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Background: Maternal prenatal depression is a known risk factor for early-life psychopathology among offspring; however, potential risk transmission mechanisms need to be distinguished. We aimed to test the relative importance of passive genetic transmission, direct exposure, and indirect exposure in the association between maternal prenatal depressive symptoms and early-life internalising and externalising psychopathology in offspring., Methods: We used structural equation modelling of phenotypic data and genetically informative relationships from the families of participants in the Norwegian Mother and Child Birth Cohort Study (MoBa). The analytic subsample of MoBa used in the current study comprises 22 195 mothers and 35 299 children. We used mothers' self-reported depressive symptoms during pregnancy, as captured by the Symptom Checklist, and their reports of symptoms of psychopathology in their offspring during the first few years of life (measured at 18, 36, and 60 months using the Child Behavior Checklist)., Findings: Maternal prenatal depressive symptoms were found to be associated with early-life psychopathology primarily via intergenerationally shared genetic factors, which explained 41% (95% CI 36-46) of variance in children's internalising problems and 37% (30-44) of variance in children's externalising problems. For internalising problems, phenotypic transmission also contributed significantly, accounting for 14% (95% CI 5-19) of the association, but this contribution was found to be explained by exposure to concurrent maternal depressive symptoms, rather than by direct exposure in utero., Interpretation: Associations between maternal prenatal depressive symptoms and offspring behavioural outcomes in early childhood are likely to be at least partially explained by shared genes. This genetic confounding should be considered when attempting to quantify risks posed by in-utero exposure to maternal depressive symptoms., Funding: UK Economic and Social Research Council, Norwegian Research Council, Norwegian Ministries of Health and Care Services, and Education & Research, Wellcome Trust, Royal Society, and National Institute for Health Research., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Genes and the environment contribute to variation in adult body mass index [BMI (in kg/m 2 )], but factors modifying these variance components are poorly understood. Objective: We analyzed genetic and environmental variation in BMI between men and women from young adulthood to old age from the 1940s to the 2000s and between cultural-geographic regions representing high (North America and Australia), moderate (Europe), and low (East Asia) prevalence of obesity. Design: We used genetic structural equation modeling to analyze BMI in twins ≥20 y of age from 40 cohorts representing 20 countries (140,379 complete twin pairs). Results: The heritability of BMI decreased from 0.77 (95% CI: 0.77, 0.78) and 0.75 (95% CI: 0.74, 0.75) in men and women 20-29 y of age to 0.57 (95% CI: 0.54, 0.60) and 0.59 (95% CI: 0.53, 0.65) in men 70-79 y of age and women 80 y of age, respectively. The relative influence of unique environmental factors correspondingly increased. Differences in the sets of genes affecting BMI in men and women increased from 20-29 to 60-69 y of age. Mean BMI and variances in BMI increased from the 1940s to the 2000s and were greatest in North America and Australia, followed by Europe and East Asia. However, heritability estimates were largely similar over measurement years and between regions. There was no evidence of environmental factors shared by co-twins affecting BMI. Conclusions: The heritability of BMI decreased and differences in the sets of genes affecting BMI in men and women increased from young adulthood to old age. The heritability of BMI was largely similar between cultural-geographic regions and measurement years, despite large differences in mean BMI and variances in BMI. Our results show a strong influence of genetic factors on BMI, especially in early adulthood, regardless of the obesity level in the population., (© 2017 American Society for Nutrition.)

