Gene-environment interplay in ADHD. Anita Thapar

Transcription

1 Gene-environment interplay in ADHD Anita Thapar

2 Overview of talk Genetic contribution to ADHD Environmental risk factors and their interplay with genes Conclusions and clinical implications

3 Evidence that genes contribute to ADHD

4 Evidence that genes contribute to Runs in families ADHD More than 14 published twin studiesconsistent findings of high heritability h 2 =75%-91% 5 adoption studies-consistent with a genetic aetiology Not purely inherited

5 Identifying specific gene variants Common variants Rare mutations

6 Common gene variants Dopamine D4, D5 and DAT gene variants implicated in meta-analyses of worldwide data Each one has small effect size Genome-wide searches underway Identifying novel biological mechanisms

7 Subtle chromosomal anomalies Copy number variants CNVs Rare copy number variants- deletions or duplications Implicated in intellectual disability, schizophrenia, autism

8 Large rare copy number variants in ADHD ADHD/Controls 14% vs 7% CNV(n) Burden of all CNVs ADHD Controls ratio P n=366/1047 RATE x10-5 ADHD (IQ 70)/Controls 11% CNV(n) n=319/1047 RATE ADHD (IQ<70)/Controls 36% CNV(n) n=33/1047 RATE x10-6

9 Large, rare chromosome deletions and duplications in ADHD Replicated findings of increased burden Notable regions 16p13.1 and 15q11-13 duplications Biological overlap with autism and schizophrenia Mixture of de novo and inherited mutations Environmental risks may increase de novo mutations

10 Environmental risk factors and their interplay with genes Which environmental risks are causal?

11 Pre and peri-natal risk factors maternal smoking in pregnancy ** Pooled OR= 2.39 maternal stress/anxiety in pregnancy* maternal alcohol and drug use Low birth weight/preterm * Pooled odds ratio= 2.64 Pre/peri-natal complications

12 Postnatal and childhood factors Family adversity- parenting, negative parentchild relationships Extreme adversity in infancy/early childhood

13 Testing causal effects of environment Is association due to reverse causation (e.g. child psychopathology leading to risk environment) Is association due to confounding social, family/inherited factors?

14 Mother s genes genetic link Maternal Smoking in pregnancy environmental causation e.g. nicotine, carbon monoxide Placental blood flow Child ADHD

15 Mother s genes genetic link Maternal Smoking in pregnancy environmental causation e.g. nicotine, carbon monoxide Placental blood flow Child ADHD

16 IVF study Children who are unrelated to mother who undergoes pregnancy, children who are related If maternal smoking in pregnancy has real risk effects on the child, it will not matter if the child is related or unrelated to the woman undergoing the pregnancy

17 Smoking in pregnancy Environmental pathways Inherited pathways Lower birth weight ADHD

18 Stress in pregnancy Environmental pathways Inherited pathways prematurity Lower birth weight ADHD

19 Negative Family relationships and parenting Antisocial behaviour-treatment studies and longitudinal studies show causal effects ADHD treatment and longitudinal studies suggest child symptoms lead to negative relationships

20 Early deprivation Romanian adopted away orphans study-exposure to severe early deprivation led to ADHD symptoms Need research on causal effects of milder forms of early adversity

21 Animal studies Early poor maternal care can lead to offspring behavioural changes Early poor maternal care results in genomic changes (epigenetics) Epigenetic changes transmitted across generations

22 Conclusions

23 Summary Genes and environmental risks are not deterministic Not all exposed to risk have problems, not all who have problems have been exposed to the risk Contribution of inherited factors, specific types of gene variants Rare copy number variants, multiple small effect common variants

24 Summary Risks including gene variants are not diagnosis specific Environmental risks (pre and postnatal) -need more research on which are causal E can exert their risks by changing G

25 Clinical messages Genetic testing not warranted Genetic contribution does not necessarily mean biological treatments or that E is not important Screen parents for ADHD type problems Policy/public health measures to reduce ADHD? Need evidence Further research on outcomes of ADHD

26 Acknowledgements Funding from Wellcome Trust, Action Medical Research, Baily Thomas Sharifah Syed, Charlotte Davies, Joanna Martin, Irina Zaharieva, Evie Stergyiakouli Kate Langley, Nigel Williams, Peter Holmans, Michael Owen, Michael O Donovan. Gordon Harold, Frances Rice