Birmingham and Beyond.

Nick Martin was a doctoral student of mine at the University of Birmingham in the mid 1970s. In this review, I discuss two of Nick's earliest and most seminal contributions to the field of behavior genetics. First, Martin and Eaves' (1977) extension of the model-fitting approach to multivariate data, which laid the theoretical groundwork for a generation of multivariate behavior genetic studies. Second, the Martin et al.'s (1978) manuscript on the power of the classical twin design, which showed that thousands of twin pairs would be required in order to reliably estimate components of variance, and has served as impetus for the formation of large-scale twin registries across the world. I discuss these contributions against the historical backdrop of a time when we and others were struggling with the challenge of figuring out how to incorporate gene-by-environment interaction, gene-environment correlation, mate selection and cultural transmission into more complex genetic models of human behavior.

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.

Extended Twin Study of Alcohol Use in Virginia and Australia.

Drinking alcohol is a normal behavior in many societies, and prior studies have demonstrated it has both genetic and environmental sources of variation. Using two very large samples of twins and their first-degree relatives (Australia ≈ 20,000 individuals from 8,019 families; Virginia ≈ 23,000 from 6,042 families), we examine whether there are differences: (1) in the genetic and environmental factors that influence four interrelated drinking behaviors (quantity, frequency, age of initiation, and number of drinks in the last week), (2) between the twin-only design and the extended twin design, and (3) the Australian and Virginia samples. We find that while drinking behaviors are interrelated, there are substantial differences in the genetic and environmental architectures across phenotypes. Specifically, drinking quantity, frequency, and number of drinks in the past week have large broad genetic variance components, and smaller but significant environmental variance components, while age of onset is driven exclusively by environmental factors. Further, the twin-only design and the extended twin design come to similar conclusions regarding broad-sense heritability and environmental transmission, but the extended twin models provide a more nuanced perspective. Finally, we find a high level of similarity between the Australian and Virginian samples, especially for the genetic factors. The observed differences, when present, tend to be at the environmental level. Implications for the extended twin model and future directions are discussed.

Cross-Cultural Comparison of Genetic and Cultural Transmission of Smoking Initiation Using an Extended Twin Kinship Model.

BACKGROUND: Considerable evidence from twin and adoption studies indicates that genetic and shared environmental factors play a role in the initiation of smoking behavior. Although twin and adoption designs are powerful to detect genetic and environmental influences, they do not provide information on the processes of assortative mating and parent-offspring transmission and their contribution to the variability explained by genetic and/or environmental factors. METHODS: We examined the role of genetic and environmental factors in individual differences for smoking initiation (SI) using an extended kinship design. This design allows the simultaneous testing of additive and non-additive genetic, shared and individual-specific environmental factors, as well as sex differences in the expression of genes and environment in the presence of assortative mating and combined genetic and cultural transmission, while also estimating the regression of the prevalence of SI on age. A dichotomous lifetime 'ever' smoking measure was obtained from twins and relatives in the 'Virginia 30,000' sample and the 'Australian 25,000'. RESULTS: Results demonstrate that both genetic and environmental factors play a significant role in the liability to SI. Major influences on individual differences appeared to be additive genetic and unique environmental effects, with smaller contributions from assortative mating, shared sibling environment, twin environment, cultural transmission, and resulting genotype-environment covariance. Age regression of the prevalence of SI was significant. The finding of negative cultural transmission without dominance led us to investigate more closely two possible mechanisms for the lower parent-offspring correlations compared to the sibling and DZ twin correlations in subsets of the data: (1) age × gene interaction, and (2) social homogamy. Neither of the mechanism provided a significantly better explanation of the data. CONCLUSIONS: This study showed significant heritability, partly due to assortment, and significant effects of primarily non-parental shared environment on liability to SI.

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.

Genotype × Environment Interaction in Psychiatric Genetics: Deep Truth or Thin Ice?

BACKGROUND: There continues to be significant investment in the detection of genotype × environment interaction (G × E) in psychiatric genetics. The implications of the method of assessment for the genetic analysis of psychiatric disorders are examined for simulated twin data on symptom scores and environmental covariates. METHODS: Additive and independent genetic and environmental risks were simulated for 10,000 monozygotic (MZ) and 10,000 dizygotic (DZ) twin pairs and the 'subjects' administered typical simulated checklists of clinical symptoms and environmental factors. A variety of standard tests for G × E were applied to the simulated additive risk scores, sum scores derived from the checklists and transformed sum scores. RESULTS: All analyses revealed no evidence for G × E for latent risk but marked evidence for G × E and other effects of modulation in the sum scores. These effects were all removed by transformation. An integrated genetic and psychometric model, accounting for both the causes of latent liability and a theory of measurement, was fitted to a sample of the simulated sum-score data and showed that there was no significant modulation of the parameters of the genetic model by environmental covariates (i.e., no G × E). CONCLUSIONS: Claims to detect G × E based on analytical methods that ignore the theory of measurement must be subjected to greater scrutiny prior to publication.

