Kate Langley

Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis

Shade matching should not only be carried out in daylight conditions but under other light sources.

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.

Practitioner Review: What have we learnt about the causes of ADHD?

Background Attention deficit hyperactivity disorder (ADHD) and its possible causes still attract controversy. Genes, pre and perinatal risks, psychosocial factors and environmental toxins have all been considered as potential risk factors. Method This review (focussing on literature published since 1997, selected from a search of PubMed) critically considers putative risk factors with a focus on genetics and selected environmental risks, examines their relationships with ADHD and discusses the likelihood that these risks are causal as well as some of the main implications. Results No single risk factor explains ADHD. Both inherited and noninherited factors contribute and their effects are interdependent. ADHD is familial and heritable. Research into the inherited and molecular genetic contributions to ADHD suggest an important overlap with other neurodevelopmental problems, notably, autism spectrum disorders. Having a biological relative with ADHD, large, rare copy number variants, some small effect size candidate gene variants, extreme early adversity, pre and postnatal exposure to lead and low birth weight/prematurity have been most consistently found as risk factors, but none are yet known to be definitely causal. There is a large literature documenting associations between ADHD and a wide variety of putative environmental risks that can, at present, only be regarded as correlates. Findings from research designs that go beyond simply testing for association are beginning to contest the robustness of some environmental exposures previously thought to be ADHD risk factors. Conclusions The genetic risks implicated in ADHD generally tend to have small effect sizes or be rare and often increase risk of many other types of psychopathology. Thus, they cannot be used for prediction, genetic testing or diagnostic purposes beyond what is predicted by a family history. There is a need to consider the possibility of parents and siblings being similarly affected and how this might impact on engagement with families, influence interventions and require integration with adult services. Genetic contributions to disorder do not necessarily mean that medications are the treatment of choice. We also consider how findings might influence the conceptualisation of ADHD, public health policy implications and why it is unhelpful and incorrect to dichotomise genetic/biological and environmental explanations. It is essential that practitioners can interpret genetic and aetiological research findings and impart informed explanations to families.

A Replicated Molecular Genetic Basis for Subtyping Antisocial Behavior in Children With Attention-Deficit/Hyperactivity Disorder

CONTEXT Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder that in some cases is accompanied by antisocial behavior. OBJECTIVE To test if variations in the catechol O-methyltransferase gene (COMT) would prove useful in identifying the subset of children with ADHD who exhibit antisocial behavior. DESIGN Three independent samples composed of 1 clinical sample of ADHD cases and 2 birth cohort studies. PARTICIPANTS Participants in the clinical sample were drawn from child psychiatry and child health clinics in England and Wales. The 2 birth cohort studies included 1 sample of 2232 British children born in 1994-1995 and a second sample of 1037 New Zealander children born in 1972-1973. MAIN OUTCOME MEASURES Diagnosis of ADHD and measures of antisocial behavior. RESULTS We present replicated evidence that the COMT valine/methionine polymorphism at codon 158 (COMT Val158Met) was associated with phenotypic variation among children with ADHD. Across the 3 samples, valine/valine homozygotes had more symptoms of conduct disorder, were more aggressive, and were more likely to be convicted of criminal offenses compared with methionine carriers. CONCLUSIONS The findings confirm the presence of genetic heterogeneity in ADHD and illustrate how genetic information may provide biological evidence pointing to clinical subtypes.

Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3

Objective: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology. Method: The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium. Results: The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. Conclusions: These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5–3.6), this locus could be an important contributor to ADHD etiology.

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.

Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT 1B receptor gene in 273 nuclear families from a multi-centre sample

Attention deficit hyperactivity disorder (ADHD) is a highly heritable and heterogeneous disorder, which usually becomes apparent during the first few years of childhood. Imbalance in dopamine neurotransmission has been suggested as a factor predisposing to ADHD. However, evidence has suggested an interaction between dopamine and serotonin systems in the pathophysiology of the disorder. Studies using selective agonists of the different 5-HT receptors microinjected into selected brain structures have shown a positive modulating effect on the functional activities of the mesotelencephalic dopaminergic system. This suggests that some of the genetic predisposition to ADHD might be due to DNA variation at serotonin system genes. In this study, we investigated polymorphisms in HTR1B and HTR2A (which encode the serotonin receptors 5-HT1B and 5-HT2A respectively) in a European ADHD sample. Using haplotype based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) analyses, we observed significant preferential transmission of the allele 861G of the HTR1B in the total sample (for HHRR; χ2 = 7.4, P = 0.0065 and TDT; (χ2 = 6.4, P = 0.014). Analysis of HTR2A failed to reveal evidence of association or linkage between the His452Tyr polymorphism and ADHD in the total sample. However, a significantly increased transmission of the allele 452His was observed in the Irish sample alone (χ2 = 4.9, P = 0.026). These preliminary data suggest an important role for the serotonin system in the development of ADHD. Further studies, preferentially including different ethnic groups are required to substantiate these findings.

