Facing the Methodological Challenge in Dissecting the Genetics of ADHD: A Case for Deep Phenotyping and Heterogeneity Reduction.

TitleFacing the Methodological Challenge in Dissecting the Genetics of ADHD: A Case for Deep Phenotyping and Heterogeneity Reduction.
Publication TypeJournal Article
Year of Publication2020
AuthorsSengupta SM, Grizenko N, Fortier M-È, Ter-Stepanian M, Joober R
JournalJ Can Acad Child Adolesc Psychiatry
Volume29
Issue3
Pagination188-201
Date Published2020 Aug
ISSN1719-8429
Abstract

Objective: The aetiology of ADHD is complex, with genetic and environmental factors both implicated in the disorder. The most recent ADHD genome-wide association study identified 12 loci that showed significant association with the disorder. However, as highlighted by the authors, these loci "only capture a tiny fraction" of the risk for ADHD. It has been suggested that it may be important to disentangle: (1) the clinical complexity of the disorder, and (2) the complex interaction between genetic and environmental factors, in order to better dissect the aetiology of the disorder.Method: We have conducted a clinically-relevant Pharmaco-Behavioural Genetic study in a large group of children with ADHD (~850 families) over the last 15 years. The study includes detailed evaluation of quantitative behavioural and neuropsychological phenotypes, as well as short-term response of these phenotypes to treatment with a fixed dose of methylphenidate (0.5mg/kg in a b.i.d. dose). Specific genetic markers and environmental factors were examined for their association with these dimensions.Results: Here we present results that highlight the importance of examining genetic association with quantitative traits, including those constructs having relevance to Research Domain Criteria (RDoC). Further, we demonstrate that by conducting association analysis in groups of children stratified based on exposure to key environmental exposure (maternal smoking or stress during pregnancy), we are able to increase the sensitivity for finding genes involved in the disorder.Conclusion: These results suggest that deep phenotyping and heterogeneity reduction may be imperative in order to uncover the "missing heritability" of the disorder.

Alternate JournalJ Can Acad Child Adolesc Psychiatry
PubMed ID32774401
PubMed Central IDPMC7391869