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.

Nominal association with CHRNA4 variants and nicotine dependence.

Nicotine binds to nicotinic acetylcholine receptors and studies in animal models have shown that α4ß2 receptors mediate many behavioral effects of nicotine. Human genetics studies have provided support that variation in the gene that codes for the α4 subunit influences nicotine dependence (ND), but the evidence for the involvement of the ß2 subunit gene is less convincing. In this study, we examined the genetic association between variation in the genes that code for the α4 (CHRNA4) and ß2 (CHRNB2) subunits of the nicotinic acetylcholine receptor and a quantitative measure of lifetime DSM-IV ND symptom counts. We performed this analysis in two longitudinal family-based studies focused on adolescent antisocial drug abuse: the Center on Antisocial Drug Dependence (CADD, N = 313 families) and Genetics of Antisocial Drug Dependence (GADD, N = 111 families). Family-based association tests were used to examine associations between 14 single nucleotide polymorphisms (SNPs) in CHRNA4 and CHRNB2 and ND symptoms. Symptom counts were corrected for age, sex and clinical status prior to the association analysis. Results, when the samples were combined, provided modest evidence that SNPs in CHRNA4 are associated with ND. The minor allele at both rs1044394 (A; Z = 1.988, P = 0.047, unadjusted P-value) and rs1044396 (G; Z = 2.398, P = 0.017, unadjusted P-value) was associated with increased risk of ND symptoms. These data provide suggestive evidence that variation in the α4 subunit of the nicotinic acetylcholine receptor may influence ND liability.

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.

Developmental epidemiology of drug use and abuse in adolescence and young adulthood: Evidence of generalized risk.

Past studies highlight a narrowing gender gap and the existence of a shared etiology across substances of abuse; however, few have tested developmental models using longitudinal data. We present data on developmental trends of alcohol, tobacco, and marijuana use, abuse and dependence assessed during adolescence and young adulthood in a community-based Colorado twin sample of 1733 respondents through self-report questionnaires and structured psychiatric interviews. Additionally, we report on the rates of multiple substance use and disorders at each developmental stage, and the likelihood of a substance use disorder (SUD; i.e., abuse or dependence) diagnosis in young adulthood based on adolescent drug involvement. Most notably, we evaluate whether the pattern of multiple substance use and disorders and likelihood ratios across substances support a model of generalized risk. Lastly, we evaluate whether the ranked magnitudes of substance-specific risk match the addiction liability ranking. Substance use and SUDs are developmental phenomena, which increase from adolescence to young adulthood with few and inconsistent gender differences. Adolescents and young adults are not specialized users, but rather tend to use or abuse multiple substances increasingly with age. Risk analyses indicated that progression toward a SUD for any substance was increased with prior involvement with any of the three substances during adolescence. Despite the high prevalence of alcohol use, tobacco posed the greatest substance-specific risk for developing subsequent problems. Our data also confirm either a generalized risk or correlated risk factors for early onset substance use and subsequent development of SUDs.

Genetic and environmental contributions to retrospectively reported DSM-IV childhood attention deficit hyperactivity disorder.

BACKGROUND: A variety of methodologies and techniques converge on the notion that adults and children with attention deficit hyperactivity disorder (ADHD) have similar deficits, but there is limited knowledge about whether adult retrospective reports reflect similar genetic and environmental influences implicated in childhood ADHD. METHOD: DSM-IV ADHD symptoms were collected retrospectively from 3896 young adults participating in the National Longitudinal Study of Adolescent Health. Responses from this genetically informative sample of same- and opposite-sex twins and siblings were used to determine the magnitude of genetic and environmental influences. Possible gender differences in these effects were also examined. The degree of familial specificity of the genetic and environmental influences on the Inattentive and Hyperactive-Impulsive symptom dimensions was also determined. RESULTS: Additive genetic effects contributed moderately to DSM-IV Inattentive, Hyperactive-Impulsive and Combined ADHD subtypes (heritability estimates of 0.30-0.38). Individual-specific influences accounted for the remaining proportion of the variance. Both genetic and individual-specific environmental effects contributed to the covariation of Inattentive and Hyperactive-Impulsive symptomologies. CONCLUSIONS: Results from our genetic analyses agree with previous findings based on self-assessment of current and retrospectively reported ADHD symptoms in adolescents and adults. Large individual-specific environmental influences as identified here suggest that current questionnaires used for retrospective diagnoses may not provide the most accurate reconstruction of the etiological influences on childhood ADHD in general population samples.

