A Bivariate Twin Study of Lifetime cannabis Initiation and Lifetime Regular Tobacco Smoking Across Three Different Countries.

Regular cigarette smoking and cannabis consumption are strongly positively related to each other, yet few studies explore their underlying variation and covariation. We evaluated the genetic and environmental decomposition of variance and covariance of these two traits in twin data from three countries with different social norms and legislation. Data from the Netherlands Twin Register, FinnTwin12/16, and the Minnesota Center for Twin Family Research (total N = 21,617) were analyzed in bivariate threshold models of lifetime regular smoking initiation (RSI) and lifetime cannabis initiation (CI). We ran unstratified models and models stratified by sex and country. Prevalence of RSI was lowest in the Netherlands and prevalence of CI was highest in Minnesota. In the unstratified model, genetic (A) and common environmental factors (C) contributed substantially to the liabilities of RSI (A = 0.47, C = 0.34) and CI (A = 0.28, C = 0.51). The two liabilities were significantly phenotypically (rP = 0.56), genetically (rA = 0.74), and environmentally correlated in the unstratified model (rC = 0.47and rE = 0.48, representing correlations between common and unique environmental factors). The magnitude of phenotypic correlation between liabilities varied by country but not sex (Minnesota rP ~ 0.70, Netherlands rP ~ 0.59, Finland rP ~ 0.45). Comparisons of decomposed correlations could not be reliably tested in the stratified models. The prevalence and association of RSI and CI vary by sex and country. These two behaviors are correlated because there is genetic and environmental overlap between their underlying latent liabilities. There is heterogeneity in the genetic architecture of these traits across country.

Cohort Effects on Tobacco Consumption and its Genetic and Environmental Variance Among Finnish Adults born between 1880-1957.

INTRODUCTION: Population research indicates that smoking behaviors in Finland have varied over time by sex and birth cohort. Smoking behaviors are influenced by genes and the environment; like the behaviors themselves, these underlying influences are not necessarily stable over time and may be modifiable by national drug policy. METHODS: We utilized longitudinal mixed effects models and causal-common-contingent twin models to evaluate sex and cohort effects on tobacco consumption and the underlying genetic and environmental variance components in a birth cohort sample of same-sex twins born in Finland between 1880-1957, assessed in 1975, 1981, 1990, and 2011. RESULTS: We identified significant main effects of age, sex, and cohort on quantity of cigarette consumption, as well as significant age×cohort and sex×cohort interactions. We also identified sex and cohort effects on the liability to initiate regular smoking and the magnitude of variation underlying quantity of cigarette consumption. That said, heritability and environmental contributions to both traits were not different between the four sex×cohort groups. CONCLUSIONS: Our results indicate sex and cohort effects on the prevalence of smoking and its underlying variation. Our results on changing prevalence mirror existing population-level research in Finnish samples, but we did not identify differences in heritability found in other studies of cohort effects in tobacco use, potentially due to power issues. These results highlight the importance of considering age, cohort, and timing of policy changes when evaluating changes in substance consumption across time. IMPLICATIONS: This study identifies sex and cohort effects influencing tobacco consumption in a sample of Finnish adult twins born between 1880-1957. Our results are in line with other population level research in Finland and research on cohort effects influencing alcohol use in the same sample. Our results highlight the intertwining effects of age, cohort, sex, and substance policies on substance use.

Using Instrumental Variables to Measure Causation over Time in Cross-Lagged Panel Models.

Cross-lagged panel models (CLPMs) are commonly used to estimate causal influences between two variables with repeated assessments. The lagged effects in a CLPM depend on the time interval between assessments, eventually becoming undetectable at longer intervals. To address this limitation, we incorporate instrumental variables (IVs) into the CLPM with two study waves and two variables. Doing so enables estimation of both the lagged (i.e., "distal") effects and the bidirectional cross-sectional (i.e., "proximal") effects at each wave. The distal effects reflect Granger-causal influences across time, which decay with increasing time intervals. The proximal effects capture causal influences that accrue over time and can help infer causality when the distal effects become undetectable at longer intervals. Significant proximal effects, with a negligible distal effect, would imply that the time interval is too long to estimate a lagged effect at that time interval using the standard CLPM. Through simulations and an empirical application, we demonstrate the impact of time intervals on causal inference in the CLPM and present modeling strategies to detect causal influences regardless of the time interval in a study. Furthermore, to motivate empirical applications of the proposed model, we highlight the utility and limitations of using genetic variables as IVs in large-scale panel studies.