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.

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.

Comparison of Twin and Extended Pedigree Designs for Obtaining Heritability Estimates.

This study explores power assumptions relating to extended pedigree designs (EPD) and classical twin designs (CTD). We conducted statistical analyses to compare the power of the two designs for examining neuroimaging phenotypes, varying heritability and varying whether shared environmental variance is fixed or free. Results indicated that CTDs have more power to estimate heritability, with the exception of one condition: in EPDs, the power increases relative to CTDs when shared environmental variance contributes to sibling similarity only. We additionally show that assuming a priori that shared environmental effects play no role in a phenotype-as is commonly done in pedigree designs-can lead to substantially biased heritability estimates. General results indicate that both CTDs and EPDs obtain quite precise heritability estimates. Finally, we discuss methodological considerations relating to assumptions about age effects and shared environment.

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.

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.

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.

Problems and pit-falls in testing for G × E and epistasis in candidate gene studies of human behavior.

Conclusions about the genetic architecture of a phenotype relating to the contributions of genetic additivity, dominance, epistasis or genotype × environment interaction, depend upon the statistical and distributional properties of the measured trait. This dependence is frequently ignored in contemporary genetic studies and can radically change the conclusions that may be drawn from the data. The interdependence of the conclusions about genetic architecture and instruments used for behavioral measurement is explored by simulated studies of the interaction between candidate genes and measured environment in psychiatric genetics. Trait values are simulated (N = 100,000) under several commonly encountered scenarios and subjected to two simulated 20-item psychological tests each comprising items with different patterns of difficulty and sensitivity to variation (discriminating power) in the latent trait. Test scores are generated for each test by summing the binary responses across all items. The full model for digenic additive and non-additive genetic effects and G × E is fitted to the trait values and test scores under a range of different simulated genetic architectures. Untransformed test scores show complex patterns of epistasis and G × E even when the underlying effects of genes and environment are purely additive and the transformation of symptom counts does not fully recover the simulated underlying genetic architecture. Accordingly, failing to allow for the theory of measurement when analyzing details of genetic architecture may frequently lead to replicable over-reporting of interactions and mislead potential investigators and funding agencies.

Moderating the covariance between family member's substance use behavior.

Twin and family studies implicitly assume that the covariation between family members remains constant across differences in age between the members of the family. However, age-specificity in gene expression for shared environmental factors could generate higher correlations between family members who are more similar in age. Cohort effects (cohort × genotype or cohort × common environment) could have the same effects, and both potentially reduce effect sizes estimated in genome-wide association studies where the subjects are heterogeneous in age. In this paper we describe a model in which the covariance between twins and non-twin siblings is moderated as a function of age difference. We describe the details of the model and simulate data using a variety of different parameter values to demonstrate that model fitting returns unbiased parameter estimates. Power analyses are then conducted to estimate the sample sizes required to detect the effects of moderation in a design of twins and siblings. Finally, the model is applied to data on cigarette smoking. We find that (1) the model effectively recovers the simulated parameters, (2) the power is relatively low and therefore requires large sample sizes before small to moderate effect sizes can be found reliably, and (3) the genetic covariance between siblings for smoking behavior decays very rapidly. Result 3 implies that, e.g., genome-wide studies of smoking behavior that use individuals assessed at different ages, or belonging to different birth-year cohorts may have had substantially reduced power to detect effects of genotype on cigarette use. It also implies that significant special twin environmental effects can be explained by age-moderation in some cases. This effect likely contributes to the missing heritability paradox.

Resolving the effects of maternal and offspring genotype on dyadic outcomes in genome wide complex trait analysis ("M-GCTA").

Genome wide complex trait analysis (GCTA) is extended to include environmental effects of the maternal genotype on offspring phenotype ("maternal effects", M-GCTA). The model includes parameters for the direct effects of the offspring genotype, maternal effects and the covariance between direct and maternal effects. Analysis of simulated data, conducted in OpenMx, confirmed that model parameters could be recovered by full information maximum likelihood (FIML) and evaluated the biases that arise in conventional GCTA when indirect genetic effects are ignored. Estimates derived from FIML in OpenMx showed very close agreement to those obtained by restricted maximum likelihood using the published algorithm for GCTA. The method was also applied to illustrative perinatal phenotypes from ~4,000 mother-offspring pairs from the Avon Longitudinal Study of Parents and Children. The relative merits of extended GCTA in contrast to quantitative genetic approaches based on analyzing the phenotypic covariance structure of kinships are considered.

