Gene–Environment interactions in the development of combined type ADHD: Evidence for a synapse-based model
Open accessAbstract
To determine the mechanism of interaction of prenatal smoking exposure and child genotype in the development of attention deficit/hyperactivity disorder (ADHD), polymorphisms in the CHRNA4 gene were tested for interactions with prenatal smoking exposure on risk for ADHD subtypes using multiple logistic regression. An exon 5 polymorphism demonstrated a significant interaction with history of maternal smoking during pregnancy for increasing risk for severe combined type ADHD (OR = 3.0, 95% CI 1.1-8.4 for population-defined severe combined type, OR = 3.9 95% CI 1.2-13.1 for DSM-IV defined combined subtype ADHD). This interaction increased the effects of previously reported interactions for the DRD4 and DAT1 genes with prenatal smoking exposure. Given the known functions and the known areas of expression of these three genes at the dopaminergic synapse in the pre-frontal cortex, the results are compatible with a synapse-based model of the development of this form of ADHD. The subtype specificity of these findings supports the concept that ADHD is composed of a group of distinct disorders.
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Early adverse childhood experiences, family conflict, low socioeconomic status, and neglect predict more severe ADHD trajectories and greater comorbidity.
“Early adverse childhood experiences (ACEs), family conflict, low socioeconomic status, and neglect predict more severe ADHD trajectories and greater comorbidity”
From ADHD in Adulthood: Clinical Presentation, Comorbidities, and Treatment Perspectives (2025) · cites this paper as [64]
Table I (Discussion; page not provided) shows that negative expressed emotions at home and conduct disorder or ODD were more common in the severe combined ADHD group than in the few-symptom group. That is an association, not evidence that family conflict predicts later ADHD trajectories or comorbidity. The paper does not establish the claimed effects of ACEs or neglect, and its family-income comparisons were not statistically significant. (LLM, conf=0.86)
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References 27 · Cited by 99
Research works printed but not linked: 1
- Reiersen AM, Neuman RJ, Constantino JN, Volk HE, Todd RD. (in press). Intersection of Autism and ADHD: Evidence for a Distinct Syndrome Influenced by Genes and by Gene-Environment. Genetic and Environ- mental Influences on Developmental: Psychopathology and Wellness: American Psychiatric Publishing, Inc. (ADHD) predominantly hyperactive/impulsive and combined subtypes. Behav Brain Sci 28(3):397-419; discussion 419-68.
- Authors
- Todd, R. D., & Neuman, R. J.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Todd, Richard D.
- Venue
- American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
- Publisher
- Wiley
- Published
- 2007-10-22
- Volume
- 144B
- Issue
- 8
- Pages
- 971-975
- ISSN
- 1552-4841 (ISSN-L)
- 1552-485X
- OpenAlex
- W2100729371
- Cited by
- 99
- References
- 27
- Citations by year
- 2025: 3 · 2024: 3 · 2023: 3 · 2022: 1 · 2021: 13 · 2020: 2 · 2019: 1 · 2018: 11 · 2017: 1 · 2016: 1 · 2015: 4 · 2014: 6 · 2013: 4 · 2012: 4
- FWCI
- 7.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Medical Genetics Part B Neuropsychiatric Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (NIMH 52813)
- National Institute of Mental Health
- National Institute of Neurological Disorders and Stroke (NS 43762, R01NS043762)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Substance Exposure Effects
- Keywords
- attention deficit hyperactivity disorder, combined type ADHD, gene-environment interaction, prenatal smoking exposure, smoking during pregnancy, CHRNA4, ADHD subtypes, DRD4, DAT1, dopaminergic synapse, prefrontal cortex
- MeSH terms
- Adolescent, Adult, Alleles, Attention Deficit Disorder with Hyperactivity, Child, Female, Genotype, Humans, Male, Polymorphism, Genetic, Pregnancy, Prenatal Exposure Delayed Effects, Receptors, Nicotinic, Smoking, Synapses, Twins, Genetic Variation, Logistic Models
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