ADHD co-morbidities: A review of implication of gene × environment effects with dopamine-related genes

https://doi.org/10.1016/j.neubiorev.2022.104757Get rights and content

Highlights

  • Much of health burden by ADHD is owing to co-morbidities.

  • Major co-morbidities include depression, substance use disorder and obesity.

  • Co-morbidities have early origin and genetic and environmental components.

  • Genes shaping the dopamine system impact ADHD and co-morbidities over life course.

  • The whole dopamine gene cluster should be examined in gene × environment analyses.

Abstract

ADHD is a major burden in adulthood, where co-morbid conditions such as depression, substance use disorder and obesity often dominate the clinical picture. ADHD has substantial shared heritability with other mental disorders, contributing to comorbidity. However, environmental risk factors exist but their interaction with genetic makeup, especially in relation to comorbid disorders, remains elusive. This review for the first time summarizes present knowledge on gene x environment (GxE) interactions regarding the dopamine system. Hitherto, mainly candidate (GxE) studies were performed, focusing on the genes DRD4, DAT1 and MAOA. Some evidence suggest that the variable number tandem repeats in DRD4 and MAOA may mediate GxE interactions in ADHD generally, and comorbid conditions specifically. Nevertheless, even for these genes, common variants are bound to suggest risk only in the context of gender and specific environments. For other polymorphisms, evidence is contradictory and less convincing. Particularly lacking are longitudinal studies testing the interaction of well-defined environmental factors with polygenic risk scores reflecting the dopamine system in its entirety.

Section snippets

ADHD and comorbidity; genes and environments

Attention deficit hyperactivity disorder (ADHD) is a growing public health concern, addressed in multiple genetic studies. This review has the objective to summarize the findings with focus on two aspects: on the dopaminergic system where the culprit of ADHD, according to correlative and experimental studies in animals and humans, is likely to lie, and on the role of environment(s) that may mold the genetic predispositions into pathogenetic process. To that end the major dopamine system shaping

ADHD and dopamine

As the genetic studies reveal a contribution of multiple genes to ADHD, the underlying pathogenesis of the disorder remains unknown. One of the most plausible hypotheses implies that genes with impact on the central dopamine system are implicated in the etiopathology of ADHD, and that might interact with environmental conditions. This gains support from multiple, converging lines of evidence. Drugs used to treat ADHD act on catecholaminergic neurotransmission, and both cortical and subcortical

Dopamine gene variants and G × E with particular reference to ADHD

The general theme of G × E in ADHD will receive limited treatment here as it is extensive on its own and has been recently reviewed elsewhere (Franke and Buitelaar, 2018, Nigg et al., 2010). The reports on candidate gene variants and environmental factors moderating each other in the development of ADHD represent a large variety of genotypes and environmental factors, and herewith the focus will be on the dopamine system. Indeed, dopamine-related genes have been examined most often, and DRD4,

Co-morbidity of ADHD with depression and negative emotionality, addiction and substance use disorders (SUD), and obesity and eating disorders

In community samples the rate of major depressive disorder in youths with ADHD is 5.5 times higher than in youths without ADHD; rates in different studies have been in the range of 12.5–50% (Angold et al., 1999). In clinical samples the comorbidity rate is even higher (Daviss, 2008). The prevalence of clinical depression is more than nine times higher in adults with ADHD (Chen et al., 2018). Depression, similarly to ADHD, is a dimensional state, and persistent negative emotionality, including

Caveats and perspectives

In summary, the role of dopamine neurons and genes encoding the pivotal proteins for dopaminergic neurotransmission in ADHD, depression, substance use disorders and obesity is beyond doubt, and that they are involved in the frequently occurring co-morbidity of ADHD with these other conditions is highly likely. Nonetheless, direct evidence for this mostly remains to be produced. A large number of factors that has placed limitations to relevant studies exist and these have to be addressed in

Acknowledgments

This research was supported by the Estonian Research Council (PRG1213) and the European Commission Horizon 2020 Programme Projects CoCA (No 667302) and Eat2beNICE (No 728018).

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