Tom A. McAdams

Polygenic associations with neurodevelopmental traits may reflect both direct and indirect genetic effects. However, evidence separating these effects is limited and mixed, and rarely spans development or reporters, or triangulates across methods. We triangulated twin-comparison and trio-based analyses in the Twins Early Development Study, using eight polygenic scores (PGS) and repeated parent, teacher and self-reports of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) traits from ages 4 to 26. Analyses included up to 7,259 offspring with observed or imputed parental genetic data. Both approaches consistently supported direct genetic effects of ADHD and ASD PGS on corresponding traits, whereas evidence for within-trait indirect effects was limited. Cross-trait indirect effects emerged for several PGS, particularly in parent reports, and some were unexpectedly negative. These findings suggest that within-trait polygenic prediction of ADHD and ASD traits mainly reflects direct rather than indirect genetic effects, whereas cross-trait associations reflect some indirect genetic effects.

Background: ADHD has been associated with BMI, across the lifespan. A possible mechanism linking ADHD and BMI is binge eating symptoms. Previous research has found associations between ADHD, binge eating symptoms, and BMI. However, the role of genetic and environmental influences on these associations remains unclear. Method: We utilized data from the Twins Early Development Study, comprising 4,363 monozygotic and 8,575 dizygotic twin pairs. ADHD symptoms in childhood and adolescence were assessed using parent-reported questionnaires. Adult ADHD symptoms were measured using both self-report and parent-report questionnaires. Phenotypic mediation models examined whether binge eating symptoms mediated the association between ADHD and BMI, without controlling for genetic confounding. Subsequently, the etiological architecture underlying the associations among the three traits across childhood, adolescence, and adulthood were investigated by incorporating genetic and environmental influences into the models. Results: Binge eating symptoms significantly mediated the association between ADHD symptoms and BMI in both adolescence and adulthood. However, these mediation effects were no longer present once genetic and environmental influences were incorporated into the models. The best-fitting model in childhood, adolescence, and adulthood was Cholesky decomposition models, where covariance between traits was explained by shared etiology. Conclusions: This twin study reveals shared liability across ADHD, binge eating symptoms, and BMI. The mediating role of binge eating symptoms in the relationship between ADHD symptoms and BMI was largely confounded by shared genetic influences. Intervention strategies could focus more on common underlying behavioral and self-regulatory mechanisms across these traits, as well as placing more emphasis on symptom patterns within families.

Importance Adverse childhood experiences are associated with later severe mental health conditions, but the extent to which these associations reflect a causal effect of adversity rather than confounding remains unclear. Objective To test whether within-twin-pair differences in reported adverse childhood experiences predict differences in severe mental health conditions in early adulthood, and to decompose covariation between adverse childhood experiences and severe mental health conditions into genetic and environmental components.Design Setting and Participants This study used data from the Twins Early Development Study, a population-based cohort of twins born in England and Wales (1994-1996), with assessments at ages 12, 14, 16, 21, and 26. Within-twin-pair regression and bivariate biometric twin models were used to distinguish potential causal effects from familial confounding.Exposures Childhood maltreatment (abuse and neglect, retrospective, ages 21 and 26) and peer victimization (bullying, prospective, ages 12, 14, 16).Main Outcomes and Measures Seventeen measures of severe mental health conditions spanning psychosis-spectrum symptoms, (hypo)manic symptoms, self-harm and suicidal behaviour, and reported diagnoses.Results Outcomes were assessed at ages 21 (13,794 individuals) and 26 (11,436 individuals). After false discovery rate correction, childhood maltreatment was associated with all 17 outcomes at the population level and peer victimization with 16. Monozygotic within-pair models were estimable for 14 outcomes. All 14 maltreatment associations remained significant, with pooled symptom estimates attenuating by 21% (0.30 to 0.24) and pooled odds ratios of 1.85 vs 1.95 at the population level. Only 2 peer victimization associations remained (paranoia and hallucinations at age 21), with attenuation of 53% (0.20 to 0.09) and pooled odds ratios of 1.18 vs 1.59. Bivariate biometric twin models supported the within-pair findings while also demonstrating that all covariances were partially attributable to shared genetic liability.Conclusions and Relevance Associations between adverse childhood experiences and severe mental health conditions in young adulthood reflected both shared genetic liability and potential causal effects. Childhood maltreatment showed more persistent within-pair associations than peer victimization, consistent with a greater contribution of non-shared environmental effects. Findings highlight childhood maltreatment as a potentially modifiable pathway to severe psychopathology, supporting the importance of trauma-informed care.