Genetic and Environmental Variation in Continuous Phenotypes in the ABCD Study®.

Twin studies yield valuable insights into the sources of variation, covariation and causation in human traits. The ABCD Study® (abcdstudy.org) was designed to take advantage of four universities known for their twin research, neuroimaging, population-based sampling, and expertise in genetic epidemiology so that representative twin studies could be performed. In this paper we use the twin data to: (i) provide initial estimates of heritability for the wide range of phenotypes assessed in the ABCD Study using a consistent direct variance estimation approach, assuring that both data and methodology are sound; and (ii) provide an online resource for researchers that can serve as a reference point for future behavior genetic studies of this publicly available dataset. Data were analyzed from 772 pairs of twins aged 9-10 years at study inception, with zygosity determined using genotypic data, recruited and assessed at four twin hub sites. The online tool provides twin correlations and both standardized and unstandardized estimates of additive genetic, and environmental variation for 14,500 continuously distributed phenotypic features, including: structural and functional neuroimaging, neurocognition, personality, psychopathology, substance use propensity, physical, and environmental trait variables. The estimates were obtained using an unconstrained variance approach, so they can be incorporated directly into meta-analyses without upwardly biasing aggregate estimates. The results indicated broad consistency with prior literature where available and provided novel estimates for phenotypes without prior twin studies or those assessed at different ages. Effects of site, self-identified race/ethnicity, age and sex were statistically controlled. Results from genetic modeling of all 53,172 continuous variables, including 38,672 functional MRI variables, will be accessible via the user-friendly open-access web interface we have established, and will be updated as new data are released from the ABCD Study. This paper provides an overview of the initial results from the twin study embedded within the ABCD Study, an introduction to the primary research domains in the ABCD study and twin methodology, and an evaluation of the initial findings with a focus on data quality and suitability for future behavior genetic studies using the ABCD dataset. The broad introductory material is provided in recognition of the multidisciplinary appeal of the ABCD Study. While this paper focuses on univariate analyses, we emphasize the opportunities for multivariate, developmental and causal analyses, as well as those evaluating heterogeneity by key moderators such as sex, demographic factors and genetic background.

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.

Genetic and environmental contributions to the relationships between brain structure and average lifetime cigarette use.

Chronic cigarette use has been consistently associated with differences in the neuroanatomy of smokers relative to nonsmokers in case-control studies. However, the etiology underlying the relationships between brain structure and cigarette use is unclear. A community-based sample of male twin pairs ages 51-59 (110 monozygotic pairs, 92 dizygotic pairs) was used to determine the extent to which there are common genetic and environmental influences between brain structure and average lifetime cigarette use. Brain structure was measured by high-resolution structural magnetic resonance imaging, from which subcortical volume and cortical volume, thickness and surface area were derived. Bivariate genetic models were fitted between these measures and average lifetime cigarette use measured as cigarette pack-years. Widespread, negative phenotypic correlations were detected between cigarette pack-years and several cortical as well as subcortical structures. Shared genetic and unique environmental factors contributed to the phenotypic correlations shared between cigarette pack-years and subcortical volume as well as cortical volume and surface area. Brain structures involved in many of the correlations were previously reported to play a role in specific aspects of networks of smoking-related behaviors. These results provide evidence for conducting future research on the etiology of smoking-related behaviors using measures of brain morphology.

Lindon J. Eaves, Ph.D., M.A. (Oxon), D.Sc. Theory-model-data.

