The Concept of Resistance to Substance Use and a Research Approach: The Resist! Project.

Illicit substance use is dangerous in both acute and chronic forms, frequently resulting in lethal poisoning, addiction, and other negative consequences. Similar to research in other psychiatric conditions, whose ultimate goal is to enable effective prevention and treatment, studies in substance use are focused on factors elevating the risk for the disorder. The rapid growth of the substance use problem despite the effort invested in fighting it, however, suggests the need in changing the research approach. Instead of attempting to identify risk factors, whose neutralization is often infeasible if not impossible, it may be more promising to systematically reverse the perspective to the factors enhancing the aspect of liability to disorder that shares the same dimension but is opposite to risk, that is, resistance to substance use. Resistance factors, which enable the majority of the population to remain unaffected despite the ubiquity of psychoactive substances, may be more amenable to translation. While the resistance aspect of liability is symmetric to risk, the resistance approach requires substantial changes in sampling (high-resistance rather than high-risk) and using quantitative indices of liability. This article provides an overview and a practical approach to research in resistance to substance use/addiction, currently implemented in a NIH-funded project. The project benefits from unique opportunities afforded by the data originating from two longitudinal twin studies, the Virginia Twin Study of Adolescent and Behavioral Development and the Minnesota Twin Family Study. The methodology described is also applicable to other psychiatric disorders.

Educational attainment of same-sex and opposite-sex dizygotic twins: An individual-level pooled study of 19 twin cohorts.

Comparing twins from same- and opposite-sex pairs can provide information on potential sex differences in a variety of outcomes, including socioeconomic-related outcomes such as educational attainment. It has been suggested that this design can be applied to examine the putative role of intrauterine exposure to testosterone for educational attainment, but the evidence is still disputed. Thus, we established an international database of twin data from 11 countries with 88,290 individual dizygotic twins born over 100 years and tested for differences between twins from same- and opposite-sex dizygotic pairs in educational attainment. Effect sizes with 95% confidence intervals (CI) were estimated by linear regression models after adjusting for birth year and twin study cohort. In contrast to the hypothesis, no difference was found in women (ß = -0.05 educational years, 95% CI -0.11, 0.02). However, men with a same-sex co-twin were slightly more educated than men having an opposite-sex co-twin (ß = 0.14 educational years, 95% CI 0.07, 0.21). No consistent differences in effect sizes were found between individual twin study cohorts representing Europe, the USA, and Australia or over the cohorts born during the 20th century, during which period the sex differences in education reversed favoring women in the latest birth cohorts. Further, no interaction was found with maternal or paternal education. Our results contradict the hypothesis that there would be differences in the intrauterine testosterone levels between same-sex and opposite-sex female twins affecting education. Our findings in men may point to social dynamics within same-sex twin pairs that may benefit men in their educational careers.

Common Liabilities in Internalizing Symptoms and Cigarette Use in Adolescence.

INTRODUCTION: Substance use and mood disorders account for about 10% of the global burden of disease and, among adolescents, are a significant source of disability. The present study examined whether additive genetic or shared environmental factors influenced the covariance of internalizing symptoms and cigarette use during adolescence when both of these problems begin to increase. AIMS AND METHODS: We used data (n = 1230 pairs of twins) from the Virginia Twin Study of Adolescent Behavioral Development (mean age = 15.3) to decompose the variance of internalizing symptoms, cigarette initiation, and quantity of cigarettes smoked in a variance decomposition model that included a beta coefficient to allow for estimates of cigarette initiation to influence quantity of cigarettes smoked. RESULTS: In biometric models we were able to equate all parameter estimates by sex. After identifying the best fitting model, parameter estimates were calculated and the significance of overlapping paths between internalizing symptoms and cigarette initiation were tested. After accounting for the genetic architecture of cigarette initiation and quantity smoked, the covariance between internalizing symptoms and cigarette use was accounted for by sex-specific shared and unique environmental factors. CONCLUSIONS: Among adolescents, the overlap in risk factors between internalizing symptoms and cigarette use is because of non-genetic, environmental factors. Further exploration of the environmental sources of variance involved in the onset of adolescents internalizing symptoms and cigarette use is warranted. IMPLICATIONS: We find that during adolescence common environmental factors influence the association between internalizing symptoms and cigarette use. Correlated vulnerabilities because of environmental sources between internalizing and cigarette use may be open to intervention and likely will influence the progression of internalizing and cigarette use.