Genetic and environmental influences on age at sexual initiation in the Colorado Adoption Project.

Whereas the majority of research on adolescent sexual initiation has focused solely on environmental factors, the present study used behavioral genetic analyses to investigate the relative contributions of genetic and environmental influences. Structural equation models were fitted to data from adoptive and non-adoptive sibling pairs (231 biologically related pairs and 169 unrelated pairs) from the Colorado Adoption Project. Information from censored individuals who had not yet experienced sexual initiation was maximized by adapting the twin survival analysis method of Pickles et al. (Behav Genet 24(5):457-468, 1994) to accommodate adoptive and non-adoptive siblings. Point estimates of variance components from an ACE model, including additive genetic (A), shared environmental (C), and non-shared environmental (E) influences were 28%, 24%, and 48%, respectively. Despite the lower point estimate for shared environmental effects than additive genetic effects, a CE model provided the best fit to the data. However, because adoptive siblings provide a direct estimate of shared environmental influences there is greater power to detect shared environmental effects in adoption designs. Evidence for genetic influences from our data were somewhat lower than those obtained in previous twin studies, possibly reflecting a return to more socially conservative sexual attitudes, changing sexual behaviors, or ambiguities in the wording of questions commonly used in research on adolescent sexuality.

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.

Parent-offspring resemblance for reading performance at 7, 12 and 16 years of age in the Colorado Adoption Project.

BACKGROUND: The study aimed to conduct the first analysis of CAP parent-offspring resemblance for reading performance in children aged 7, 12 and 16 years, and to assess the etiology of individual differences in reading performance of children at 16 years of age. METHOD: The Reading Recognition subtest of the Peabody Individual Achievement Test was administered to children in the Colorado Adoption Project (CAP) at 7, 12 and 16 years of age, and to their adoptive and nonadoptive parents when the children were 7 years of age. RESULTS: Resulting parent-offspring correlations in adoptive families were not significant at any age, but correlations between scores of nonadoptive control parents and their offspring were significant at all three ages. CONCLUSIONS: Results obtained from behavioral genetic model-fitting analyses of data from parents and their children tested at age 16 are consistent with results of studies of twins and siblings indicating that individual differences in reading performance are due substantially to genetic influences. In contrast, environmental transmission from parents to offspring was negligible, suggesting that environmental influences on individual differences in the reading performance of children are largely independent of parental reading performance.

Stability of genetic and environmental influences on reading performance at 7, 12, and 16 years of age in the Colorado Adoption Project.

The etiology of the longitudinal stability of reading performance was assessed by analyzing data from adoptive and nonadoptive sibling pairs (206 pairs at age 7, 195 pairs at age 12, and 110 pairs at age 16) tested in the Colorado Adoption Project (CAP). Results of longitudinal behavioral genetic analyses confirmed previous findings of moderate genetic influence on individual differences in reading performance at 7 and 12 years of age (a2 = .44 and .38, respectively), with somewhat higher heritability at age 16 (a2 = .57). Corresponding shared environmental influences were negligible (c2 = .07, .09, and .07). Moreover, common genetic influences were responsible for 66% of the observed stability (rp) between ages 7 and 12 (.62), 62% of that between ages 12 and 16 (rp = .74), and 88% of that between ages 7 and 16 (rp = .55). Of particular interest, no new heritable variation was detected at either 12 or 16 years of age, suggesting that genetic influences at 7 years of age are amplified at the later ages. In contrast, new nonshared environmental influences (including measurement error) were manifested at each age, suggesting the possible importance of nonshared environmental factors (e.g., instructional methods, teachers, peers) for the development of individual differences in reading performance between 7 and 16 years of age.

