Attention deficit hyperactivity disorder (ADHD) and antisocial behaviour are common, extremely disabling disorders which have major adverse sequalae in childhood and later life. Despite being such an important clinical problem, their aetiology and pathogenesis are poorly understood. Available evidence suggests that both genetic and environmental risk factors are important.

Many studies have demonstrated significant association between prenatal exposure to alcohol, tobacco, marijuana and diabetes mellitus and child behaviour outcomes including ADHD and CD, although such findings are equivocal.

Each prenatal exposure has been shown by some animal studies to result in biological alterations to the developing foetus which could, in turn, influence child behaviour.

However, each of these prenatal risk factors is also associated with additional familial characteristics including social adversity, parental psychopathology and other social deficits, each of which have been associated with childhood behaviour problems. Furthermore, willingness to engage in risky behaviours during pregnancy is also associated with antisocial behaviour, impulsivity and ADHD symptoms in the mother.

Therefore, it is currently unknown whether these prenatal exposures lead to direct intrauterine effects on the developing foetus with long term consequences for childhood behavioural problems, or if observed associations arise instead via confounding inheritance of familial factors.

The aim of this proposal is to further explore the causal pathways for association between prenatal exposures and childhood ADHD and antisocial behaviour.

To this end, the aim of this proposal is to test the contrasting hypotheses that either:

1) Associations between prenatal exposure to alcohol, tobacco and marijuana, diabetes and childhood developmental disorders are the result of direct intrauterine effects OR

2) Such associations are due to genetic or other confounding factors.

The project will utilise data from three different samples, ALSPAC, the Cardiff IVF sample and data from the Swedish population registries.

Specifically in the ALSPAC sample, I propose to:

1. Test for associations between prenatal exposure to alcohol, tobacco, marijuana use, diabetes mellitus and offspring symptoms and diagnoses of ADHD and CD using regression analyses. Where this work has previously been undertaken, I will utilise previously published data or collaborate with other researchers.

2. Test which of the competing hypotheses account for these associations using methods comparing: Maternal and paternal exposure; pre and postnatal exposure; and a mendelian randomisation instrumental variable approach

3. Based on the findings of the earlier aims and suggestions from previous literature, I will investigate:

a. Whether causal associations arise via their influences on cognitive or other phenotypes or

b. Which confounding factors appear to best account for non-causal associations.

I propose to investigate genetic variants which are robustly associated with the risk exposures (smoking, alcohol and substance use and diabetes) which have been identified through GWAS and candidate gene studies. As this is a constantly changing field of research and much of the work is currently being undertaken by ALSPAC collaborators, I will nominate the proposed genetic variants at a later stage (of course with additional approval by the executive committee). However, it is anticipated that these will be variants previously genotyped within the ALSPAC sample, mainly on the Illumina 550k chip. I will also include funding in my proposal for additional genotyping of candidate variants which might not already be genotyped within the ALSPAC sample.

Current data required:

Parent & Teacher reports of ADHD & DAWBA diagnoses at 7 & 11 years

Parent & Teacher reports of antisocial behaviour & DAWBA CD diagnoses at 7 & 11 years

Child antisocial behaviour measures from focus visits

Age (parents & child at assessments)

Gender

Birth weight

Maternal & Paternal smoking during pregnancy

Current Maternal & Paternal smoking (current to ADHD diagnoses)

Mother & Father alcohol use during pregnancy and current (7 years)

Mother and father marijuana and other substance use during and after pregnancy

Mother and father diabetes diagnoses during pregnancy (maternal report and data from antenatal notes) and since birth

SES & Mother's education

Mother & Father psychopathology (time of pregnancy and current); ADHD, CD, Anxiety & Depression

Child cognitive assessments (IQ & neuropsychological test data, Key stage 1 & 2 results)

Mother & Child genotypes chosen from GWAS and association studies