Cross-disorder genetic analyses implicate dopaminergic signaling as a biological link between attention-deficit/hyperactivity disorder and obesity measures

  • Attention-Deficit/Hyperactivity Disorder (ADHD) is frequently comorbid with other psychiatric disorders and also with somatic conditions, such as obesity. In addition to the clinical overlap, significant genetic correlations have been found between ADHD and obesity as well as body mass index (BMI). The biological mechanisms driving this association are largely unknown, but some candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the link between ADHD and obesity measures. Using the largest GWAS summary statistics currently available for ADHD (N=53,293), BMI (N=681,275), and obesity (N=98,697), we first tested the association of dopaminergic and circadian rhythm gene sets with each phenotype. This hypothesis-driven approach showed that the dopaminergic gene set was associated with both ADHD (P=5.81×10−3) and BMI (P=1.63×10−5), while the circadian rhythm gene set was associated with BMI only (P=1.28×10−3). We then took a data-driven approach by conducting genome-wide ADHD-BMI and ADHD-obesity gene-based meta-analyses, followed by pathway enrichment analyses. This approach further supported the implication of dopaminergic signaling in the link between ADHD and obesity measures, as the Dopamine-DARPP32 Feedback in cAMP Signaling pathway was significantly enriched in both the ADHD-BMI and ADHD-obesity gene-based meta-analysis results. Our findings suggest that dopaminergic neurotransmission, partially through DARPP-32-dependent signaling, is a key player underlying the genetic overlap between ADHD and obesity measures. Uncovering the shared etiological factors underlying the frequently observed ADHD-obesity comorbidity may have important implications in terms of preventive interventions and/or efficient treatment of these conditions.

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Metadaten
Author:Nina Roth MotaORCiD, Geert PoelmansORCiD, Marieke KleinORCiD, Bàrbara Torrico, Noèlia Fernàndez-CastilloORCiDGND, Bru CormandORCiD, Andreas ReifORCiDGND, Barbara FrankeORCiDGND, Alejandro Arias VásquezORCiD
URN:urn:nbn:de:hebis:30:3-837802
URL:https://www.biorxiv.org/content/10.1101/573808v1
DOI:https://doi.org/10.1101/573808
Parent Title (English):bioRxiv
Publisher:bioRxiv
Document Type:Preprint
Language:English
Date of Publication (online):2019/03/11
Date of first Publication:2019/03/11
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2024/04/15
Issue:573808 Version 1
Edition:Version 1
Page Number:25
HeBIS-PPN:51816120X
Institutes:Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International