Frances Rice

The genetic aetiology of childhood depression: a review

BACKGROUND We review the evidence for the familiality of major depressive disorder (MDD) and the genetic aetiology of depressive symptoms in children and adolescents. METHODS Databases and reference lists were searched for family, twin and adoption studies of childhood MDD and childhood depressive symptoms. Data from independent family studies that fulfilled specified inclusion criteria were pooled and odds ratios were calculated for top-down and bottom-up family studies. RESULTS Estimates of familial risk differ by control group and by study design (odds ratio range 1.70, 3.98). Twin studies show that depressive symptoms in young people are heritable although rater and measurement issues are important. Adoption studies show little evidence for a genetic influence on depressive symptoms. CONCLUSIONS MDD in young people is familial although control group and study design affect the magnitude of the familial risk. Estimates of heritability from twin and adoption studies vary widely and few firm conclusions can be made regarding the genetic aetiology of depressive symptoms in childhood. Areas that require future work include the examination of rater effects, measurement issues, the effects of age and comorbidity and reasons for the discrepancy between twin and adoption findings.

Prenatal smoking might not cause attention-deficit/hyperactivity disorder: evidence from a novel design

Background It 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. Methods The 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. Results Association 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. Conclusions Our 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.

Archival ReportPrenatal Smoking Might Not Cause Attention-Deficit/Hyperactivity Disorder: Evidence from a Novel Design

Background It 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. Methods The 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. Results Association 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. Conclusions Our 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.

Assessing the effects of age, sex and shared environment on the genetic aetiology of depression in childhood and adolescence

BACKGROUND Depressive symptoms and disorder are experienced by a significant proportion of young people and have long-lasting deleterious effects. The aims of the current investigation were to examine the aetiology of depressive symptoms using a twin design. In particular to examine the effects of sex, age, maternal depression and anxiety symptoms and to examine the aetiology of high depression scores. METHODS Questionnaires were sent to the families of a population-based sample of twins aged between 8 and 17 years. Parents and children over the age of 11 were asked to complete the Mood and Feelings Questionnaire and Hospital Anxiety and Depression Scale (mothers only). Responses were obtained from 1463 families and data were analysed using genetic model fitting and DeFries and Fulker regression analysis. RESULTS Depressive symptoms, particularly when self-rated, were significantly genetically influenced. There was evidence of significant heterogeneity according to age, with shared environmental factors more important and genetic factors less important for children aged 8 to 10 than for adolescents aged 11 to 17 years. Some but not all of the shared environmental influences on parent-rated depressive symptoms were accounted for by maternal symptoms of depression and anxiety. There was a significant effect of gender for self-rated depressive symptoms. For boys, genetic factors were of greater importance and common environmental influences of less importance than for girls. Shared environmental effects had a substantial influence on high self-rated depression scores. Adolescents who scored highly on self-rated depression questionnaires experienced significantly more shared life events and their mothers had significantly higher internalising symptoms than adolescents who scoredwithin the normal range. CONCLUSIONS The results of this study add to the evidence that the aetiology of depressive symptoms differs by age, with genetic factors becoming more important from childhood to adolescence. Some but not all of the shared environmental effect observed for mother-rated depression scores is due to maternal depression and anxiety symptoms. For self-rated depressive symptoms, the importance of genetic and environmental factors may also differ by sex, with genetic influences more important for boys. The aetiology of high depression symptom scores, when self-rated, appears to differ from scores within the normal range in that shared environmental factors appear to be more important. Further research is needed to identify these shared environmental factors using longitudinal models that test genetic and environmental mediation.

The impact of gestational stress and prenatal growth on emotional problems in offspring: a review

Objective:  Events occurring very early in life, even prenatally, may have long‐term effects on future health and behaviour. The influence of poor foetal growth and gestational stress in the mother on the risk of emotional problems in offspring was reviewed.

Depressive symptoms in children and adolescents: changing aetiological influences with development

BACKGROUND Evidence suggests that depressive symptoms become increasingly heritable as children grow into adolescence. However, the literature is not entirely consistent in this respect and existing longitudinal twin studies have examined changes within adolescence only. METHOD Parent and self-report questionnaire data were used to examine the genetic and environmental influences on depressive symptoms in a UK sample of 670 twin pairs aged 5-17. Age effects were examined cross-sectionally and longitudinally using data collected over a 3-year period. RESULTS Cross-sectional analyses showed that shared environmental effects had significant influence in younger children but not in adolescence, when depression scores were significantly more heritable. The results of these cross-sectional analyses were supported when two waves of parent-report data collected over three years were analysed. Significant new genetic influences emerged in adolescence but no new shared environmental influences. Some sex differences were found, with girls showing greater genetic influence than boys, but only from parent-report data. CONCLUSIONS These findings support and extend earlier work which has shown increasing genetic influence on depressive symptoms as children grow into adolescence.