Optimal sibship selection for genotyping in quantitative trait locus linkage analysis.

In this paper we present a novel method for selecting optimally informative sibships of any size for quantitative trait locus (QTL) linkage analysis. The method allocates a quantitative index of potential informativeness to each sibship on the basis of observed trait scores and an assumed true QTL model. Any sample of phenotypically screened sibships can therefore be easily rank-ordered for selective genotyping. The quantitative index is the sibship's expected contribution to the non-centrality parameter. This expectation represents the weighted sum of chi(2) test statistics that would be obtained given the observed trait values over all possible sibship genotypic configurations; each configuration is weighted by the likelihood of it occurring given the assumed true genetic model. The properties of this procedure are explored in relation to the accuracy of the assumed true genetic model and sibship size. In comparison to previous methods of selecting phenotypically extreme sibships for genotyping, the proposed method is considerably more efficient and is robust with regard to the specification of the genetic model.

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.

Parental concordance and comorbidity for psychiatric disorder and associate risks for current psychiatric symptoms and disorders in a community sample of juvenile twins.

In this report we characterize associations between parental psychiatric disorders and children's psychiatric symptoms and disorders using a population-based sample of 850 twin families. Juvenile twins are aged 8-17 years and are personally interviewed about their current history of DSM-III-R conduct, depression, oppositional-defiant, overanxious, and separation anxiety disorders using the CAPA-C. Mothers and fathers of twins are personally interviewed about their lifetime history of DSM-III-R alcoholism, antisocial personality disorder, generalized anxiety disorder, major depression, panic disorder/agoraphobia, social phobia, and simple phobia using a modified version of the SCID and the DIS. Generalized least squares and logistic regression are used to identify the juvenile symptoms and disorders that are significantly associated with parental psychiatric histories. The specificity of these associations is subsequently explored in a subset of families with maternal plus parental psychiatric histories with a prevalence > 1%. Parental depression that is not comorbid or associated with a different spousal disorder is associated with a significantly elevated level of depression and overanxious disorder symptoms and a significantly increased risk for overanxious disorder. Risks are higher for both symptomatic domains in association with maternal than paternal depression, and highest in association with maternal plus paternal depression. Risks for otherjuvenile symptoms and disorders index the comorbid and spousal histories with which parental depression is commonly associated. Paternal alcoholism that is not comorbid or associated with a maternal disorder is not significantly associated with current psychiatric symptoms or disorders in offspring. Risks for oppositional-defiant or conduct symptoms/disorders in the offspring of alcoholic parents index parental comorbidity and/or other spousal histories.

Common genetic and environmental vulnerability for alcohol and tobacco use in a volunteer sample of older female twins.

OBJECTIVE: A growing body of literature supports a shared genetic vulnerability underlying the use of alcohol and tobacco. We report patterns of genetic and environmental correlations for alcohol and tobacco use in a volunteer sample of older, white, female twins using three different levels of severity for alcohol use and smoking. METHOD: A community-based sample of 1,926 female twins aged 50 to 96 was recruited through advertisements in a newsletter of the American Association of Retired Persons. Subjects were asked to rate alcohol and tobacco use over their lifetimes. Three levels of severity for alcohol use and smoking were coded: ever drank, weekly drinking, problem drinking; ever smoked, daily smoking of one-half pack or more, daily smoking of at least one pack or more. Twin correlations for alcohol and tobacco use measures were fit using a structural equation-modeling package (Mx). RESULTS: There were significant genetic correlations between problem drinking and ever smoking and using at least one-half pack per day. For problem drinking/ever smoking, R = 1.0 (95% CI: 0.32-1.0); for problem drinking/smoking at least one-half pack/day, R = 1.0 (95% CI: 0.43-1.0). CONCLUSIONS: The shared genetic influence on alcohol use and smoking in women is clearest for those subjects with the highest severity of alcohol use and problem drinking.

