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Genotype-by-environment interaction (GxE) studies probe heterogeneity in response to risk factors or interventions. Popular methods for estimation of GxE examine multiplicative interactions between individual genetic and environmental measures. However, risk factors and interventions may modulate the total variance of an epidemiological outcome that itself represents the aggregation of many other etiological components. We expand the traditional GxE model to directly model genetic and environmental moderation of the dispersion of the outcome. We derive a test statistic, [xi], for inferring whether an interaction identified between individual genetic and environmental measures represents a more general pattern of moderation of the total variance in the phenotype by either the genetic or the environmental measure. We validate our method via extensive simulation, and apply it to investigate genotype-by-birth year interactions for Body Mass Index (BMI) with polygenic scores in the Health and Retirement Study (N = 11,586) and individual genetic variants in the UK Biobank (N = 380,605). We find that changes in the penetrance of a genome-wide polygenic score for BMI across birth year are partly representative of a more general pattern of expanding BMI variation across generations. Three individual variants found to be more strongly associated with BMI among later born individuals, were also associated with the magnitude of variability in BMI itself within any given birth year, suggesting that they may confer general sensitivity of BMI to a range of unmeasured factors beyond those captured by birth year. We introduce an expanded GxE regression model that explicitly models genetic and environmental moderation of the dispersion of the outcome under study. This approach can determine whether GxE interactions identified are specific to the measured predictors or represent a more general pattern of moderation of the total variance in the outcome by the genetic and environmental measures.

Interest in the study of gene-environment interaction has recently grown due to the sudden availability of molecular genetic data--in particular, polygenic scores--in many long-running longitudinal studies. Identifying and estimating statistical interactions comes with several analytic and inferential challenges; these challenges are heightened when used to integrate observational genomic and social science data. We articulate some of these key challenges, provide new perspectives on the study of gene-environment interactions, and end by offering some practical guidance for conducting research in this area. Given the sudden availability of well-powered polygenic scores, we anticipate a substantial increase in research testing for interaction between such scores and environments. The issues we discuss, if not properly addressed, may impact the enduring scientific value of gene-environment interaction studies.

Dysregulation of biological stress response, as measured by cortisol output, has been a primary candidate mechanism for how social experiences become biologically embedded. Cortisol is the primary output of the hypothalamic pituitary adrenal (HPA) axis. Cortisol levels vary systematically across the day and change in response to both sudden, acute stress experiences as well as prolonged exposure to environmental stress. Using data from 8- to 15-year-old twins in the Texas Twin Project, we investigate the extent to which genetic influences are shared across different measures of cortisol output: chronic cortisol accumulations in hair (n = 1,104), diurnal variation in salivary output (n = 488), and salivary response to a standardized, acute in-laboratory stressor (n = 537). Multivariate twin models indicate that genetic factors regulating cortisol response to the in-laboratory stressor are separable from those regulating baseline cortisol levels, naturally occurring diurnal variation in cortisol, and hair cortisol levels. These findings illustrate that novel environments can reveal unique genetic variation, reordering people in terms of their observed phenotype rather than only magnifying or mitigating preexisting differences.

Cognitive performance is both heritable and sensitive to environmental inputs and sustained practice over time. However, it is currently unclear how genetic effects on cognitive performance change over the course of learning. We examine how polygenic scores (PGS) created from genome-wide association studies of educational attainment and cognitive performance are related to improvements in performance across nine cognitive tests (measuring perceptual speed, working memory, and episodic memory) administered to 131 adults (N = 51, ages = 20-31, and N = 80, ages = 65-80 years) repeatedly across 100 days. We observe that PGS associations with performance on a given task can change over the course of learning, with the specific pattern of change in associations differing across tasks. PGS correlations with pre-test to post-test scores may mask variability in how soon learning occurs over the course of practice. The associations between PGS and learning do not appear to simply reconstitute patterns of association between baseline performance and subsequent learning. Associations involving PGSs, however, were small with large confidence intervals. Intensive longitudinal research such as that described here may be of substantial value for clarifying the genetics of learning when implemented as far larger scale.

