady rise in vaginal pressure was noted during bladder filling. In six patients (4.4%), one or more spontaneous vaginal contractions were noted during the course of the study, whereas in 68 (48.9%), spontaneous rectal contractions were present. Of the 68 cases where spontaneous rectal contractions were noted, these contractions faded away in 53 cases (77.9%) as the study progressed. CONCLUSIONS: Rectal pressure and vaginal pressure are not the same during filling and voiding cystometry. Although they are reasonable approximations of each other for most qualitative clinical diagnostic purposes, potentially significant differences in subtracted detrusor pressure may occur, depending on which pressure is used as the approximation of intra-abdominal pressure. This may affect clinical management decisions in individual patients. The technique used for approximating abdominal pressure must be stated clearly in any report or publication dealing with subtracted cystometry.

Early childhood heart rate does not predict externalizing behavior problems at age 7 years.

OBJECTIVE: In previous research, low resting heart rate in childhood and adolescence has been shown to predict aggressive and/or delinquent behavior at subsequent ages. It has been found that heart rate recorded as early as age 3 years could predict externalizing behavior at age 11 years. This study explored the possibility of a similar relationship between heart rate and externalizing behavior problems. METHOD: Heart rate recorded at ages 14, 20, 24, 36 months and 7 years was used to predict combined parental ratings on the Aggressive and Delinquent Behavior scales of the Child Behavior Checklist (CBCL/4-18) as well as the Externalizing composite scale measured at age 7 years. Subjects consisted of same-sex twin pairs, treated as singletons in the present study, participating in the MacArthur Longitudinal Twin Study. Subjects were grouped into high and low heart rate groups and also into high CBCL/4-18 scoring and low CBCL/4-18 scoring groups. RESULTS: Heart rate was not significantly related to scores on either of the 2 subscales or the Externalizing composite scale at any age. Heart rate group membership did not predict CBCL/4-18 scores. Conversely, CBCL/4-18 group membership did not predict heart rate at any age. CONCLUSION: In this sample, heart rate does not predict externalizing behavior at age 7.

Urodynamic characteristics of women with complete posthysterectomy vaginal vault prolapse.

OBJECTIVES: To review the symptoms and lower urinary tract function in women with posthysterectomy vaginal vault prolapse. METHODS: A retrospective review was carried out of the urodynamic records of 19 women with posthysterectomy vaginal vault prolapse who had been evaluated in the Bladder Function Laboratory of the Department of Obstetrics and Gynecology at Duke University Medical Center. RESULTS: A full urodynamic evaluation was carried out on 19 women who had had a hysterectomy and who had subsequently experienced complete prolapse of the vaginal vault. Vaginal eversion produced massive distortion of the lower urinary tract and was associated with complex symptoms. Among the cystometric findings in these patients was an early average first desire to void (94 mL) and a reduced average cystometric capacity (370 mL). Symptoms of voiding difficulty were common. During noninstrumented uroflowmetry, the average peak and mean flow rates were reduced in these women (16.5 mL/s and 8.1 mL/s, respectively), suggestive of functional obstruction of the outlet due to the prolapse. Pressure-flow voiding studies showed a reduced peak flow rate (11 mL/s) with an increased detrusor pressure at peak flow (50 cm H2O), also indicative of functional obstruction. All women underwent urethrocystoscopy, and no patient had a urethral stricture or urethral stenosis. Although symptoms of urgency (79%) and urge incontinence (63%) were common, detrusor instability was confirmed by urodynamic studies in only 3 women (16%), suggesting that urge-related symptoms in these women may often be due to anatomic distortion of the lower urinary tract rather than to detrusor overactivity. "Genuine" stress incontinence was documented in only 2 women (11%) during cystometry; however, when these patients were examined with full bladders with their prolapses reduced and returned to a normal anatomic position with a single-bladed speculum, the physical sign of stress incontinence was demonstrated in all 9 women (47%) who had a complaint of stress incontinence. This suggests that massive vaginal prolapse may mask an incompetent continence mechanism, which may then be revealed after surgical repair of the prolapse. CONCLUSIONS: Women with posthysterectomy vaginal vault prolapse present complicated reconstructive problems for the pelvic surgeon. The same pathophysiological process may produce both voiding dysfunction and stress incontinence. These patients should be evaluated carefully before surgical repair is undertaken. Stress incontinence may not be demonstrated in these patients unless they are examined with a full bladder with their prolapse carefully reduced to a normal anatomic position. Women who demonstrate stress incontinence with the vaginal prolapse reduced and the urethra supported normally should be suspected of having "type III" incontinence (demonstrable stress incontinence in the presence of normal urethral support). Women with these findings may require a suburethral sling procedure if they are to remain continent after correction of posthysterectomy vaginal vault eversion.

Genetic selection disrupts stability of mouse brain weight development.

Fuller Brain Weight Selection lines are well differentiated for 42-day brain weight and a high degree of genetic homogeneity for trait-relevant genes is indicated. Using these lines, random bred descendants of the foundation population and an inbred line, biometrical analysis of brain growth from birth to 23 days was attempted. While strain means differ as expected, within and between litter variances for genetically heterogeneous mice were typically no greater than for more genetically homogeneous selected lines. Possible explanations involving gestational age, intra-uterine and postnatal competition and ontogenetic buffering are discussed.

The application of structural equation modeling to maternal ratings of twins' behavioral and emotional problems.