Heritability, stability, and prevalence of tonic and phasic irritability as indicators of disruptive mood dysregulation disorder.

BACKGROUND: Little is known about genetic and environmental influences on the components of disruptive mood dysregulation disorder (DMDD), tonic irritability (i.e., irritable mood) and phasic irritability (i.e., temper outbursts). This study examined prevalence, stability, and heritability of tonic irritability, phasic irritability, and a DMDD proxy (pDMDD) based on DSM-5 criteria. METHODS: pDMDD was derived using data from clinical interviews of parents and their twins (N = 1,431 twin pairs), ages 8-17, participating in Waves 1 and 2 of the Virginia Twin Study of Adolescent Behavioral Development. Biometrical modeling was used to compare a common pathway model (CPM) and an independent pathway model (IPM), and heritability estimates were obtained for pDMDD using the symptoms of irritable mood (tonic irritability; DMDD Criterion D), intense temper outbursts (phasic irritability; DMDD Criterion A), and frequent temper outbursts (phasic irritability; DMDD Criterion C). RESULTS: Lifetime prevalence of pDMDD was 7.46%. The stability of DMDD symptoms and the pDMDD phenotype across approximately one year were moderate (.30-.69). A CPM was a better fit to the data than an IPM. Phasic irritability loaded strongly onto the pDMDD latent factor (.89-.96) whereas tonic irritability did not (.28). Genetic influences accounted for approximately 59% of the variance in the latent pDMDD phenotype, with the remaining 41% of the variance due to unique environmental effects. The heritability of tonic irritability (54%) was slightly lower than that of frequent and intense temper (components of phasic irritability; 61% and 63%, respectively). CONCLUSIONS: Compared to tonic irritability, phasic irritability appears to be slightly more stable and heritable, as well as a stronger indicator of the latent factor. Furthermore, environmental experiences appear to play a substantial role in the development of irritability and DMDD, and researchers should seek to elucidate these mechanisms in future work.

The Mid-Atlantic Twin Registry of Virginia Commonwealth University.

The Mid-Atlantic Twin Registry (MATR) is a population-based registry of more than 60,000 twins primarily born or living in Virginia, North Carolina and South Carolina. Researchers may utilize the MATR for administration of research services, including study recruitment, data or sample (e.g., DNA) collection, archival dataset creation, as well as data collection through mailed, phone or online surveys. In addition, the MATR houses the MATR Repository, with over 1700 DNA samples primarily from whole blood available for researchers interested in DNA genotyping. For over 40 years MATR twins have participated in research studies with investigators from a range of scientific disciplines and institutions. These studies, which have resulted in numerous publications, explored diverse topics, including substance use, smoking behaviors, developmental psychopathology, bullying, children's health, cardiovascular disease, cancer, the human microbiome, epigenetics of aging, children of twins and sleep homeostasis. Researchers interested in utilizing twins are encouraged to contact the MATR to discuss potential research opportunities.

Cross-Lagged Analysis of Interplay Between Differential Traits in Sibling Pairs: Validation and Application to Parenting Behavior and ADHD Symptomatology.

Understanding the factors that contribute to behavioral traits is a complex task, and partitioning variance into latent genetic and environmental components is a useful beginning, but it should not also be the end. Many constructs are influenced by their contextual milieu, and accounting for background effects (such as gene-environment correlation) is necessary to avoid bias. This study introduces a method for examining the interplay between traits, in a longitudinal design using differential items in sibling pairs. The model is validated via simulation and power analysis, and we conclude with an application to paternal praise and ADHD symptoms in a twin sample. The model can help identify what type of genetic and environmental interplay may contribute to the dynamic relationship between traits using a cross-lagged panel framework. Overall, it presents a way to estimate and explicate the developmental interplay between a set of traits, free from many common sources of bias.

