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A systematic understanding of the aetiology of neurodevelopmental disorders (NDDs) and their co-occurrence with other conditions during childhood and adolescence remains incomplete. In the current meta-analysis, we synthesized the literature on (1) the contribution of genetic and environmental factors to NDDs, (2) the genetic and environmental overlap between different NDDs, and (3) the co-occurrence between NDDs and disruptive, impulse control and conduct disorders (DICCs). Searches were conducted across three platforms: Web of Science, Ovid Medline and Ovid Embase. Studies were included only if 75% or more of the sample consisted of children and/or adolescents and the studies had measured the aetiology of NDDs and DICCs using single-generation family designs or genomic methods. Studies that had selected participants on the basis of unrelated diagnoses or injuries were excluded. We performed multilevel, random-effects meta-analyses on 296 independent studies, including over four million (partly overlapping) individuals. We further explored developmental trajectories and the moderating roles of gender, measurement, geography and ancestry. We found all NDDs to be substantially heritable (family-based heritability, 0.66 (s.e. = 0.03); SNP heritability, 0.19 (s.e. = 0.03)). Meta-analytic genetic correlations between NDDs were moderate (grand family-based genetic correlation, 0.36 (s.e. = 0.12); grand SNP-based genetic correlation, 0.39 (s.e. = 0.19)) but differed substantially between pairs of disorders. The genetic overlap between NDDs and DICCs was strong (grand family-based genetic correlation, 0.62 (s.e. = 0.20)). While our work provides evidence to inform and potentially guide clinical and educational diagnostic procedures and practice, it also highlights the imbalance in the research effort that has characterized developmental genetics research.

The DNA revolution has energized research on interactions between genes and environments (GxE) by creating indices of G (polygenic scores) that are powerful predictors of behavioral traits. Here, we test the extent to which polygenic scores for attention-deficit/hyperactivity disorder and neuroticism moderate associations between parent reports of their children’s environmental risk (E) at ages 3 and 4 and teacher ratings of behavior problems (hyperactivity/inattention, conduct problems, emotional symptoms, and peer relationship problems) at ages 7, 9 and 12. The sampling frame included up to 6687 twins from the Twins Early Development Study. Our analyses focused on relative effect sizes of G, E and GxE in predicting behavior problems. G, E and GxE predicted up to 2%, 2% and 0.4%, respectively, of the variance in externalizing behavior problems (hyperactivity/inattention and conduct problems) across ages 7, 9 and 12, with no clear developmental trends. G and E predictions of emotional symptoms and peer relationship problems were weaker. A quarter (12 of 48) of our tests of GxE were nominally significant (p = .05). Increasing the predictive power of G and E would enhance the search for GxE.

Genome-wide association (GWA) studies have uncovered DNA variants associated with individual differences in general cognitive ability (g), but these are far from capturing heritability estimates obtained from twin studies. A major barrier to finding more of this ‘missing heritability’ is assessment––the use of diverse measures across GWA studies as well as time and the cost of assessment. In a series of four studies, we created a 15-min (40-item), online, gamified measure of g that is highly reliable (alpha = 0.78; two-week test-retest reliability = 0.88), psychometrically valid and scalable; we called this new measure Pathfinder. In a fifth study, we administered this measure to 4,751 young adults from the Twins Early Development Study. This novel g measure, which also yields reliable verbal and nonverbal scores, correlated substantially with standard measures of g collected at previous ages (r ranging from 0.42 at age 7 to 0.57 at age 16). Pathfinder showed substantial twin heritability (0.57, 95% CIs = 0.43, 0.68) and SNP heritability (0.37, 95% CIs = 0.04, 0.70). A polygenic score computed from GWA studies of five cognitive and educational traits accounted for 12% of the variation in g, the strongest DNA-based prediction of g to date. Widespread use of this engaging new measure will advance research not only in genomics but throughout the biological, medical, and behavioural sciences.