Maximizing the flow of students through the science, technology, engineering, and math (STEM) pipeline is important to promoting human capital development and reducing economic inequality. A critical juncture in the STEM pipeline is the highly cumulative sequence of secondary school math courses. Students from disadvantaged schools are less likely to complete advanced math courses. Here, we conduct an analysis of how the math pipeline differs across schools using student "polygenic scores," which are DNA-based indicators of propensity to succeed in education. We integrated genetic and official school transcript data from over 3000 European-ancestry students from U.S. high schools. We used polygenic scores as a molecular tracer to understand how the flow of students through the high school math pipeline differs in socioeconomically advantaged versus disadvantaged schools. Students with higher education polygenic scores were tracked to more advanced math already at the beginning of high school and persisted in math for more years. Analyses using genetics as a molecular tracer revealed that the dynamics of the math pipeline differed by school advantage. Compared to disadvantaged schools, advantaged schools buffered students with low polygenic scores from dropping out of math. Across all schools, even students with exceptional polygenic scores (top 2%) were unlikely to take the most advanced math classes, suggesting substantial room for improvement in the development of potential STEM talent. These results link new molecular genetic discoveries to a common target of educational-policy reforms.

Performance in everyday spatial orientation tasks (e.g., map reading and navigation) has been considered functionally separate from performance on more abstract object-based spatial abilities (e.g., mental rotation and visualization). However, few studies have examined the link between spatial orientation and object-based spatial skills, and even fewer have done so including a wide range of spatial tests. To examine this issue and more generally to test the structure of spatial ability, we used a novel gamified battery to assess six tests of spatial orientation in a virtual environment and examined their association with ten object-based spatial tests, as well as their links to general cognitive ability (g). We further estimated the role of genetic and environmental factors in underlying variation and covariation in these spatial tests. Participants (N = 2660; aged 19-22) were part of the Twins Early Development Study. The six tests of spatial orientation clustered into a single 'Navigation' factor that was 64% heritable. Examining the structure of spatial ability across all 16 tests, three, substantially correlated, factors emerged: "Navigation, Object Manipulation," and "Visualization." These, in turn, loaded strongly onto a general factor of Spatial Ability, which was highly heritable (84%). A large portion (45%) of this high heritability was independent of g. The results point towards the existence of a common genetic network that supports all spatial abilities.

Behavioral and molecular genetic research has established that child cognitive ability and academic performance are substantially heritable, but genetic variation does not account for all of the stratification of cognitive and academic outcomes across families. Which specific contexts and experiences contribute to these "shared environmental" influences on cognitive ability and academic achievement? Using an ethnically and socioeconomically diverse sample of N = 1728 twins ages 7-20 from the Texas Twin Project, we identified specific measured family, school, and neighborhood socioecological contexts that statistically accounted for latent shared environmental variance in cognitive abilities and academic skills. Composite measures of parent socioeconomic status (SES), school demographic composition, and neighborhood SES accounted for moderate proportions of variation in IQ and achievement. Total variance explained by the multilevel contexts ranged from 15% to 22%. The influence of family SES on IQ and achievement overlapped substantially with the influence of school and neighborhood predictors. Together with race, the measured socioecological contexts explained 100% of shared environmental influences on IQ and approximately 79% of shared environmental influences on both verbal comprehension and reading ability. In contrast, nontrivial proportions of shared environmental variation in math performance were left unexplained. We highlight the potential utility of constructing "polyenvironmental risk scores" in an effort to better predict developmental outcomes and to quantify children's and adolescents' interrelated networks of experiences. A video abstract of this article can be viewed at: https://youtu.be/77E_DctFsr0