Deep Sequencing of 71 Candidate Genes to Characterize Variation Associated with Alcohol Dependence.

BACKGROUND: Previous genomewide association studies (GWASs) have identified a number of putative risk loci for alcohol dependence (AD). However, only a few loci have replicated and these replicated variants only explain a small proportion of AD risk. Using an innovative approach, the goal of this study was to generate hypotheses about potentially causal variants for AD that can be explored further through functional studies. METHODS: We employed targeted capture of 71 candidate loci and flanking regions followed by next-generation deep sequencing (mean coverage 78X) in 806 European Americans. Regions included in our targeted capture library were genes identified through published GWAS of alcohol, all human alcohol and aldehyde dehydrogenases, reward system genes including dopaminergic and opioid receptors, prioritized candidate genes based on previous associations, and genes involved in the absorption, distribution, metabolism, and excretion of drugs. We performed single-locus tests to determine if any single variant was associated with AD symptom count. Sets of variants that overlapped with biologically meaningful annotations were tested for association in aggregate. RESULTS: No single, common variant was significantly associated with AD in our study. We did, however, find evidence for association with several variant sets. Two variant sets were significant at the q-value <0.10 level: a genic enhancer for ADHFE1 (p = 1.47 × 10-5 ; q = 0.019), an alcohol dehydrogenase, and ADORA1 (p = 5.29 × 10-5 ; q = 0.035), an adenosine receptor that belongs to a G-protein-coupled receptor gene family. CONCLUSIONS: To our knowledge, this is the first sequencing study of AD to examine variants in entire genes, including flanking and regulatory regions. We found that in addition to protein coding variant sets, regulatory variant sets may play a role in AD. From these findings, we have generated initial functional hypotheses about how these sets may influence AD.

A Genetic Epidemiological Mega Analysis of Smoking Initiation in Adolescents.

INTRODUCTION: Previous studies in adolescents were not adequately powered to accurately disentangle genetic and environmental influences on smoking initiation (SI) across adolescence. METHODS: Mega-analysis of pooled genetically informative data on SI was performed, with structural equation modeling, to test equality of prevalence and correlations across cultural backgrounds, and to estimate the significance and effect size of genetic and environmental effects according to the classical twin study, in adolescent male and female twins from same-sex and opposite-sex twin pairs (N = 19 313 pairs) between ages 10 and 19, with 76 358 longitudinal assessments between 1983 and 2007, from 11 population-based twin samples from the United States, Europe, and Australia. RESULTS: Although prevalences differed between samples, twin correlations did not, suggesting similar etiology of SI across developed countries. The estimate of additive genetic contributions to liability of SI increased from approximately 15% to 45% from ages 13 to 19. Correspondingly, shared environmental factors accounted for a substantial proportion of variance in liability to SI at age 13 (70%) and gradually less by age 19 (40%). CONCLUSIONS: Both additive genetic and shared environmental factors significantly contribute to variance in SI throughout adolescence. The present study, the largest genetic epidemiological study on SI to date, found consistent results across 11 studies for the etiology of SI. Environmental factors, especially those shared by siblings in a family, primarily influence SI variance in early adolescence, while an increasing role of genetic factors is seen at later ages, which has important implications for prevention strategies. IMPLICATIONS: This is the first study to find evidence of genetic factors in liability to SI at ages as young as 12. It also shows the strongest evidence to date for decay of effects of the shared environment from early adolescence to young adulthood. We found remarkable consistency of twin correlations across studies reflecting similar etiology of liability to initiate smoking across different cultures and time periods. Thus familial factors strongly contribute to individual differences in who starts to smoke with a gradual increase in the impact of genetic factors and a corresponding decrease in that of the shared environment.

