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. 2020 Aug;29(3):188-201.
Epub 2020 Aug 1.

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

Sarojini M Sengupta  1   2 , Natalie Grizenko  1   2 , Marie-Ève Fortier  1 , Marina Ter-Stepanian  3   4 , Ridha Joober  1   2   5   6
Affiliations

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

Sarojini M Sengupta et al. J Can Acad Child Adolesc Psychiatry. 2020 Aug.

Abstract
in English, French

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.

Objectif: L’étiologie du trouble de déficit d’attention avec hyperactivité (TDAH) est complexe, puisque des facteurs tant génétiques qu’environnementaux y sont impliqués. L’étude d’association pangénomique du TDAH la plus récente a identifié 12 loci qui présentaient une association significative avec le trouble. Toutefois, comme le soulignent les auteurs, ces loci ne « représentent qu’une infime fraction » du risque de TDAH. Il est suggéré qu’il peut être important de démêler: (1) la complexité clinique du trouble et (2) l’interaction complexe entre les facteurs génétiques et environnementaux, afin de mieux décortiquer l’étiologie du trouble.

Méthode: Nous avons mené une étude de génétique pharmaco-comportementale importante sur le plan clinique auprès d’un groupe nombreux d’enfants souffrant du TDAH (~850 familles) au cours des 15 dernières années. L’étude comporte une évaluation détaillée des phénotypes comportementaux et neuropsychologiques quantitatifs, ainsi que la réponse à court terme de ces phénotypes au traitement par dose fixe de méthylphénidate (0,5 mg/kg dans une dose deux fois par jour). Les marqueurs génétiques spécifiques et les facteurs environnementaux ont été examinés relativement à leur association à ces dimensions.

Résultats: Nous présentons ici les résultats qui soulignent l’importance d’examiner l’association génétique avec les traits quantitatifs, y compris ces construits qui ont rapport aux critères du domaine de recherche (RDoC). En outre, nous démontrons qu’en menant une analyse d’association dans des groupes d’enfants stratifiés selon leur exposition à une exposition environnementale principale (le tabagisme maternel ou le stress durant la grossesse), nous sommes capables d’accroître la sensibilité propice à trouver des gènes impliqués dans le trouble.

Conclusion: Ces résultats suggèrent qu’un phénotypage profond et une réduction de l’hétérogénéité peuvent être impératifs afin de découvrir « l’héritabilité manquante » du trouble.

Keywords: ADHD genetics; RDoC; cognition; environmental factors; gene-environment interplay; pharmacogenetics.

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Figures

Figure 1
Figure 1
Gene (G) modulates behaviour (B) but not the response of B to MPH (rB) (H1 in the manuscript)
Figure 2A
Figure 2A
Gene (G) modulates response of behaviour to MPH (rB) but not the behaviour itself (B) (H2 in the manuscript). Depiction that G and its protein product P modulates rB, but does not affect B. This modulation could be due to pharmaco-kinetic factors, that regulate drug bio-availability, or pharmaco-dynamic factors, that modulate the affinity of the receptor to the drug (illustrated by the blue crescent surrounding P).
Figure 2B
Figure 2B
Gene (G) modulates behaviour (B) and response of B to MPH (rB) (H3 in the manuscript)
See this image and copyright information in PMC

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