We begin this special issue by providing a glimpse into the career of Dr. Lindon J. Eaves, from the perspectives of a student, postdoc, instructor, assistant to associate and full professor over the last 20 odd years. We focus primarily on Lindon's contributions to methodological issues and research designs to address them, in particular those related to models for extended twin-family designs, for the development of adolescent behavior, for genotype-environment covariation and interaction, and their application to the Virginia 30,000 and the Virginia Twin Study of Adolescent Behavioral Development. We then introduce the collection of papers in this special festschrift issue of Behavior Genetics, celebrating Dr. Eaves achievements over the last 40 years.

Twin-based Mendelian Randomization Analyses Highlight Smoking's Effects on Blood DNA Methylation, with Putative Reverse Causation.

Epigenome-wide association studies (EWAS) aim to identify differentially methylated loci associated with complex traits and disorders. EWAS of cigarette smoking shows some of the most widespread DNA methylation (DNAm) associations in blood. However, traditional EWAS cannot differentiate between causation and confounding, leading to ambiguity in etiological interpretations. Here, we apply an integrated approach combining Mendelian Randomization and twin-based Direction-of-Causation analyses (MR-DoC) to examine causality underlying smoking-associated blood DNAm changes in the Netherlands Twin Register (N=2577). Evidence across models suggests that current smoking's causal effects on DNAm likely drive many of the previous EWAS findings, implicating functional pathways relevant to several adverse health outcomes of smoking, including hemopoiesis, cell- and neuro-development, and immune regulation. Additionally, we find evidence of potential reverse causal influences at some DNAm sites, with 17 of these sites enriched for gene regulatory functional elements in the brain. The top three sites with evidence of DNAm's effects on smoking annotate to genes involved in G protein-coupled receptor signaling (GNG7, RGS3) and innate immune response (SLC15A4), elucidating potential biological risk factors for smoking. This study highlights the utility of integrating genotypic and DNAm measures in twin cohorts to clarify the causal relationships between health behaviors and blood DNAm.

Reconsidering the heritability of intelligence in adulthood: taking assortative mating and cultural transmission into account.

Heritability estimates of general intelligence in adulthood generally range from 75 to 85%, with all heritability due to additive genetic influences, while genetic dominance and shared environmental factors are absent, or too small to be detected. These estimates are derived from studies based on the classical twin design and are based on the assumption of random mating. Yet, considerable positive assortative mating has been reported for general intelligence. Unmodeled assortative mating may lead to biased estimates of the relative magnitude of genetic and environmental factors. To investigate the effects of assortative mating on the estimates of the variance components of intelligence, we employed an extended twin-family design. Psychometric IQ data were available for adult monozygotic and dizygotic twins, their siblings, the partners of the twins and siblings, and either the parents or the adult offspring of the twins and siblings (N = 1314). Two underlying processes of assortment were considered: phenotypic assortment and social homogamy. The phenotypic assortment model was slightly preferred over the social homogamy model, suggesting that assortment for intelligence is mostly due to a selection of mates on similarity in intelligence. Under the preferred phenotypic assortment model, the variance of intelligence in adulthood was not only due to non-shared environmental (18%) and additive genetic factors (44%) but also to non-additive genetic factors (27%) and phenotypic assortment (11%).This non-additive nature of genetic influences on intelligence needs to be accommodated in future GWAS studies for intelligence.

Modeling extended twin family data I: description of the Cascade model.

The classical twin design uses data on the variation of and covariation between monozygotic and dizygotic twins to infer underlying genetic and environmental causes of phenotypic variation in the population. By using data from additional relative classes, such as parents, extended twin family designs more comprehensively describe the causes of phenotypic variation. This article introduces an extension of previous extended twin family models, the Cascade model, which uses information on twins as well as their siblings, spouses, parents, and children to differentiate two genetic and six environmental sources of phenotypic variation. The Cascade also relaxes assumptions regarding mating and cultural transmission that existed in previous extended twin family designs. The estimation of additional parameters and relaxation of assumptions is potentially important, not only because it allows more fine-grained descriptions of the causes of phenotypic variation, but more importantly, because it can reduce the biases in parameter estimates that exist in earlier designs.

Racial differences in heritability of cigarette smoking in adolescents and young adults.