Attitudes to Gun Control in an American Twin Sample: Sex Differences in the Causes of Variation.

The genetic and social causes of individual differences in attitudes to gun control are estimated in a sample of senior male and female twin pairs in the United States. Genetic and environmental parameters were estimated by weighted least squares applied to polychoric correlations for monozygotic (MZ) and dizygotic (DZ) twins of both sexes. The analysis suggests twin similarity for attitudes to gun control in men is entirely genetic while that in women is purely social. Although the volunteer sample is small, the analysis illustrates how the well-tested concepts and methods of genetic epidemiology may be a fertile resource for deepening our scientific understanding of biological and social pathways that affect individual risk to gun violence.

Life course persistent and adolescence limited conduct disorder in a nationally representative US sample: prevalence, predictors, and outcomes.

PURPOSE: The course of conduct disorder (CD) is heterogeneous. Moffitt proposed the heuristic of life course persistent (LCP) and adolescence limited (AL) to differentiate etiologically distinct forms of antisocial behavior (AB), each with distinct predictors and consequences, although a few studies have assessed this demarcation within the context of CD. The objective of this study was to apply Moffitt's taxonomy in a nationally representative US sample to investigate the prevalence, predictors, and outcomes of LCP and AL CD. METHODS: Data come from the Collaborative Psychiatric Epidemiology Studies, a set of population-based nationally representative cross-sectional surveys (N = 20,130). Predictors included harsh discipline, maternal and paternal closeness, poverty in childhood, history of learning disability, parental deviance, and nativity. Outcomes included substance use, employment status, education attainment, marital status, income level, and self-rated mental and physical health. RESULTS: The prevalence of LCP and AL CD was 0.5 and 4.6%, respectively, for females, and 1.9 and 5.1%, respectively, for males. Low childhood SES [Odds Ratio (OR) = 3.49], lack of maternal closeness (OR = 2.50), and history of harsh discipline (OR = 2.17) increased odds of LCP group membership. The LCP group had higher odds of developing substance use disorders (OR = 2.00) relative to AL. CONCLUSIONS: LCP CD is more strongly influenced by childhood environment and confers increased odds for substance use problems in adulthood relative to AL CD.

Deep Sequencing of Three Loci Implicated in Large-Scale Genome-Wide Association Study Smoking Meta-Analyses.

INTRODUCTION: Genome-wide association study meta-analyses have robustly implicated three loci that affect susceptibility for smoking: CHRNA5\CHRNA3\CHRNB4, CHRNB3\CHRNA6 and EGLN2\CYP2A6. Functional follow-up studies of these loci are needed to provide insight into biological mechanisms. However, these efforts have been hampered by a lack of knowledge about the specific causal variant(s) involved. In this study, we prioritized variants in terms of the likelihood they account for the reported associations. METHODS: We employed targeted capture of the CHRNA5\CHRNA3\CHRNB4, CHRNB3\CHRNA6, and EGLN2\CYP2A6 loci and flanking regions followed by next-generation deep sequencing (mean coverage 78×) to capture genomic variation in 363 individuals. We performed single locus tests to determine if any single variant accounts for the association, and examined if sets of (rare) variants that overlapped with biologically meaningful annotations account for the associations. RESULTS: In total, we investigated 963 variants, of which 71.1% were rare (minor allele frequency < 0.01), 6.02% were insertion/deletions, and 51.7% were catalogued in dbSNP141. The single variant results showed that no variant fully accounts for the association in any region. In the variant set results, CHRNB4 accounts for most of the signal with significant sets consisting of directly damaging variants. CHRNA6 explains most of the signal in the CHRNB3\CHRNA6 locus with significant sets indicating a regulatory role for CHRNA6. Significant sets in CYP2A6 involved directly damaging variants while the significant variant sets suggested a regulatory role for EGLN2. CONCLUSIONS: We found that multiple variants implicating multiple processes explain the signal. Some variants can be prioritized for functional follow-up.