The application of structural equation modeling to twin data is used to assess the impact of genetic and environmental factors on children's behavioral and emotional functioning. The models are applied to the maternal ratings of behavior of a subsample of 515 monozygotic and 749 dizygotic juvenile twin pairs, ages 8 through 16, obtained through mailed questionnaires as part of the Medical College of Virginia Adolescent Behavioral Development Twin Project. The importance of genetic, shared, and specific environmental factors for explaining variation is reported for both externalizing and internalizing behaviors, as well as significant differences in the causes of variation in externalizing behaviors among young boys and girls. The usefulness of applying structural equation models to data on monozygotic and dizygotic twins and the potential implications for addressing clinically relevant questions regarding the causes of psychopathology are discussed.

Substance use, abuse and dependence in adolescence: prevalence, symptom profiles and correlates.

We present data on the lifetime prevalence of substance use, abuse and dependence in adolescents obtained through structured psychiatric interviews and self-report questionnaires. Most notably, we evaluate symptom profiles based on DSM-IV abuse and dependence criteria for tobacco, alcohol and marijuana, including a gender comparison. Participants are 3,072 adolescents (12-18 years) drawn from three community-based family samples in Colorado. Age trends suggest that substance use is a developmental phenomenon, which increases almost linearly from early to late adolescence. Substance use disorders are less common than experimentation in adolescence, but approximately 1 in 4 adolescents in the oldest cohorts meets criteria for abuse for at least one substance, and 1 in 5 meets criteria for substance dependence. By age 18 nearly 1 in 3 adolescents report daily smoking and 8.6% meet criteria for tobacco dependence. Although alcohol is the most commonly abused substance (10%), a slightly larger proportion of adolescents meet criteria for dependence on marijuana (4.3%) than alcohol (3.5%). Gender differences in prevalence of use more often show greater use in males than females. Males more frequently meet criteria for dependence on alcohol and marijuana in late adolescence, while females are more often nicotine dependent. A comparison of abuse and dependence symptom profiles shows some interesting variability across substances, and suggests that manifestations of a subset of symptoms are gender specific.

A family history and direct interview study of the familial aggregation of substance abuse: the adolescent substance abuse study.

The adolescent substance abuse (ASA) study collected information concerning drug use and psychopathology on male adolescent probands in treatment for substance abuse and also on matched control adolescents, as well as all available family members of both groups. Information was obtained through direct interview and the family history method of assessment. Both methods revealed greater alcohol and drug use, conduct disorder (CD) and antisocial personality disorder (ASP) in the relatives of treatment probands as compared with control relatives. These results suggest familial transmission, not only for alcohol abuse, but also for non-alcohol substance abuse. Familial transmission for CD and ASP is also evident for both male and female relatives, although the prevalence of these disorders is significantly greater in males than females.

A twin study of cardiac reactivity and its relationship to parental blood pressure.

The cardiac reactivity of 40 monozygotic and 40 dizygotic pairs of young male twins was monitored during psychological challenge, as afforded by a video game. The observed pattern of variation could not be accounted for solely by environmental factors. In fact, a simple genetic model that implicated additive genetic effects, along with those stemming from individual environments, best fitted the data. In addition, cardiac reactions were substantially greater for subjects whose parents both had relatively elevated blood pressure. Overall, these data suggest individual differences in cardiac reactivity have a heritable component, and that high reactivity may be a precursor of elevated blood pressure.

Temporal and inter-task consistency of heart rate reactivity during active psychological challenge: a twin study.

Heart rate was monitored while 22 pairs of young male monozygotic and 29 pairs of young male dizygotic twins were exposed to a video game and a mental arithmetic task. The heart rate reactions of the monozygotic twins showed much greater concordance than those of the dizygotic twins. Analysis of the data for the 102 individuals demonstrated reliable inter-task consistency of heart rate reaction. In addition, comparison of the heart rate reactions of ten pairs of monozygotic and ten pairs of dizygotic twins who had been tested more than a year earlier and their present reactivities revealed impressive temporal consistency.

Genetic and environmental structure of the Tridimensional Personality Questionnaire: three or four temperament dimensions?

Previous phenotypic factor analyses suggest that C. R. Cloninger's Tridimensional Personality Questionnaire (TPQ; 1987c) assesses 4 rather than 3 temperament dimensions. The purpose of this study was to determine whether Cloninger's revised 4-factor model showed incremental validity over his original model and to investigate the convergent and discriminant validity of Cloninger's dimensions in comparison to the personality dimensions proposed by H. J. Eysenck (1981) and J. A. Gray (1970). The sample included 2,420 women and 870 men (aged 50-96) from a volunteer population-based sample of twins. Joint phenotypic factor analyses supported Cloninger's 4-dimensional temperament model. A 4-dimensional genetical factor structure was also confirmed in genetic analyses of the TPQ higher order dimensions in women. For men only 3 genetic factors were necessary to explain the genetic variance among the TPQ dimensions.

Genetic architecture of olfactory discriminative avoidance conditioning in Drosophila melanogaster.

Recent claims to have demonstrated associative learning ability in Drosophila melanogaster raise questions about the adaptive significance of behavioral modifiability of this species. In a strain survey and a 9 X 9 half diallel cross study of olfactory discriminative avoidance conditioning, a low narrow heritability and strong directional dominance or heterosis controlling nonrandom phenotypic variation were found. Furthermore, the predicted inbreeding depression and asymmetrical response to bidirectional genetic selection were both observed. The genetic architecture revealed in these experiments is consistent with a close association between this conditioning phenotype and evolutionary fitness. Predictions from this interpretation to the nature of new mutations have been confirmed, and a possible role for conditioning in courtship behavior has been identified.