Objective Chromosome 22q11.2 deletion syndrome is a neurogenetic disorder associated with high rates of schizophrenia and other psychiatric conditions. The authors report what is to their knowledge the first large-scale collaborative study of rates and sex distributions of psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome. The associations among psychopathology, intellect, and functioning were examined in a subgroup of participants. Method The 1,402 participants with 22q11.2 deletion syndrome, ages 6–68 years, were assessed for psychiatric disorders with validated diagnostic instruments. Data on intelligence and adaptive functioning were available for 183 participants ages 6 to 24 years. Results Attention deficit hyperactivity disorder (ADHD) was the most frequent disorder in children (37.10%) and was overrepresented in males. Anxiety disorders were more prevalent than mood disorders at all ages, but especially in children and adolescents. Anxiety and unipolar mood disorders were overrepresented in females. Psychotic disorders were present in 41% of adults over age 25. Males did not predominate in psychotic or autism spectrum disorders. Hierarchical regressions in the subgroup revealed that daily living skills were predicted by the presence of anxiety disorders. Psychopathology was not associated with communication or socialization skills. Conclusions To the authors' knowledge, this is the largest study of psychiatric morbidity in 22q11.2 deletion syndrome. It validates previous findings that this condition is one of the strongest risk factors for psychosis. Anxiety and developmental disorders were also prevalent. These results highlight the need to monitor and reduce the long-term burden of psychopathology in 22q11.2 deletion syndrome.

BackgroundIt is widely considered that exposure to maternal cigarette smoking in pregnancy has risk effects on offspring attention-deficit/hyperactivity disorder (ADHD). This view is supported by consistent observations of association. It is, however, impossible to be certain of adequate control for confounding factors with observational designs. We use a novel “natural experiment” design that separates prenatal environmental from alternative inherited effects.MethodsThe design is based on offspring conceived with Assisted Reproductive Technologies recruited from 20 fertility clinics in the United Kingdom and United States who were: 1) genetically unrelated, and 2) related to the woman who underwent the pregnancy. If maternal smoking in pregnancy has true risk effects, association will be observed with ADHD regardless of whether mother and offspring are related or unrelated. Data were obtained from 815 families of children ages 4 years–11 years with parent questionnaires and antenatal records. Birth weight was used as a comparison outcome. The key outcome considered was child ADHD symptoms.ResultsAssociation between smoking in pregnancy and lower birth weight was found in unrelated and related mother-offspring pairs, consistent with a true risk effect. However, for ADHD symptoms, the magnitude of association was significantly higher in the related pairs (β = .102, p < .02) than in the unrelated pairs (β= −.052, p > .10), suggesting inherited effects.ConclusionsOur findings highlight the need to test causal hypotheses with genetically sensitive designs. Inherited confounds are not necessarily removed by statistical controls. The previously observed association between maternal smoking in pregnancy and ADHD might represent an inherited effect.

BackgroundExposure to prenatal stress is associated with later adverse health and adjustment outcomes. This is generally presumed to arise through early environmentally mediated programming effects on the foetus. However, associations could arise through factors that influence mothers' characteristics and behaviour during pregnancy which are inherited by offspring.MethodA ‘prenatal cross-fostering’ design where pregnant mothers are related or unrelated to their child as a result of in vitro fertilization (IVF) was used to disentangle maternally inherited and environmental influences. If links between prenatal stress and offspring outcome are environmental, association should be observed in unrelated as well as related mother–child pairs. Offspring birth weight and gestational age as well as mental health were the outcomes assessed.ResultsAssociations between prenatal stress and offspring birth weight, gestational age and antisocial behaviour were seen in both related and unrelated mother–offspring pairs, consistent with there being environmental links. The association between prenatal stress and offspring anxiety in related and unrelated groups appeared to be due to current maternal anxiety/depression rather than prenatal stress. In contrast, the link between prenatal stress and offspring attention deficit hyperactivity disorder was only present in related mother–offspring pairs and therefore was attributable to inherited factors.ConclusionsGenetically informative designs can be helpful in testing whether inherited factors contribute to the association between environmental risk factors and health outcomes. These results suggest that associations between prenatal stress and offspring outcomes could arise from inherited factors and post-natal environmental factors in addition to causal prenatal risk effects.

Maternal smoking during pregnancy appears to show an association with offspring ADHD symptoms that is additional to the effects of genes and not attributable to shared rater effects, clinical referral biases, or covariation with antisocial behavior.

The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. Imaging data was collected from 10 centers worldwide, including 474 subjects with 22q11DS (age=18.2±8.6; 46.9% female) and 315 typically-developing, matched controls (age=18.0±9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen’s d=0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d=−1.01/−1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

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Twins were recruited through alcohol and drug treatment programs. With structural equation modeling, genetic and environmental estimates were obtained for use and DSM-III abuse/dependence of sedatives, opioids, cocaine, stimulants, and cannabis as well as any illicit drug. Analyses were conducted separately for males and females. Models included thresholds based on population prevalence of use or abuse/dependence and ever having been in treatment. Genetic influences were found for most measures. They were generally stronger for males than females and for clinical diagnoses of abuse/dependence compared to use. Common environmental influences played a greater role in use than abuse/dependence.