Testing Models for the Contributions of Genes and Environment to Developmental Change in Adolescent Depression.

We tested two models to identify the genetic and environmental processes underlying longitudinal changes in depression among adolescents. The first assumes that observed changes in covariance structure result from the unfolding of inherent, random individual differences in the overall levels and rates of change in depression over time (random growth curves). The second assumes that observed changes are due to time-specific random effects (innovations) accumulating over time (autoregressive effects). We found little evidence of age-specific genetic effects or persistent genetic innovations. Instead, genetic effects are consistent with a gradual unfolding in the liability to depression and rates of change with increasing age. Likewise, the environment also creates significant individual differences in overall levels of depression and rates of change. However, there are also time-specific environmental experiences that persist with fidelity. The implications of these differing genetic and environmental mechanisms in the etiology of depression are considered.

Age of onset and the subclassification of conduct/dissocial disorder.

BACKGROUND: Conduct Disorder (CD) is a markedly heterogeneous psychiatric condition. Moffitt (1993) proposed that subclassification of CD should be according to age of onset. Our goals were to compare childhood-onset and adolescent-onset CD in terms of differences in phenotypic risk factors, genetic analyses, and factors associated with the persistence of antisocial behavior into young adulthood. METHODS: The data are from the Virginia Twin Study of Adolescent Behavioral Development (VTSABD) and Young Adult Follow-Up (YAFU). Childhood-onset CD was defined as CD beginning at or before age 11. Adolescent-onset CD was defined as having CD onset between ages 14 and 17. These subgroups were compared on ADHD, young adult antisocial behavior (ASB), family dysfunction, and parental depression. Genetic analyses compare childhood-onset and adolescent-onset CD, as well as their cooccurrence with ADHD and ASB. Finally, predictors of persistence were examined. RESULTS: Childhood-onset CD was significantly associated with ADHD, ASB, family dysfunction, and parental depression. Adolescent-onset CD was marginally associated with parental depression (p = .05) but not with any of the other risk factors. Univariate genetic models showed that both childhood-onset and adolescent-onset CD involve a large genetic liability accounting for 62% and 65% of the variance, respectively. A common genetic factor (as well as an ADHD-specific factor) accounted for the cooccurrence of childhood-onset CD and ADHD. The cooccurrence of childhood-onset CD and ASB are reflected by a common genetic factor with genetic specific effects on ASB. There was no etiological link between adolescent-onset CD and either ADHD or ASB. Both ADHD and family dysfunction were significantly associated with the persistence of antisocial behavior into young adulthood. CONCLUSIONS: Phenotypic findings differentiated between childhood-onset and adolescent-onset CD. ADHD and family dysfunction predicted persistence of antisocial behavior into young adulthood.

Genetic and Environmental Influences on Smoking Behavior across Adolescence and Young Adulthood in the Virginia Twin Study of Adolescent Behavioral Development and the Transitions to Substance Abuse Follow-Up.

Little is known regarding the underlying relationship between smoking initiation and current quantity smoked during adolescence into young adulthood. It is possible that the influences of genetic and environmental factors on this relationship vary across sex and age. To investigate this further, the current study applied a common causal contingency model to data from a Virginia-based twin study to determine: (1) if the same genetic and environmental factors are contributing to smoking initiation and current quantity smoked; (2) whether the magnitude of genetic and environmental factor contributions are the same across adolescence and young adulthood; and (3) if qualitative and quantitative differences in the sources of variance between males and females exist. Study results found no qualitative or quantitative sex differences in the relationship between smoking initiation and current quantity smoked, though relative contributions of genetic and environmental factors changed across adolescence and young adulthood. More specifically, smoking initiation and current quantity smoked remain separate constructs until young adulthood, when liabilities are correlated. Smoking initiation is explained by genetic, shared, and unique environmental factors in early adolescence and by genetic and unique environmental factors in young adulthood; while current quantity smoked is explained by shared environmental and unique environmental factors until young adulthood, when genetic and unique environmental factors play a larger role.