Investigating the Contribution of Common Genetic Variants to the Risk and Pathogenesis of ADHD

Objective: A major motivation for seeking disease-associated genetic variation is to identify novel risk processes. Although rare copy number variants (CNVs) appear to contribute to attention deficit hyperactivity disorder (ADHD), common risk variants (single-nucleotide polymorphisms [SNPs]) have not yet been detected using genome-wide association studies (GWAS). This raises the concern as to whether future larger-scale, adequately powered GWAS will be worthwhile. The authors undertook a GWAS of ADHD and examined whether associated SNPs, including those below conventional levels of significance, influenced the same biological pathways affected by CNVs. Method: The authors analyzed genome-wide SNP frequencies in 727 children with ADHD and 5,081 comparison subjects. The gene sets that were enriched in a pathway analysis of the GWAS data (the top 5% of SNPs) were tested for an excess of genes spanned by large, rare CNVs in the children with ADHD. Results: No SNP achieved genome-wide significance levels. As previously reported in a subsample of the present study, large, rare CNVs were significantly more common in case subjects than comparison subjects. Thirteen biological pathways enriched for SNP association significantly overlapped with those enriched for rare CNVs. These included cholesterol-related and CNS development pathways. At the level of individual genes, CHRNA7, which encodes a nicotinic receptor subunit previously implicated in neuropsychiatric disorders, was affected by six large duplications in case subjects (none in comparison subjects), and SNPs in the gene had a gene-wide p value of 0.0002 for association in the GWAS. Conclusions: Both common and rare genetic variants appear to be relevant to ADHD and index-shared biological pathways.

What have we learnt about the causes of ADHD

Background Attention deficit hyperactivity disorder (ADHD) and its possible causes still attract controversy. Genes, pre and perinatal risks, psychosocial factors and environmental toxins have all been considered as potential risk factors. Method This review (focussing on literature published since 1997, selected from a search of PubMed) critically considers putative risk factors with a focus on genetics and selected environmental risks, examines their relationships with ADHD and discusses the likelihood that these risks are causal as well as some of the main implications. Results No single risk factor explains ADHD. Both inherited and noninherited factors contribute and their effects are interdependent. ADHD is familial and heritable. Research into the inherited and molecular genetic contributions to ADHD suggest an important overlap with other neurodevelopmental problems, notably, autism spectrum disorders. Having a biological relative with ADHD, large, rare copy number variants, some small effect size candidate gene variants, extreme early adversity, pre and postnatal exposure to lead and low birth weight/prematurity have been most consistently found as risk factors, but none are yet known to be definitely causal. There is a large literature documenting associations between ADHD and a wide variety of putative environmental risks that can, at present, only be regarded as correlates. Findings from research designs that go beyond simply testing for association are beginning to contest the robustness of some environmental exposures previously thought to be ADHD risk factors. Conclusions The genetic risks implicated in ADHD generally tend to have small effect sizes or be rare and often increase risk of many other types of psychopathology. Thus, they cannot be used for prediction, genetic testing or diagnostic purposes beyond what is predicted by a family history. There is a need to consider the possibility of parents and siblings being similarly affected and how this might impact on engagement with families, influence interventions and require integration with adult services. Genetic contributions to disorder do not necessarily mean that medications are the treatment of choice. We also consider how findings might influence the conceptualisation of ADHD, public health policy implications and why it is unhelpful and incorrect to dichotomise genetic/biological and environmental explanations. It is essential that practitioners can interpret genetic and aetiological research findings and impart informed explanations to families.

Adolescent clinical outcomes for young people with attention-deficit hyperactivity disorder.

BACKGROUND Attention-deficit hyperactivity disorder (ADHD) is recognised as a common, disabling condition. Little information is available regarding the long-term outcomes for individuals with ADHD in the UK. AIMS To examine the 5-year outcome for a UK cohort of children with diagnosed, treated ADHD and identify whether maternal and social factors predict key outcomes. METHOD One hundred and twenty-six school-aged children (mean age 9.4 years, s.d. = 1.7) diagnosed with ADHD were reassessed 5 years later during adolescence (mean age 14.5 years, s.d. = 1.7) for ADHD, conduct disorder and other antisocial behaviours. RESULTS Most adolescents (69.8%) continued to meet full criteria for ADHD, were known to specialist services and exhibited high levels of antisocial behaviour, criminal activity and substance use problems. Maternal childhood conduct disorder predicted offspring ADHD continuity; maternal childhood conduct disorder, lower child IQ and social class predicted offspring conduct disorder symptoms. CONCLUSIONS The treatment and monitoring of ADHD need to be intensified as outcomes are poor especially in offspring of mothers with childhood conduct disorder symptoms.