Bipolar disorder (BPD) is associated with altered regional brain function during the performance of cognitive tasks. The relative contribution of genetic and environmental risk factors for BPD to these changes has not yet been quantified. We sought to address this issue in a functional neuroimaging study of people who varied in their risk for BPD. Functional magnetic resonance imaging was used to study 124 subjects (29 twin and 9 sibling pairs with at least one member with BPD, and 24 healthy twin pairs) performing a working memory task. We assessed the influence of risk for BPD on regional brain function during the task in a two stage process. Firstly, we identified areas where there were group differences in activation. Secondly, we estimated the heritability and phenotypic correlation of activation and BPD using genetic modeling. BPD was associated with increased activation in the anterior cingulate, orbitofrontal, medial prefrontal, and left precentral cortices, and in the precuneus. Within these regions, activation in the orbitofrontal cortex rendered the most significant heritability estimate (h 2 =0.40), and was significantly correlated with BPD phenotype (r ph =0.29). A moderate proportion of the genetic influences (r g =0.69) acting on both BPD and on the degree of orbitofrontal activation were shared. These findings suggest that genetic factors that confer vulnerability to BPD alter brain function in BPD., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Social anxiety (SA) is a common condition associated with social and communication (SC) difficulties in typically developing young people, as well as those with autism spectrum disorder (ASD). Whether SC difficulties place children at risk for developing SA is unclear. Using a longitudinal design, the present study aimed to disentangle the relationship between SA symptoms and SC difficulties using a population-based sample of 9,491 children from the Avon Longitudinal Study of Parents and Children (ALSPAC)., Method: Parent-reported data on SC difficulties and SA symptoms were collected at ages 7, 10, and 13 years. A cross-lagged panel model was used to investigate the longitudinal stability and directional relationship between latent SC difficulties and SA constructs over time., Results: More SC difficulties were associated with greater SA symptoms at all ages. Earlier SC difficulties predicted a small but significant amount of variance in later SA symptoms. The reverse relationship from SA to SC difficulties was not observed. The relationship from SC difficulties to SA was strongest from age 7 to 10 years. No sex differences were observed., Conclusion: The evidence suggests that SC difficulties may be an important risk factor for the development of SA. These findings suggest the potential usefulness of incorporating social skills training alongside effective interventions to prevent or alleviate symptoms of SA in childhood., (Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Disorders on the autism spectrum, as well as autistic traits in the general population, have been found to be both highly stable across age and highly heritable at individual ages. However, little is known about the overlap in genetic and environmental influences on autistic traits across age and the contribution of such influences to trait stability itself. The present study investigated these questions in a general population sample of twins., Method: More than 6,000 twin pairs were rated on an established scale of autistic traits by their parents at 8, 9, and 12 years of age and by their teachers at 9 and 12 years of age. Data were analyzed using structural equation modeling., Results: The results indicated that, consistently across raters, not only were autistic traits stable, and moderately to highly heritable at individual ages, but there was also a high degree of overlap in genetic influences across age. Furthermore, autistic trait stability could largely be accounted for by genetic factors, with the environment unique to each twin playing a minor role. The environment shared by twins had virtually no effect on the longitudinal stability in autistic traits., Conclusions: Autistic traits are highly stable across middle childhood. and this stability is caused primarily by genetic factors., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Electrophysiological and hemodynamic activity is altered in attention-deficit/hyperactivity disorder (ADHD) during tasks requiring cognitive control. Frontal midline theta oscillations are a cortical correlate of cognitive control influencing behavioral outcomes including reaction times. Reaction time variability (RTV) is consistently increased in ADHD and is known to share genetic effects with the disorder. The etiological relationship between the cognitive control system, RTV, and ADHD is unknown. In a sample of twins selected for ADHD and matched control subjects, we aimed to quantify the strength of the phenotypic, genetic, and environmental relationships between event-related midline theta oscillations, RTV, and ADHD., Methods: Our sample included 134 participants aged 12 to 15 years: 67 twin pairs (34 monozygotic; 33 dizygotic) with concordance or discordance for ADHD symptomatology assessed at 8, 10, and 12 years of age. Our main outcome measures were frontal midline theta activity, derived from both channel and source decomposed electroencephalographic data, and behavioral performance on a response-choice arrow flanker task known to elicit theta activity., Results: Variability