Cross-disorder genetic analyses implicate dopaminergic signaling as a biological link between Attention-Deficit/Hyperactivity Disorder and obesity measures
Year: 2020
Type: article
Study design: Observational Study
Abstract: ABSTRACT Attention-Deficit/Hyperactivity Disorder (ADHD) and obesity are frequently comorbid, genetically correlated, and share brain substrates. The biological mechanisms driving this association are unclear, but candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the genetic link between ADHD and obesity measures and investigate associations of overlapping genes with brain volumes. We tested the association of dopaminergic and circadian rhythm gene sets with ADHD, body mass index (BMI), and obesity (using GWAS data of N=53,293, N=681,275, and N=98,697, respectively). We then conducted genome-wide ADHD-BMI and ADHD-obesity gene-based meta-analyses, followed by pathway enrichment analyses. Finally, we tested the association of ADHD-BMI overlapping genes with brain volumes (primary GWAS data N=10,720–10,928; replication data N=9,428). The dopaminergic gene set was associated with both ADHD (P=5.81×10 −3 ) and BMI (P=1.63×10 −5 ), the circadian rhythm was associated with BMI (P=1.28×10 −3 ). The genome-wide approach also implicated the dopaminergic system, as the Dopamine-DARPP32 Feedback in cAMP Signaling pathway was enriched in both ADHD-BMI and ADHD-obesity results. The ADHD-BMI overlapping genes were associated with putamen volume (P=7.7×10 −3 ; replication data P=3.9×10 −2 ) – a brain region with volumetric reductions in ADHD and BMI and linked to inhibitory control. Our findings suggest that dopaminergic neurotransmission, partially through DARPP-32-dependent signaling and involving the putamen, is a key player underlying the genetic overlap between ADHD and obesity measures. Uncovering shared etiological factors underlying the frequently observed ADHD-obesity comorbidity may have important implications in terms of prevention and/or efficient treatment of these conditions.
Source: Neuropsychopharmacology
Institutions: Radboud University Nijmegen, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, University Medical Center Utrecht, Centre for Biomedical Network Research on Rare Diseases, Institut de Recerca Sant Joan de Déu, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona, University Hospital Frankfurt
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,760
Funders: European Commission, Deutsche Forschungsgemeinschaft, Vrije Universiteit Amsterdam, Bundesministerium für Bildung und Forschung, Generalitat de Catalunya, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Ministerio de Economía y Competitividad, European College of Neuropsychopharmacology, Servier, Neuraxpharm, Horizon 2020 Framework Programme, Agència de Gestió d'Ajuts Universitaris i de Recerca
Awards: G1137426806, G1151563582, G16286648, G2045506754, G2783655308, Mastering skills in the training Network for attention deficit hyperactivity and autism spectrum Disorders, G3288897321, G3319013621, G3507519538, G3552952322, G3654821277, G4077098235, G408622963, G4167878811, G434337789, G4406419128, G4937468798, Effects of Nutrition and Lifestyle on Impulsive, Compulsive, and Externalizing behaviours, G5808246334, Comorbid Conditions of Attention deficit / hyperactivity disorder, G6400842840, G697019932, G7450244311, G8042824225, G816376308, G872823698
OpenAlex ID: W2998725968