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.

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 aggregation for conduct disorder symptomatology: the role of genes, marital discord and family adaptability.

BACKGROUND: There is extensive evidence of statistical associations between family discord/ maladaptation and antisocial behaviour in the children, but questions remain on the extent to which the psychopathological risks are genetically or environmentally mediated. METHODS: Twin pairs (N = 1,350), aged 8 to 16 years, in the general population-based Virginia Twin Study of Adolescent Behavioral Development were assessed using the Child and Adolescent Psychiatric Assessment interview administered separately to both twins and both parents. Structured interviews for parental lifetime psychiatric disorders were also administered to the mothers and fathers. Maternal reports on Olsson's Family Adaptability and Cohesiveness questionnaire and the Dyadic Adjustment Scale were used as indices of the family environment. A path analytical model based on an extended twin-family design was used to test hypotheses about parent offspring similarity for conduct disorder symptomatology. RESULTS: Family discord and maladaptation, which intercorrelated at 0.63, were associated with a roughly two-fold increase in risk for conduct disorder symptomatology. When parental conduct disorder was included in the model the environmental mediation effect for family maladaptation remained, but that for family discord was lost. CONCLUSION: It is concluded that there is true environmental mediation from family maladaptation, operating as a shared effect, which accounts for 3.5 % of the phenotypic variance. The assumptions underlying this genetic research strategy are made explicit, together with its strengths and limitations.

Variance-Components QTL linkage analysis of selected and non-normal samples: conditioning on trait values.

Standard variance-components quantitative trait loci (QTL) linkage analysis can produce an elevated rate of type 1 errors when applied to selected samples and non-normal data. Here we describe an adjustment of the log-likelihood function based on conditioning on trait values. This leads to a likelihood ratio test that is valid in selected samples and non-normal data, and equal in power to alternative methods for analyzing selected samples that require knowledge of the ascertainment procedure or the trait values of non-selected individuals.

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.

Power of linkage versus association analysis of quantitative traits, by use of variance-components models, for sibship data.

Optimal design of quantitative-trait loci (QTL) mapping studies requires a precise understanding of the power of QTL linkage versus QTL association analysis, under a range of different conditions. In this article, we investigate the power of QTL linkage and association analyses for simple random sibship samples, under the variance-components model proposed by Fulker et al. After a brief description of an extension of this variance-components model, we show that the powers of both linkage and association analyses are crucially dependent on the proportion of phenotypic variance attributable to the QTL. The main difference between the two tests is that, whereas the power of association is directly related to the QTL heritability, the power of linkage is related more closely to the square of the QTL heritability. We also describe both how the power of linkage is attenuated by incomplete linkage and incomplete marker information and how the power of association is attenuated by incomplete linkage disequilibrium.

An exploration of the genetic and environmental etiology of heart rate in infancy and middle childhood.

Heart rate was recorded on 210 MZ and 174 DZ same sex twin pairs participating in the MacArthur Longitudinal Twin Study (MALTS) at age 14, 20, 24, 36 months and 7 years. Heart rate was monitored in the laboratory at all ages. At ages 14 to 36 months, heart rate was monitored prior to a set of cognitive tasks. At age 7 years heart rate was recorded during a mood-eliciting videotaped presentation. At this age only heart rate monitored during neutral portions of the presentation were used. Mean heart rate declines substantially across this age range, but is similar in boys and girls and for MZ and DZ twins at each age. Heart rate is moderately correlated across all time points suggesting that individual differences in heart rate are relatively stable over this age range. Multivariate genetic and environmental models were fitted to the raw data. In general, genetic factors contribute to the stability of individual differences over time. Shared and non-shared environment factors tended to be occasion specific, with non-shared environment contributing substantially to the individual variation at each age. Shared environment and non-shared environment also contributed a modicum to the stability across time. Thus, individual differences in resting heart rate is a relatively stable, heritable trait from infancy to early childhood.