Shared genetic and environmental influences on early temperament and preschool psychiatric disorders in Hispanic twins.

OBJECTIVE: Despite an increasing recognition that psychiatric disorders can be diagnosed as early as preschool, little is known how early genetic and environmental risk factors contribute to the development of psychiatric disorders during this very early period of development. METHOD: We assessed infant temperament at age 1, and attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and separation anxiety disorder (SAD) at ages 3 through 5 years in a sample of Hispanic twins. Genetic, shared, and non-shared environmental effects were estimated for each temperamental construct and psychiatric disorder using the statistical program MX. Multivariate genetic models were fitted to determine whether the same or different sets of genes and environments account for the co-occurrence between early temperament and preschool psychiatric disorders. RESULTS: Additive genetic factors accounted for 61% of the variance in ADHD, 21% in ODD, and 28% in SAD. Shared environmental factors accounted for 34% of the variance in ODD and 15% of SAD. The genetic influence on difficult temperament was significantly associated with preschool ADHD, SAD, and ODD. The association between ODD and SAD was due to both genetic and family environmental factors. The temperamental trait of resistance to control was entirely accounted for by the shared family environment. CONCLUSIONS: There are different genetic and family environmental pathways between infant temperament and psychiatric diagnoses in this sample of Puerto Rican preschool age children.

Genome-Wide Meta-Analysis of Longitudinal Alcohol Consumption Across Youth and Early Adulthood.

The public health burden of alcohol is unevenly distributed across the life course, with levels of use, abuse, and dependence increasing across adolescence and peaking in early adulthood. Here, we leverage this temporal patterning to search for common genetic variants predicting developmental trajectories of alcohol consumption. Comparable psychiatric evaluations measuring alcohol consumption were collected in three longitudinal community samples (N=2,126, obs=12,166). Consumption-repeated measurements spanning adolescence and early adulthood were analyzed using linear mixed models, estimating individual consumption trajectories, which were then tested for association with Illumina 660W-Quad genotype data (866,099 SNPs after imputation and QC). Association results were combined across samples using standard meta-analysis methods. Four meta-analysis associations satisfied our pre-determined genome-wide significance criterion (FDR<0.1) and six others met our 'suggestive' criterion (FDR<0.2). Genome-wide significant associations were highly biological plausible, including associations within GABA transporter 1, SLC6A1 (solute carrier family 6, member 1), and exonic hits in LOC100129340 (mitofusin-1-like). Pathway analyses elaborated single marker results, indicating significant enriched associations to intuitive biological mechanisms, including neurotransmission, xenobiotic pharmacodynamics, and nuclear hormone receptors (NHR). These findings underscore the value of combining longitudinal behavioral data and genome-wide genotype information in order to study developmental patterns and improve statistical power in genomic studies.

Heritability of DUI convictions: a twin study of driving under the influence of alcohol.

BACKGROUND: The study was undertaken to assess the relative contributions of genetic and environmental influences on drunk-driving. METHODS: Driving records of a cohort of male and female twins (N = 17,360) from the Mid-Atlantic Twin Registry were examined. Structural equation models were used to estimate the magnitude of genetic and environmental effects on male and female phenotypes, and test for gender differences. RESULTS: There were significant gender and age effects. Compared with females, males were five times more likely to engage in driving under the influence. Among persons aged 21-49 years, the risk for drunk-driving was eight times that for those aged 50+ years and five times greater than those ≤20 years. In both males and females, aged 21-49 years, a large proportion (57%) of the variance in drunk-driving was due to genetic factors and the remaining 43% due to individual specific environmental influences. CONCLUSIONS: Drunk-driving is under significant genetic influence in both males and females. Our findings suggest that a different set of genes influence DUIs in men and women.

The Mid-Atlantic Twin Registry, revisited.