Symptoms of anxiety and depression are commonly comorbid and partially share a genetic etiology. Mean levels of anxiety and depression increase over the transition to adolescence, particularly in girls, suggesting a possible role of pubertal development in the activation of underlying genetic risks. The current study examined how genetic and environmental influences on anxiety and depression differed by chronological age and pubertal status. We analyzed composite scores from child self-reports and parent informant-reports of internalizing symptomology in a racially and socioeconomically diverse sample of 1,913 individual twins from 1,006 pairs (ages 8--20 years) from the Texas Twin Project. Biometric models tested age and pubertal status as moderators of genetic and environmental influences shared between and specific to anxiety and depression to determine whether etiology of internalizing symptomology differs across development as a function of age or puberty. Genetic influences did not increase as a function of age or puberty, but instead shared environmental effects decreased with age. In an exploratory model that considered the moderators simultaneously, developmental differences in etiology were reflected in genetic and environmental effects unique to depression. Results suggest that genetic variance in internalizing problems is relatively constant during adolescence, with environmental influences more varied across development.

This study explores the co-development of two related but separate reading skills, reading fluency and reading comprehension, across Grades 1-4. A bivariate biometric dual change score model was applied to longitudinal data collected from 1,784 twin pairs between the ages of 6 and 10 years. Grade 1 skills were influenced by highly overlapping genetic and environmental factors. Growth in both skills was influenced by highly overlapping shared environmental factors. Cross-lagged parameters indicated bidirectional effects, with stronger effects from fluency to comprehension change than from comprehension to fluency change.

Parents' expectations for their children's ultimate educational attainment have been hypothesized to play an instrumental role in socializing academically relevant child behaviors, beliefs, and abilities. In addition to social transmission of educationally relevant values from parents to children, parental expectations and child characteristics may transact bidirectionally. We explore this hypothesis using both longitudinal and genetically informative twin data from the Early Childhood Longitudinal Study--Birth and Kindergarten cohorts. Our behavior genetic results indicate that parental expectations partly reflect child genetic variation, even as early as 4 years of age. Two classes of child characteristics were hypothesized to contribute to these child-to-parent effects: behavioral tendencies (approaches toward learning and problem behaviors) and achievement (math and reading). Using behavior genetic models, we find within-twin-pair associations between these child characteristics and parental expectations. Using longitudinal cross-lagged models, we find that initial variation in child characteristics predicts future educational expectations above and beyond previous educational expectations. These results are consistent with transactional frameworks in which parent-to-child and child-to-parent effects co-occur.

Aging-related declines occur in many different domains of cognitive function during middle and late adulthood. However, whether a global dimension underlies individual differences in changes in different domains of cognition and whether global genetic influences on cognitive changes exist is less clear. We addressed these issues by applying multivariate growth curve models to longitudinal data from 857 individuals from the Swedish Adoption/Twin Study of Aging, who had been measured on 11 cognitive variables representative of verbal, spatial, memory, and processing speed abilities up to 5 times over up to 16 years between ages 50 and 96 years. Between ages 50 and 65 years scores on different tests changed relatively independently of one another, and there was little evidence for strong underlying dimensions of change. In contrast, over the period between 65 and 96 years of age, there were strong interrelations among rates of change both within and across domains. During this age period, variability in rates of change were, on average, 52% domain-general, 8% domain-specific, and 39% test-specific. Quantitative genetic decomposition indicated that 29% of individual differences in a global domain-general dimension of cognitive changes during this age period were attributable to genetic influences, but some domain-specific genetic influences were also evident, even after accounting for domain-general contributions. These findings are consistent with a balanced global and domain-specific account of the genetics of cognitive aging.

