The overarching hypothesis of this proposal is that combined type ADHD, as defined by population-based criteria, is a distinct form of ADHD resulting from a combination of genetic and environmental factors creating a distinct developmental profile of neurophysiological functioning, brain structure, motor coordination problems and autistic-like symptomatology. The specific goal of this project is to replicate and expand current studies suggesting important gene-environment interactions in the development of combined type ADHD. Previous investigators have demonstrated that the risk for ADHD is increased in the presence of maternal smoking during pregnancy and certain genotypes of dopamine pathway genes (including the DRD4, dopamine transporter and CHRNA4 genes). Recently, we tested for the interaction of maternal smoking with these candidate genes and have demonstrated marked gene-environment interaction effects which increases the likelihood of developing combined type ADHD from 2.5 to 15-fold. In the current study we will recruit a new sample of 200 epidemiologically ascertained sibling pairs discordant for the presence of combined type ADHD, as defined by population-based criteria. The sibling pairs will be extensively studied for psychopathology, prenatal and early postnatal exposures to maternal, paternal and second hand smoke as well as maternal substance use and abuse. The DRD4, SLC6A3 and CHRNA4 genes will be resequenced in these new sibling pairs and our original sample of 100 dizygotic twin pairs. Using a combination of in silico and in vitro approaches, functional DNA sequence variations in these three genes will be identified. Our primary hypotheses are that maternal smoking during pregnancy and child genotype at the DRD4, DAT and CHRNA4 loci will demonstrate interactive effects on risk of combined type ADHD as well as autistic and motor coordination symptomatology. These effects will be larger for newly defined functional sequence changes. Paternal smoking during pregnancy and second hand smoking exposure during early life will further increase risk. This study takes advantage of an existing epidemiological set of families with four or more full siblings characterized for ADHD and autistic symptoms, allowing the efficient identification of discordant sibling pairs as well as allowing estimates of the impact of any findings in the general population. Subjects of this project could also serve as a longitudinal population-based cohort for extension of our findings of gene-environment interactions to structural and functional imaging as well as neuropsychological studies.

Public Health Relevance

This study takes advantage of an existing epidemiological set of families with four or more full siblings characterized for Attention Deficit/Hyperactivity Disorders (ADHD) and autistic symptoms which allow the efficient identification of discordant sibling pairs and estimates of the impact of prenatal smoking and candidate gene variants in the general population. Functional candidate gene sequence variations will be identified and correlated with clinical features. These research findings could provide important public health information about children, adolescents and adults who have such disorders and the impact these diseases have on the fields of child-development, genetics and environmental toxicology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH083823-04
Application #
8114042
Study Section
Child Psychopathology and Developmental Disabilities Study Section (CPDD)
Program Officer
Friedman-Hill, Stacia
Project Start
2008-09-23
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$641,350
Indirect Cost
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Micalizzi, Lauren; Marceau, Kristine; Brick, Leslie A et al. (2018) Inhibitory control in siblings discordant for exposure to maternal smoking during pregnancy. Dev Psychol 54:199-208
Marceau, Kristine; Cinnamon Bidwell, L; Karoly, Hollis C et al. (2018) Within-Family Effects of Smoking during Pregnancy on ADHD: the Importance of Phenotype. J Abnorm Child Psychol 46:685-699
Bidwell, L Cinnamon; Marceau, Kristine; Brick, Leslie A et al. (2017) Prenatal Exposure Effects on Early Adolescent Substance Use: Preliminary Evidence From a Genetically Informed Bayesian Approach. J Stud Alcohol Drugs 78:789-794
Knopik, Valerie S; Marceau, Kristine; Bidwell, L Cinnamon et al. (2016) Smoking during pregnancy and ADHD risk: A genetically informed, multiple-rater approach. Am J Med Genet B Neuropsychiatr Genet 171:971-81
Huentelman, Matthew J; Muppana, Leela; Corneveaux, Jason J et al. (2015) Association of SNPs in EGR3 and ARC with Schizophrenia Supports a Biological Pathway for Schizophrenia Risk. PLoS One 10:e0135076
Mulligan, Richard C; Reiersen, Angela M; Todorov, Alexandre A (2014) Attention-Deficit/Hyperactivity Disorder, Autistic Traits, and Substance Use Among Missouri Adolescents. Scand J Child Adolesc Psychiatr Psychol 2:86-92
Reiersen, Angela M; Todorov, Alexandre A (2013) Exploration of ADHD Subtype Definitions and Co-Occurring Psychopathology in a Missouri Population-Based Large Sibship Sample. Scand J Child Adolesc Psychiatr Psychol 1:3-13
Williams, Nigel M; Franke, Barbara; Mick, Eric et al. (2012) Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3. Am J Psychiatry 169:195-204
Stergiakouli, Evangelia; Hamshere, Marian; Holmans, Peter et al. (2012) Investigating the contribution of common genetic variants to the risk and pathogenesis of ADHD. Am J Psychiatry 169:186-94
Elia, Josephine; Glessner, Joseph T; Wang, Kai et al. (2011) Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nat Genet 44:78-84

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