in stimulus event-related theta phase from frontal midline cortex is strongly related to both RTV and ADHD, both phenotypically and genetically., Conclusions: This is the first finding to confirm the genetic link between the frontal midline cognitive control system and ADHD and the first to identify a genetically related neurophysiological marker of RTV in ADHD. Variability in the timing of the theta signal in ADHD may be part of a dysfunctional brain network that impairs regulation of task-relevant responses in the disorder., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Emotional lability is recognized as an associated feature of attention-deficit/hyperactivity disorder (ADHD). However, the degree of phenotypic and etiologic overlap between emotional lability and the ADHD dimensions of hyperactivity-impulsivity and inattention remains unclear. The present study examines these associations in a large, community twin sample., Method: Structural equation models were fit to data from 1,920 child and adolescent twin pairs (age range, 5-18 years). Symptoms of hyperactivity-impulsivity (HI) and inattention (IA) were assessed using a modified version of the DuPaul rating scale, completed by parents. Symptoms of emotional lability (EL) were assessed using the parent-rated Conners 10-item scale., Results: There were moderate to strong phenotypic correlations between HI, IA, and EL. Multivariate twin modeling revealed that a common pathway model best accounted for the covariance among these dimensions, represented by a highly heritable latent factor. Ad hoc analyses confirmed that all additive genetic influences on HI, IA, and EL were shared, and identified a significantly stronger association of EL with the latent ADHD factor in older than in younger individuals., Conclusions: Emotional lability was phenotypically and genetically associated with hyperactivity-impulsivity and inattention in children and adolescents. The finding that a single, heritable, latent factor accounted for covariation among these phenotypes indicates that their co-occurrence is primarily the result of overlapping genetic effects. These data support the hypothesis that emotional lability is etiologically relevant to the core ADHD phenotype, and that it should be targeted in assessment and treatment in clinical practice., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Structural brain abnormalities are consistently found in schizophrenia (Sz) and have been associated with the familial risk for the disorder. We aim to define the relative contributions of genetic and nongenetic factors to the association between structural brain abnormalities and Sz in a uniquely powered cohort (Schizophrenia Twins and Relatives consortium)., Methods: An international multicenter magnetic resonance imaging collaboration was set up to pool magnetic resonance imaging scans from twin pairs in Utrecht (The Netherlands), Helsinki (Finland), London (United Kingdom), and Jena (Germany). A sample of 684 subjects took part, consisting of monozygotic twins (n = 410, with 51 patients from concordant and 52 from discordant pairs) and dizygotic twins (n = 274, with 39 patients from discordant pairs). The additive genetic, common, and unique environmental contributions to the association between brain volumes and risk for Sz were estimated by structural equation modeling., Results: The heritabilities of most brain volumes were significant and ranged between 52% (temporal cortical gray matter) and 76% (cerebrum). Heritability of cerebral gray matter did not reach significance (34%). Significant phenotypic correlations were found between Sz and reduced volumes of the cerebrum (-.22 [-.30/-.14]) and white matter (-.17 [-.25/-.09]) and increased volume of the third ventricle (.18 [.08/.28]). These were predominantly due to overlapping genetic effects (77%, 94%, and 83%, respectively)., Conclusions: Some of the genes that transmit the risk for Sz also influence cerebral (white matter) volume., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Limited success has been achieved through previous attention-deficit/hyperactivity disorder (ADHD) linkage scans, which were all designed to map genes underlying the dichotomous phenotype. The International Multi-centre ADHD Genetics (IMAGE) project performed a whole genome linkage scan specifically designed to map ADHD quantitative trait loci (QTL)., Methods: A set of 1094 single selected Caucasian ADHD nuclear families was genotyped on a highly accurate and informative single nucleotide polymorphism (SNP) panel. Two quantitative traits measuring the children's symptoms in home and school settings were collected and standardized according to a population sample of 8000 children to reflect the developmental nature and gender prevalence difference of ADHD. Univariate linkage test was performed on both traits and their mean score., Results: A significant common linkage locus was found at chromosome 1p36 with a locus-specific heritability of 5.1% and a genomewide empirical p < .04. Setting-specific suggestive linkage signals were also found: logarithm of odds (LOD) = 2.2 at 9p23 for home trait and LOD = 2.6 at 11q21 for school trait., Conclusions: These results indicate that given large samples with proper phenotypic measures, searching for ADHD genes with a QTL strategy is an important alternative to using the clinical diagnosis. The fact that our linkage region 1p36 overlaps with the dyslexia QTL DYX8 further suggests it is potentially a pleiotropic locus for ADHD and dyslexia.