Background: Preschool involves an array of new social experiences that may impact the development of early externalizing behavior problems over the transition to grade school. Methods: Using longitudinal data from a nationally representative sample of over 600 pairs of US twins, we tested whether the genetic and environmental influences on externalizing problems differed between children who did versus did not attend preschool. Results: At age 4, the genetic and environmental etiology of externalizing did not differ by preschool attendance. In contrast, by age 5 years (kindergarten age), the genetic and environmental etiology of externalizing significantly differed by preschool attendance. Among children who did not attend preschool, externalizing at age 5 was predominantly due to environmental influences (52% shared environment, 34% non-shared environment) rather than genetic differences (13%), whereas among children who had attended preschool, externalizing at age 5 was primarily due to genes (67%), and shared environmental influences were negligible (0%). These interactions represented the differential longitudinal persistence of genes and environments that contributed to externalizing at age 4. Sensitivity analyses ruled out confounding due to early mental ability, socioeconomic status, minority status, child age, and prior history of childcare. Conclusions: These results indicate that preschool enrollment is associated with increased genetic and decreased shared environmental influences on the development of early externalizing behavior problems. (Contains 1 table, 3 figures, and 2 footnotes.)

Parenting is traditionally conceptualized as an exogenous environment that affects child development. However, children can also influence the quality of parenting that they receive. Using longitudinal data from 650 identical and fraternal twin pairs, we found that, controlling for cognitive ability at age 2 years, cognitive stimulation by parents (coded from video recorded behaviors during a dyadic task) at 2 years predicted subsequent reading ability at age 4 years. Moreover, controlling for cognitive stimulation at 2 years, children's cognitive ability at 2 years predicted the quality of stimulation received from their parents at 4 years. Genetic and environmental factors differentially contributed to these effects. Parenting influenced subsequent cognitive development through a family-level environmental pathway, whereas children's cognitive ability influenced subsequent parenting through a genetic pathway. These results suggest that genetic influences on cognitive development occur through a transactional process, in which genetic predispositions lead children to evoke cognitively stimulating experiences from their environments.

There is accumulating evidence that genetic influences on achievement are more pronounced among children living in higher socioeconomic status homes, and that these gene-by-environment interactions occur prior to children's entry into formal schooling. We hypothesized that one pathway through which socioeconomic status promotes genetic influences on early achievement is by facilitating the processes by which children select, evoke, and attend to learning experiences that are consistent with genetically influenced individual differences in their motivation to learn. We examined this hypothesis in a nationally representative sample of approximately 650 pairs of four-year old identical and fraternal twins who were administered a measure of math achievement, and rated by their parents on a broad set of items assessing learning motivation. Results indicated a genetic link between learning motivation and math achievement that varied positively with family socioeconomic status: Genetic differences in learning motivation contributed to math achievement more strongly in more advantaged homes. Once this effect of learning motivation was controlled for, gene-by-socioeconomic status interaction on math achievement was reduced from previously significant levels, to nonsignificant levels. (Contains 4 figures and 4 tables.)

Recent studies have demonstrated that genetic influences on cognitive ability and academic achievement are larger for children raised in higher socioeconomic status (SES) homes. However, little work has been done to document the psychosocial processes that underlie this Gene x Environment interaction. One process may involve the conversion of intellectual interest into academic achievement. Analyses of data from 777 pairs of 17-year-old twins indicated that Gene x SES effects on achievement scores can be accounted for by stronger influences of genes for intellectual interest on achievement at higher levels of SES. These findings are consistent with the hypothesis that higher SES affords greater opportunity for children to seek out and benefit from learning experiences that are congruent with their genetically influenced intellectual interests.

Sensation seeking is associated with an increased propensity for delinquency, and emerging research on personality change suggests that mean levels of sensation seeking increase substantially from childhood to adolescence. The current study tested whether individual differences in the rate of change of sensation seeking predicted within-person change in delinquent behavior and whether genetically influenced differences in rate of personality change accounted for this association. Sensation seeking and delinquent behavior were assessed biennially between ages 10-11 and 16-17 in a nationally representative sample of 7675 youths from the National Longitudinal Study of Youth: Children and Young Adults (CNLSY). Analyses using latent growth curve modeling found that within-person change in sensation seeking was significantly and positively correlated with within-person change in delinquency from childhood to adolescence. Furthermore, behavioral genetic analyses of a subset of 2562 sibling pairs indicated that there were substantial genetic influences on both initial levels of sensation seeking and change in sensation seeking during early adolescence, with over 80% of individual differences in change due to genetic factors. Finally, these genetically driven increases in sensation seeking were most important for predicting increases in delinquency, whereas environmental paths between sensation seeking and delinquency were not significant. These results suggest that developmental changes in delinquent behaviors during adolescence are driven by a genetically governed process of personality change. (Contains 2 tables, 6 figures, and 1 footnote.)