The Mid-Atlantic Twin Registry (MATR) is a population-based registry of more than 56,000 twins primarily born or living in Virginia, North Carolina, and South Carolina. The MATR employs several methods of ascertaining twins, and devotes considerable resources to tracking and maintaining communication with MATR participants. Researchers may utilize the MATR for administration of research services including study recruitment, collection of DNA, archival data set creation, as well as data collection through mailed, phone, or online surveys. In addition, the MATR houses the MATR Repository, with over 1,200 blood samples available for researchers interested in DNA genotyping. For over 35 years MATR twins have participated in research studies with investigators from diverse scientific disciplines and various institutions. These studies, which have resulted in numerous publications, have covered a range of topics, including the human microbiome, developmental psychopathology, depression, anxiety, substance use, epigenetics of aging, children of twins, pre-term birth, social attitudes, seizures, eating disorders, as well as sleep homeostasis. Researchers interested in utilizing twins are encouraged to contact the MATR to discuss potential research opportunities.

Genes, environments, and developmental research: methods for a multi-site study of early substance abuse.

The importance of including developmental and environmental measures in genetic studies of human pathology is widely acknowledged, but few empirical studies have been published. Barriers include the need for longitudinal studies that cover relevant developmental stages and for samples large enough to deal with the challenge of testing gene-environment-development interaction. A solution to some of these problems is to bring together existing data sets that have the necessary characteristics. As part of the National Institute on Drug Abuse-funded Gene-Environment-Development Initiative, our goal is to identify exactly which genes, which environments, and which developmental transitions together predict the development of drug use and misuse. Four data sets were used of which common characteristics include (1) general population samples, including males and females; (2) repeated measures across adolescence and young adulthood; (3) assessment of nicotine, alcohol, and cannabis use and addiction; (4) measures of family and environmental risk; and (5) consent for genotyping DNA from blood or saliva. After quality controls, 2,962 individuals provided over 15,000 total observations. In the first gene-environment analyses, of alcohol misuse and stressful life events, some significant gene-environment and gene-development effects were identified. We conclude that in some circumstances, already collected data sets can be combined for gene-environment and gene-development analyses. This greatly reduces the cost and time needed for this type of research. However, care must be taken to ensure careful matching across studies and variables.

Unraveling the effect of genes and environment in the transmission of parental antisocial behavior to children's conduct disturbance, depression and hyperactivity.

BACKGROUND: A critical issue in devising effective interventions for the treatment of children's behavioral and emotional problems identifying genuine family environmental factors that place children at risk. In most twin and family studies, environmental factors are confounded with both direct genetic risk from parents and the indirect effect of genes influencing parents' ability to provide an optimal rearing environment. The present study was undertaken to determine whether parental psychopathology, specifically parental antisocial behavior (ASP), is a genuine environmental risk factor for juvenile conduct disturbance, depression and hyperactivity, or whether the association between parental ASP and children's behavioral and emotional problems can be explained as a secondary consequence of the intergenerational transmission of genetic factors. METHODS: An extended children of twins design comprised of data collected on 2,674 adult female and male twins, their spouses, and 2,454 of their children was used to test whether genetic and/or family environmental factors best accounted for the association between parental antisocial behavior and children's behavioral problems. An age-matched sample of 2,826 juvenile twin pairs from the Virginia Twin Study of Adolescent Behavioral Development was also included to examine developmental differences in gene expression by partitioning child-specific transmissible effects from those effects that persist into adulthood. The fit of alternative models was evaluated using the statistical program Mx. RESULTS: We found distinct patterns of transmission between parental antisocial behavior and juvenile conduct, depression and hyperactivity. Genetic and family environmental factors accounted for the resemblance between parents' ASP and children's conduct disturbance. Family environmental factors alone explained the association between child depression and parental ASP, and the impact of parental ASP on hyperactivity was entirely genetic. CONCLUSIONS: These findings underscore differences in the contribution of genetic and environmental factors on the patterns of association between parental antisocial behavior and juvenile psychopathology, having important clinical implications for the prevention and amelioration of child behavioral and emotional problems.