Exploring the relationship between genetic and environmental influences on initiation and progression of substance use

Aims To examine the genetic and environmental contributions to the initiation of use and progression to more serious use of alcohol, cigarettes and marijuana during adolescence, and to examine the relationship between initiation and progression of substance use. Design The study used a twin-based design and a new theoretical model, the causal–common–contingent (CCC) model. This allows modelling of the relationship between initiation of use and progression to heavier use as a two-stage model and the examination of genetic and environmental influences on both stages, while taking into account their relationship. Participants The participants consisted of 1214 twin pairs (69% response rate) aged 11–19 years sampled from the UK population-based Cardiff Study of All Wales and North-west of England Twins (CaStANET). Measurements Data on adolescent initiation and progression to more serious use of alcohol, cigarettes and marijuana were obtained using self-report questionnaires. Findings Initiation of alcohol and progression to heavier alcohol use had separate but related underlying aetiologies. For cigarette and marijuana use the relation between initiation and progression to heavier use was stronger, suggesting greater overlap in aetiologies. For all three substances, environmental influences that make twins more similar (common environment) tended to be greater for initiation, while genetic influences were stronger for heavier use. Conclusions These findings have implications for policy decisions aimed at an adolescent and early adult age group. Specifically, these findings suggest that it may be more efficacious to focus alcohol interventions on risk factors for the development of heavier use rather than initiation of use. In contrast, interventions aimed at reducing the initiation of cigarettes and marijuana use may be more appropriate.

Disentangling prenatal and inherited influences in humans with an experimental design

Exposure to adversity in utero at a sensitive period of development can bring about physiological, structural, and metabolic changes in the fetus that affect later development and behavior. However, the link between prenatal environment and offspring outcomes could also arise and confound because of the relation between maternal and offspring genomes. As human studies cannot randomly assign offspring to prenatal conditions, it is difficult to test whether in utero events have true causal effects on offspring outcomes. We used an unusual approach to overcome this difficulty whereby pregnant mothers are either biologically unrelated or related to their child as a result of in vitro fertilization (IVF). In this sample, prenatal smoking reduces offspring birth weight in both unrelated and related offspring, consistent with effects arising through prenatal mechanisms independent of the relation between the maternal and offspring genomes. In contrast, the association between prenatal smoking and offspring antisocial behavior depended on inherited factors because association was only present in related mothers and offspring. The results demonstrate that this unusual prenatal cross-fostering design is feasible and informative for disentangling inherited and prenatal effects on human health and behavior. Disentangling these different effects is invaluable for pinpointing markers of prenatal adversity that have a causal effect on offspring outcomes. The origins of behavior and many common complex disorders may begin in early life, therefore this experimental design could pave the way for identifying prenatal factors that affect behavior in future generations.

Familial transmission of depression and antisocial behavior symptoms: disentangling the contribution of inherited and environmental factors and testing the mediating role of parenting

BACKGROUND Genetic and environmental influences on child psychopathology have been studied extensively through twin and adoption designs. We offer a novel methodology to examine genetic and environmental influences on the intergenerational transmission of psychopathology using a sample of parents and children conceived through in vitro fertilization (IVF). METHOD The sample included families with children born through IVF methods, who varied as to whether the child was genetically related or unrelated to the rearing mother and father (mother genetically related, n=434; mother genetically unrelated, n=127; father genetically related, n=403; father genetically unrelated, n=156). Using standardized questionnaires, mothers and fathers respectively reported on their own psychopathology (depression, aggression), their parenting behavior toward their child (warmth, hostility) and their childs psychopathology (depression, aggression). A cross-rater approach was used, where opposite parents reported on child symptoms (i.e. fathers reported on symptoms for the mother-child dyad, and vice versa). RESULTS For mother-child dyads, a direct association between mother depression and child depression was observed among genetically unrelated dyads, whereas a fully mediated path was observed among genetically related dyads through mother-to-child hostility and warmth. For father-child dyads, direct and mediated pathways were observed for genetically related father-child dyads. For aggression, the direct association between parent aggression and child aggression was fully mediated by parent-to-child hostility for both groups, indicating the role of parent-to-child hostility as a risk mechanism for transmission. CONCLUSIONS A differential pattern of genetic and environmental mediation underlying the intergenerational transmission of psychopathology was observed among genetically related and genetically unrelated father-child and mother-child dyads.

Psychopathy trait scores in adolescents with childhood ADHD: the contribution of genotypes affecting MAOA, 5HTT and COMT activity.

Objectives Psychopathy-related traits, especially those tapping the ‘emotional dysfunction’ aspect of psychopathy that is characterized by lack of emotional responsiveness, are thought to be of genetic origin, but molecular genetic studies are yet to be undertaken. Gene variants that affect COMT, MAOA and 5HTT activity have previously been linked to antisocial behaviour. The aims of this study were to test whether these gene variants are linked to psychopathy traits in attention-deficit hyperactivity disorder (ADHD). Methods Adolescents were followed up 5 years after an initial diagnosis of ADHD. Psychopathy trait scores were assessed [total scores and ‘emotional dysfunction’ (also referred to as ‘affective’) scores] and the MAOA 30-bp variable number of tandem repeats, SLC6A4 44-bp insertion/deletion and COMT Val158Met variants were genotyped. Results All three gene variants were associated with ‘emotional dysfunction’ scores. MAOA and 5HTT variants were associated with total psychopathy scores. The results were not explained by associated conduct disorder. Conclusion The results suggest that specific gene variants influence psychopathy traits in ADHD.