INTRODUCTION: Although epidemiologic studies suggest low levels of cigarette use among African American adolescents relative to White U.S. adolescents, it is not known whether this may be due to racial differences in the relative contribution of genes and environment to cigarette use initiation and progression to regular use. METHODS: Using data from White (n=2665) and African American (n=809) twins and full siblings sampled in the National Longitudinal Study of Adolescents, we fitted age-, sex- and race-specific variance decomposition models to estimate the magnitude of genetic and environmental effects on cigarette use initiation and cigarette use quantity in Whites and African Americans across adolescence and adulthood. We employ a causal-contingent-common pathway model to estimate the amount of variance explained in quantity of cigarettes smoked contingent on cigarette use initiation. RESULTS: African Americans had lower cigarette use prevalence from adolescence through adulthood, and used cigarettes less heavily than Whites. Race-specific causal-contingent-common pathway models indicate that racial differences in genetic and environmental contributions to cigarette use initiation and cigarette use quantities are not present in adolescence but appear in young adulthood. Additive genetic factors were an important risk factor for cigarette use initiation for White but not African American young adults and adults. CONCLUSIONS: Genetic and environmental contributions for cigarette use are similar by race in adolescence. In adulthood, genes have a stronger influence for cigarette use among White adolescents while the influence of the environment is minimal. For African Americans, both genetic and environmental influences are important in young adulthood and adulthood.

Genetic and environmental determination of tracking in static strength during adolescence.

The purpose of this study was to determine whether the observed phenotypic stability in static strength during adolescence, as measured by interage correlations in arm pull, is mainly caused by genetic and/or environmental factors. Subjects were from the Leuven Longitudinal Twin Study (n = 105 pairs, equally divided over 5 zygosity groups). Arm-pull data were aligned on age at peak height velocity to attenuate the temporal fluctuations in interage correlations caused by differences in timing of the adolescent growth spurt. Developmental genetic models were fitted using structural equation modeling. After the data were aligned on age at peak height velocity, the annual interage correlations conformed to a quasi-simplex structure over a 4-yr interval. The best-fitting models included additive genetic and unique environmental sources of variation. Additive genetic factors that already explained a significant amount of variation at previous measurement occasions explained 44.3 and 22.5% of the total variation at the last measurement occasion in boys and girls, respectively. Corresponding values for unique environmental sources of variance are 31.2 and 44.5%, respectively. In conclusion, the observed stability of static strength during adolescence is caused by both stable genetic influences and stable unique environmental influences in boys and girls. Additive genetic factors seem to be the most important source of stability in boys, whereas unique environmental factors appear to be more predominant in girls.

Growth in peak aerobic power during adolescence.

PURPOSE: To model the growth of peak aerobic power during adolescence in both sexes followed longitudinally from 10 to 18 yr. METHODS: Peak aerobic power (peak VO2) was measured annually during a maximal treadmill test with the Bruce protocol. Height and weight were measured semiannually. The Preece-Baines Model I growth function was used to fit curves to data for individuals with >/= six observations for peak aerobic power to estimate age at peak velocity (PV) for peak VO2 (age at PVPVO2), PVPVO2 (L x min(-1) x yr(-1)), and value at PVPVO2 (L x min(-1)) for each individual. Curves were successfully fitted for 83 individuals (48 males, 35 females). The model was also fitted to individual data for height and weight to estimate ages at peak height velocity (PHV) and peak weight velocity (PWV). Age at PVPVO2 was compared with ages at PHV and PWV. Pearson correlation coefficients were calculated between ages at PV and PV for peak VO2, height, and weight. RESULTS: Mean ages at PVPVO2 are 12.3 +/- 1.2 yr for females and 14.1 +/- 1.2 yr for males. Peak VO2 increases in both sexes throughout adolescence, with males having higher values than females at all ages. Age at PVPVO2 occurs nearly coincident with PHV and before PWV in both sexes. Correlation coefficients among ages at PHV, PWV, and PVPVO2 suggest a general maturity factor for body size and aerobic power. CONCLUSION: Growth in peak VO2 exhibits a clear growth spurt in both sexes during adolescence. The growth spurt occurs earlier in females but is of greater magnitude in males.

Extensions to the modeling of initiation and progression: applications to substance use and abuse.