Individual differences in symptoms of behaviour problems in childhood and adolescence are not primarily due to nature or nurture - another substantial source of variance is non-shared environment (NSE). However, few specific environmental factors have been found to account for these NSE estimates. This creates a 'missing NSE' gap analogous to the 'missing heritability' gap, which refers to the shortfall in identifying DNA differences responsible for heritability. We assessed the extent to which variance in behaviour problem symptoms during the first two decades of life can be accounted for by measured NSE effects after controlling for genetics and shared environment.The sample included 4,039 pairs of twins in the Twins Early Development Study whose environments and symptoms of behaviour problems were assessed in preschool, childhood, adolescence and early adulthood via parent, teacher and self-reports. Twin-specific environments were assessed via parent-reports, including early life adversity, parental feelings, parental discipline and classroom environment. Multivariate longitudinal twin model-fitting was employed to estimate the variance in behaviour problem symptoms at each age that could be predicted by environmental measures at the previous age.On average across childhood, adolescence and adulthood, parent-rated NSE composite measures accounted for 3.4% of the reliable NSE variance (1.0% of the total variance) in parent-rated, symptoms of behaviour problems, 0.5% (0.1%) in teacher-rated symptoms and 0.9% (0.5%) in self-rated symptoms after controlling for genetics, shared environment and error of measurement. Cumulatively across development, our parent-rated NSE measures in preschool, childhood and adolescence predicted 4.7% of the NSE variance (2.0% of the total variance) in parent-rated and 0.3% (0.2%) in self-rated behaviour problem symptoms in adulthood.The missing NSE gap between variance explained by measured environments and total NSE variance is large. Home and classroom environments are more likely to influence behaviour problem symptoms via genetics than via NSE.

Background The COVID-19 pandemic has affected all our lives, not only through the infection itself but also through the measures taken to control the spread of the virus (e.g. lockdown). Aims Here, we investigated how the COVID-19 pandemic and unprecedented lockdown affected the mental health of young adults in England and Wales. Method We compared the mental health symptoms of up to 4773 twins in their mid-20s in 2018 prior to the COVID-19 pandemic (T1) and during four-wave longitudinal data collection during the pandemic in April, July and October 2020, and in March 2021 (T2–T5) using phenotypic and genetic longitudinal designs. Results The average changes in mental health were small to medium and mainly occurred from T1 to T2 (average Cohen d = 0.14). Despite the expectation of catastrophic effects of the pandemic on mental health, we did not observe trends in worsening mental health during the pandemic (T3–T5). Young people with pre-existing mental health problems were disproportionately affected at the beginning of the pandemic, but their increased problems largely subsided as the pandemic persisted. Twin analyses indicated that the aetiology of individual differences in mental health symptoms did not change during the lockdown (average heritability 33%); the average genetic correlation between T1 and T2–T5 was 0.95, indicating that genetic effects before the pandemic were substantially correlated with genetic effects up to a year later. Conclusions We conclude that on average the mental health of young adults in England and Wales has been remarkably resilient to the effects of the pandemic and associated lockdown.

A systematic understanding of the aetiology of neurodevelopmental disorders (NDDs), their co-occurrence, and co-occurrence with other conditions during childhood and adolescence remains incomplete. This meta-analysis bridges gaps in our knowledge. First, we meta-analysed the literature on the relative contribution of genetic and environmental factors to NDDs. Second, we considered the literature on the overlap between different NDD categories. Lastly, we synthesized the literature on the co-occurrence between NDDs and disruptive, impulse control and conduct disorders (DICCs). We performed multilevel, random-effects meta-analyses on 296 independent studies, including over 4 million children and adolescents. We found all NDDs to be substantially heritable (family-based heritability (h2) = 0.66; SNP h2 = 0.19). Meta-analytic genetic correlations between NDDs, and between NDDs and DICCs were moderate to strong. However, given the paucity of available studies covering the co-occurrence of NDDs and DICCs, these could only be estimated for a few disorders. While our work provides direct evidence to inform and potentially guide clinical and educational diagnostic procedures and practice, it also highlights the imbalance in the research effort that has characterized developmental genetics research.