BackgroundAttrition in longitudinal studies often leads to healthier, more educated and less demographically representative samples at follow-up. The extent to which attrition impacts results from twin studies, and the efficacy of methods to correct for attrition, remains unclear. MethodsWe address these questions using data from the Twins Early Development Study (TEDS). First, we found that baseline variables, including twin sex, zygosity, ethnicity and maternal socioeconomic status, predicted 5–7.5% of the variance in follow-up participation. Next, we examined the impact of attrition by comparing estimated means, variances, correlations, and genetic and environmental influences before and after removing participants who did not participate at follow-up. We evaluated a range of twin measures from the Year 2, 12 and 16 time points, including internalising, externalising, educational and cognitive measures. ResultsAttrition affected means and variances, but had little material effect on correlations and genetic and environmental variance components. Finally, we evaluated the efficacy of two popular correction methods—inverse probability weighting and multiple imputation—to reduce bias, focusing on adolescent outcomes. Both methods partially reduced bias in mean estimates; however, imputation also introduced bias for some effects. ConclusionsOur results suggest that for the variables we examined in TEDS, correlations and genetic and environmental variance components are not strongly impacted by attrition. Imputation and weighting methods can reduce attrition bias when estimating means and variances but may introduce bias into estimates of association.

Parenting behaviours are often linked to childhood aggression, but many studies fail to account for shared genetics or test directionality. Using family-based designs, we control for genetic confounding and examined bidirectional effects across two samples. First, we apply a children-of-twins/siblings design in the Norwegian Mother Father and Child Cohort Study which uses genetic relatedness between family members to separate genetic and environmental components of parent-child associations. Second, we use longitudinal models in the USA-based Early Growth and Development Study, an adoption sample where parents and child are not genetically related, enabling estimation of parent-child associations without genetic confounding. Across both studies, we find evidence for genetic and environmental transmission between parenting and child aggression. We show significant child-to-parent effects on inconsistent discipline in both samples. In the children-of-twins analysis, the association between positive parenting and child aggression is shown to be due to shared genetics, where no statistically significant association is observed in the adoption sample. These findings build on the growing body of literature showing genetic influences on both aggression and parenting behaviours, whilst underscoring the value of triangulation.

Background: Attention‐deficit/hyperactivity disorder (ADHD) symptoms and emotional problems frequently co‐occur. Longitudinal data provide opportunities to understand how and why they co‐develop. Methods: Data were drawn from the Twins Early Development Study, which included 27,890 participants. Emotional problems and ADHD symptoms were parent‐reported using the Strengths and Difficulties Questionnaire and Conners' Parent Rating scales. We modeled the co‐development of ADHD symptoms and emotional problems from ages 4 to 21 using joint trajectory analysis. The predictors included polygenic scores (PGSs) for multiple psychiatric symptoms, maternal depression, family chaos, and socioeconomic status (SES). The outcomes included SES, lifetime psychiatric diagnoses, undergraduate diploma attainment, and entry into parenthood at age 26. Results: A four‐class joint trajectory model was selected as best fitting and included: ‘Low ADHD, Low emotional problems’, ‘High‐decreasing ADHD, Low emotional problems’, ‘Mid‐decreasing ADHD, Increasing emotional problems’, and ‘Increasing ADHD, Increasing emotional problems’. The consistently low‐symptom group reported lower ADHD and had lower externalizing PGSs, lower maternal depression, higher SES, and less home chaos at baseline, and higher educational attainment and fewer lifetime depression/anxiety diagnoses at 26 than groups with higher symptom levels. Those with high ADHD symptoms in childhood or increasing ADHD symptoms from childhood to adulthood had the lowest educational attainment and SES in adulthood. Conclusions: Groups characterized by increasing ADHD symptoms also tended to show increases in emotional problems, whereas increases in emotional problems did not necessarily coincide with increases in ADHD symptoms. The trajectories had distinct early‐life predictors and adult outcomes, highlighting potential intervention targets.

Background: The intergenerational transmission of obesity-related traits could propagate an accelerating cycle of obesity, if parental adiposity causally influences offspring adiposity. The extent to which intergenerational obesity associations are due to such causal effects, as opposed to genetic confounding (inheritance), is unclear. We aimed to establish whether associations between parental peri-pregnancy body mass index (BMI) and offspring birth weight (BW), BMI until 8 years of age, and 8-year-old eating behaviour are due to genetic confounding. Methods and findings: Data were from the Norwegian Mother, Father and Child Cohort Study, a prospective population-based birth cohort born between 1999 and 2009 at 50 out of 52 hospital maternity units in Norway. We compared the strength of the associations of maternal pre-pregnancy BMI versus paternal BMI during pregnancy, with offspring outcomes including birth weight and BMI assessed between age 6 months and 8 years of age, and appetite-related eating behaviour traits assessed at age 8 years via the Child Eating Behaviour Questionnaire (CEBQ), adjusting for potential confounders including parity, parental/grandparental language group and parental age, smoking, education and income). We then used an extended children of twins structural equation model (SEM) to quantify the extent to which associations were due to genetic confounding. Up to 85,866 children (51.3% male) were included in linear regression models, whereas SEM models included up to 50,999 children. Maternal BMI was more strongly associated than paternal BMI with offspring BW, but the maternal-paternal difference decreased for offspring BMI after birth. Greater parental BMI was associated with obesity-related offspring eating behaviours. SEM results indicated that genetic confounding did not explain the association between parental BMI and offspring BW, but explained the majority of the association with offspring BMI from 6 months onwards. For 8-year BMI, genetic confounding explained 79% (95% CI [62, 95]; p = 1.9 × 10 ⁻¹² ) of the covariance with maternal BMI and 94% (95% CI [72, 113]; p = 2.7 × 10 ⁻¹⁴ ) of the covariance with paternal BMI. Limitations of this study include selective recruitment and attrition, potential bias due to parental assortative mating, and that findings may not generalise beyond high-income country settings with high obesity prevalence. Conclusions: We found strong evidence that parent–child BMI associations may primarily be due to genetic confounding. When considered alongside prior evidence, this finding may argue against a strong causal effect of maternal or paternal adiposity on childhood adiposity via intrauterine or periconceptional mechanisms.