Twin data can provide valuable insight into the relationship between the stages of phenomena such as disease or substance abuse. Initiation of substance use may be caused by factors that are the same as, partially shared with, or completely independent of those that cause progression from use to abuse. Comparison of rates of progression among the cotwins of twins who do vs. do not initiate provides indirect information about the relationship between initiation and progression. Existing models for this relationship have been difficult to extend because they are usually expressed in terms of explicit integrals. In this paper, the problem is overcome by regarding the analysis of twin data on initiation and progression as a special case of missing data, in which individuals who do not initiate are regarded as having missing data on progression measures. Using the general framework for the analysis of ordinal data with missing values available in Mx makes extensions that include other variables much easier. The effects of continuous covariates such as age on initiation and progression becomes simple. Also facilitated are the examination of initiation and progression in two or more substances, and transition models with two or more steps. The methods are illustrated with data on the effects of cohort on liability to cannabis use and abuse, bivariate analysis of tobacco use and dependence and cannabis use and abuse, and the relationships between initiation of smoking, regular smoking and nicotine dependence. Other suitable applications include the relationship between symptoms and diagnosis, such as fears and the progression to phobia.

Genetic and environmental causes of tracking in explosive strength during adolescence.

PURPOSE: To determine whether the observed phenotypic stability in explosive strength during adolescence, as measured by inter-age correlations in vertical jump (VTJ), is mainly caused by genetic and/or environmental factors. METHODS: Subjects are from the Leuven Longitudinal Twin Study (LLTS) (n = 105 pairs, equally divided over five zygosity groups). VTJ data were aligned on age at peak height velocity (APHV) to attenuate the temporal fluctuations in inter-age correlations caused by differences in timing of the adolescent growth spurt. Simplex models were fitted using structural equation modelling. RESULTS: After aligning the data on APHV, the annual inter-age correlations show a clear simplex structure over a 4 year interval. The best fitting models included additive genetic and unique environmental sources of variation. Heritability estimates ranged between 60.8% (CI 37.7%-77.2%) and 87.3% (CI 74.2%-94.0%) for boys and between 76.5% (CI 56.7%-89.0%) and 88.6% (CI 77.8%-94.1%) for girls. Up to 56.4% and 62.8% of the total variation at the last measurement occasion is explained by additive genetic factors that already explained a significant amount of variation at previous measurement occasions in boys and girls respectively. It thus can be concluded that the observed stability of explosive strength during adolescence is mainly caused by a stable genetic influence in boys and girls. CONCLUSIONS: Additive genetic factors seem to be the main cause of the observed phenotypic stability in VTJ performance in boys and girls during adolescence.

Exploration of myostatin polymorphisms and the angiotensin-converting enzyme insertion/deletion genotype in responses of human muscle to strength training.

This study explores the associations between polymorphisms in two candidate genes-myostatin gene (MSTN or GDF8) and angiotensin-converting enzyme (ACE) gene-with interindividual differences in human muscle mass and strength responses to strength training. The MSTN AluI A55T (exon 1), BanII K153R, TaqI E164 K and BstNI P198A (all in exon 2) markers and the ACE insertion (I)/deletion (D) polymorphism were typed in 57 males [22.4 (3.7) years] who participated in a 10-week, high-resistance training program for the elbow flexors. Maximal strength, and maximal isometric and concentric elbow flexor torques were measured at baseline and after training. Information on muscle cross-sectional area of the upper arm was obtained by computer tomography scans. Only one individual was heterozygous for the MSTN BanII K153R variant. No allelic variant was detected at the other MSTN sites in this population. For the ACE I/D polymorphism, no evidence was found for an association of the D or I allele with baseline strength, isometric and concentric torque or arm muscle cross-sectional area [analysis of covariance (ANCOVA) 0.25< P<0.97]. Responses to the strength-training program were not associated with the ACE I/D genotype (ANCOVA 0.057< P<0.70). Borderline significance was found for larger strength gains in dynamic flexion torques for I/I genotypes. This study therefore does not support the hypothesis that an increased muscle fiber hypertrophic effect of strength training is present in D-allele carriers.