Psychiatric disorders represent a significant burden in our societies. Despite the convincing evidence pointing at gene and gene-environment interaction contributions, the role of genetics in the aetiology of psychiatric disease is still poorly understood. Forward genetic screens in animal models have helped elucidate causal links. Here we discuss the application of mutagenesis-based forward genetic approaches in common animal model species: two invertebrates, nematodes (Caenorhabditis elegans) and fruit flies (Drosophila sp.); and two vertebrates, zebrafish (Danio rerio) and mice (Mus musculus), in relation to psychiatric disease. We also discuss the use of large scale genomic studies in human populations. Despite the advances using data from human populations, animal models coupled with next-generation sequencing strategies are still needed. Although with its own limitations, zebrafish possess characteristics that make them especially well-suited to forward genetic studies exploring the aetiology of psychiatric disorders.

BackgroundOne goal of the DNA revolution is to predict problems in order to prevent them. We tested here if the prediction of behaviour problems from genome-wide polygenic scores (GPS) can be improved by creating composites across ages and across raters and by using a multi-GPS approach that includes GPS for adult psychiatric disorders as well as for childhood behaviour problems.MethodOur sample included 3,065 genotyped unrelated individuals from the Twins Early Development Study who were assessed longitudinally for hyperactivity, conduct, emotional problems and peer problems as rated by parents, teachers and children themselves. GPS created from 15 genome-wide association studies were used separately and jointly to test the prediction of behaviour problems composites (general behaviour problems, externalizing and internalizing) across ages (from age 2 to age 21) and across raters in penalized regression models. Based on the regression weights, we created multi-trait GPS reflecting the best prediction of behaviour problems. We compared GPS prediction to twin heritability using the same sample and measures.ResultsMulti-GPS prediction of behaviour problems increased from less than 2% of the variance for observed traits to up to 6% for cross-age and cross-rater composites. Twin study estimates of heritability mirrored patterns of multi-GPS prediction as they increased from less than 40% to up to 83%.ConclusionsThe ability of GPS to predict behaviour problems can be improved by using multiple GPS, cross-age composites and cross-rater composites, although the effect sizes remain modest, up to 6%. Our results can be used in any genotyped sample to create multi-trait GPS predictors of behaviour problems that will be more predictive than polygenic scores based on a single age, rater or GPS.Key pointsGenome-wide polygenic scores (GPS) can be used to predict behaviour problems in childhood, but the effect sizes are generally less than 3.5%.DNA-based prediction models of achieve greater accuracy if holistic approaches are employed, that is cross-trait, longitudinal and trans-situational approaches.The prediction of childhood behaviour problems can be improved by using multiple GPS to predict composites that aggregate behaviour problems across ages and across raters.Our results yield weights that can be applied to GPS in any study to create multi-trait GPS predictors of behaviour problems based on cross-age and cross-rater composites.As compared to individuals in the lowest multi-trait GPS decile, nearly three times as many individuals in the highest internalizing multi-trait GPS decile were diagnosed with anxiety disorder and 25% more individuals in the highest general behaviour problems and externalizing multi-trait GPS deciles have taken medication for mental health.

In the 21st century, emerging adulthood has stretched from the late teens through the twenties. Although this extended transition to adulthood can create stress, it can also offer opportunities to explore vocations and relationships that provide a better fit to individuals’ proclivities, including their genetic propensities.Here we report the results of the first systematic investigation of genetic and environmental influences on 57 psychological traits covering major issues in emerging adulthood such as aspirations, thoughts and attitudes, relationships and personality. We also investigate how these traits relate to physical and mental health, educational attainment and wellbeing using a sample of nearly 5000 pairs of UK twins aged 21-25 from the Twins Early Development Study.All 57 traits showed significant genetic influence, with an average heritability of 34% (SNP heritability ∼10%). Most of the variance (59% on average) was explained by non-shared environmental influences. These diverse traits were associated with mental health (average correlation .20), wellbeing (.16), physical health (.12) and educational attainment (.06). Shared genetic factors explained the majority of these correlations (∼50%). Together, these emerging adulthood traits explained on average 30% of the variance in the outcomes (range = 8 to 69%), suggesting that these traits relate to the outcomes additively.We conclude that the environmental uncertainties of emerging adulthood in the 21st century do not diminish the importance of genetics. As adolescents travel down long and winding roads to adulthood, their trip is substantially influenced by genetic proclivities that nudge them down different paths leading to different destinations.