Genetic influences on political ideologies: twin analyses of 19 measures of political ideologies from five democracies and genome-wide findings from three populations.

Almost 40 years ago, evidence from large studies of adult twins and their relatives suggested that between 30 and 60% of the variance in social and political attitudes could be explained by genetic influences. However, these findings have not been widely accepted or incorporated into the dominant paradigms that explain the etiology of political ideology. This has been attributed in part to measurement and sample limitations, as well the relative absence of molecular genetic studies. Here we present results from original analyses of a combined sample of over 12,000 twins pairs, ascertained from nine different studies conducted in five democracies, sampled over the course of four decades. We provide evidence that genetic factors play a role in the formation of political ideology, regardless of how ideology is measured, the era, or the population sampled. The only exception is a question that explicitly uses the phrase "Left-Right". We then present results from one of the first genome-wide association studies on political ideology using data from three samples: a 1990 Australian sample involving 6,894 individuals from 3,516 families; a 2008 Australian sample of 1,160 related individuals from 635 families and a 2010 Swedish sample involving 3,334 individuals from 2,607 families. No polymorphisms reached genome-wide significance in the meta-analysis. The combined evidence suggests that political ideology constitutes a fundamental aspect of one's genetically informed psychological disposition, but as Fisher proposed long ago, genetic influences on complex traits will be composed of thousands of markers of very small effects and it will require extremely large samples to have enough power in order to identify specific polymorphisms related to complex social traits.

The contribution of genetic and environmental factors to the duration of pregnancy.

This review describes how improvements in biometric-genetic studies of twin kinships, half-sibships, and cousinships have now demonstrated a sizeable fetal genetic and maternal genetic contribution to the spontaneous onset of labor. This is an important development because previous literature for the most part reports only an influence of the maternal genome. Current estimates of the percent of variation that is attributable to fetal genetic factors range from 11-35%; the range for the maternal genetic contribution is 13-20%. These same studies demonstrate an even larger influence of environmental sources over and above the influence of genetic sources and previously identified environmental risk factors. With these estimates in hand, a major goal for research on pregnancy duration is to identify specific allelic variation and environmental risk to account for this estimated genetic and environmental variation. A review of the current literature can serve as a guide for future research efforts.

Genetic influences on dietary variety - results from a twin study.

The heritability of variety seeking in the food domain was estimated from a large sample (N = 5,543) of middle age to elderly monozygotic and dizygotic twins from the "Virginia 30,000" twin study. Different dietary variety scores were calculated based on a semi-quantitative food choice questionnaire that assessed consumption frequencies and quantities for a list of 99 common foods. Results indicate that up to 30% of the observed variance in dietary variety was explained through heritable influences. Most of the differences between twins were due to environmental influences that are not shared between twins. Additional non-genetic analyses further revealed a weak relationship between dietary variety and particular demographic variables, including socioeconomic status, age, sex, religious faith, and the number of people living in the same household.

Fetal and maternal genes' influence on gestational age in a quantitative genetic analysis of 244,000 Swedish births.

Although there is increasing evidence that genetic factors influence gestational age, it is unclear to what extent this is due to fetal and/or maternal genes. In this study, we apply a novel analytical model to estimate genetic and environmental contributions to pregnancy history records obtained from 165,952 Swedish families consisting of offspring of twins, full siblings, and half-siblings (1987-2008). Results indicated that fetal genetic factors explained 13.1% (95% confidence interval (CI): 6.8, 19.4) of the variation in gestational age at delivery, while maternal genetic factors accounted for 20.6% (95% CI: 18.1, 23.2). The largest contribution to differences in the timing of birth were environmental factors, of which 10.1% (95% CI: 7.0, 13.2) was due to factors shared by births of the same mother, and 56.2% (95% CI: 53.0, 59.4) was pregnancy specific. Similar models fit to the same data dichotomized at clinically meaningful thresholds (e.g., preterm birth) resulted in less stable parameter estimates, but the collective results supported a model of homogeneous genetic and environmental effects across the range of gestational age. Since environmental factors explained most differences in the timing of birth, genetic studies may benefit from understanding the specific effect of fetal and maternal genes in the context of these yet-unidentified factors.

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.