High or persistent levels of aggression are associated with psychopathology and difficulties with health and education as the child develops. Parenting behaviours have been frequently associated with childhood aggression, however much of this literature does not control for the shared genetics between parent and child or investigate the direction of effects. Here, we triangulated across two family-based designs, the Norwegian Mother Father and Child Cohort Study (MoBa) and the Early Growth and Development Study (EGDS) from the United States, both of which have comparable measures and allow for direction-of-causation analysis and control for shared genetics. Analyses were pre-registered.We found converging evidence across both studies for both genetic and environmental transmission in the relationship between parenting behaviours and child aggressive behaviour, with the association between positive parenting and lower child aggression being driven primarily by shared genetics. In MoBa, 47% of the association between inconsistent parenting and child aggression was explained by shared genetics. We found significant child-to-parent effects in both the MoBa and the EGDS samples. This work shows the strength of triangulation, allowing us to describe a pattern of intergenerational association that is not dependent on a specific sample or study design.

Background: Genetic variants in family members may exert environmentally mediated indirect genetic effects on children’s attention-deficit hyperactivity disorder (ADHD) traits. We set out to quantify the indirect genetic effects of parents’ genotypes on children’s ADHD traits as measured in early and mid-childhood. Methods: We analyzed data from genotyped trios of children, mothers, and fathers of European ancestry from the Norwegian Mother, Father and Child Cohort Study (MoBa) birth cohort. Child ADHD data were available for analytic subsamples of 12,374 trios at age 5 (children 50.5% male), and 12,714 trios at age 8 (children 50.9% male). We quantified direct genetic effects of children’s genotype and indirect effects of mothers’ and fathers’ genotypes on children’s ADHD traits at each age. Results: At age 5, maternal indirect genetic effects explained roughly twice as much variance in children’s ADHD traits as did child direct genetic effects. At age 8, maternal indirect genetic effects and child direct genetic effects explained roughly equal portions of variance in child ADHD traits. However, issues with power were evident throughout analyses and precluded confident interpretation of indirect genetic effects. Conclusions: We find tentative evidence for heritable parental traits exerting environmental effects on child ADHD traits in early and mid-childhood, suggesting that maternal genotypes exert indirect effects on children’s traits after accounting for the direct effects of children’s own genotype. However, future studies with larger samples are needed to enable clear inferences on the importance of indirect genetic effects for children’s ADHD traits.

Background: Selective participation in research studies hampers researchers’ ability to draw valid and generalizable inferences from analyses. Quantifying and adjusting for selective participation is desirable, but can be challenging given the paucity of data for non-participants. Methods: We used individual-level information from population registers to predict baseline and continued participation in the Norwegian Mother, Father and Child Cohort Study (MoBa). Inverse probability weights were computed from logistic regression models with elastic-net regularization. We predicted selective participation and attrition in 296,987 mothers, of whom 29% returned the first MoBa questionnaire, and 12.5% who returned a follow-up questionnaire eight years later. To quantify bias we computed sample characteristics and outcome-exposure associations in the target population and stratified samples. To compare approaches for adjusting for bias, we computed weighted sample estimates using three sets of weights. Results: Unweighted sample estimates were systematically different from target population values, indicating bias due to selective participation. Baseline participation weights substantially reduced the impact of selection bias on mean values (93%) and associations (75%). Attrition weights performed similarly in reducing attrition bias (78% and 50%), but were less effective for reducing participation bias (22% and 14%). Discussion: Sample characteristics and effect estimates are substantially different from target population values. Participation weights were relatively effective at reducing bias due to selective participation, but attrition weights were not. Estimates from studies that use attrition weights may still contain non-negligible selection bias - particularly if the baseline sample is not representative of the target population. Future studies should prioritise opportunities for deriving sampling weights for participation as well as attrition.