Genetic liability to substance use disorders can be parsed into loci that confer general or substance-specific addiction risk. We report a multivariate genome-wide association meta-analysis that disaggregates general and substance-specific loci for published summary statistics of problematic alcohol use, problematic tobacco use, cannabis use disorder, and opioid use disorder in a sample of 1,025,550 individuals of European descent and 92,630 individuals of African descent. Nineteen independent SNPs were genome-wide significant (P < 5e-8) for the general addiction risk factor (addiction-rf), which showed high polygenicity. Across ancestries, PDE4B was significant (among other genes), suggesting dopamine regulation as a cross-substance vulnerability. An addiction-rf polygenic risk score was associated with substance use disorders, psychopathologies, somatic conditions, and environments associated with the onset of addictions. Substance-specific loci (9 for alcohol, 32 for tobacco, 5 for cannabis, 1 for opioids) included metabolic and receptor genes. These findings provide insight into genetic risk loci for substance use disorders that could be leveraged as treatment targets.

Understanding which biological pathways are specific versus general across diagnostic categories and levels of symptom severity is critical to improving nosology and treatment of psychopathology. Here, we combine transdiagnostic and dimensional approaches to genetic discovery for the first time, conducting a novel multivariate genome-wide association study of eight psychiatric symptoms and disorders broadly related to mood disturbance and psychosis. We identify two transdiagnostic genetic liabilities that distinguish between common forms of psychopathology versus rarer forms of serious mental illness. Biological annotation revealed divergent genetic architectures that differentially implicated prenatal neurodevelopment and neuronal function and regulation. These findings inform psychiatric nosology and biological models of psychopathology, as they suggest that the severity of mood and psychotic symptoms present in serious mental illness may reflect a difference in kind rather than merely in degree.

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.

Behaviors and disorders related to self-regulation, such as substance use, antisocial behavior and attention-deficit/hyperactivity disorder, are collectively referred to as externalizing and have shared genetic liability. We applied a multivariate approach that leverages genetic correlations among externalizing traits for genome-wide association analyses. By pooling data from ~1.5 million people, our approach is statistically more powerful than single-trait analyses and identifies more than 500 genetic loci. The loci were enriched for genes expressed in the brain and related to nervous system development. A polygenic score constructed from our results predicts a range of behavioral and medical outcomes that were not part of genome-wide analyses, including traits that until now lacked well-performing polygenic scores, such as opioid use disorder, suicide, HIV infections, criminal convictions and unemployment. Our findings are consistent with the idea that persistent difficulties in self-regulation can be conceptualized as a neurodevelopmental trait with complex and far-reaching social and health correlates.

Genetic factors explain a major proportion of human height variation, but differences in mean stature have also been found between socio-economic categories suggesting a possible effect of environment. By utilizing a classical twin design which allows decomposing the variation of height into genetic and environmental components, we tested the hypothesis that environmental variation in height is greater in offspring of lower educated parents. Twin data from 29 cohorts including 65,978 complete twin pairs with information on height at ages 1 to 69 years and on parental education were pooled allowing the analyses at different ages and in three geographic-cultural regions (Europe, North America and Australia, and East Asia). Parental education mostly showed a positive association with offspring height, with significant associations in mid-childhood and from adolescence onwards. In variance decomposition modeling, the genetic and environmental variance components of height did not show a consistent relation to parental education. A random-effects meta-regression analysis of the aggregate-level data showed a trend towards greater shared environmental variation of height in low parental education families. In conclusion, in our very large dataset from twin cohorts around the globe, these results provide only weak evidence for the study hypothesis.

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.