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. 2025 Feb 11.
doi: 10.1007/s00406-025-01968-3. Online ahead of print.

Increasing specificity in ADHD genetic association studies during childhood: use of the oxytocin-vasopressin pathway in attentional processes suggests specific mechanism for endophenotypes in the 2004 Pelotas birth (Brazil) cohort

Laísa Camerini  1   2 , Thais Martins-Silva  3   4   5 , Luís Augusto Rohde  4   6   7 , Iná S Santos  3 , Fernando Barros  3   8 , Júlia Pasqualini Genro  4   9 , Gabriele Ghisleni  8 , Mara Helena Hutz  4   10 , Isabel Oliveira  3   11 , Alicia Matijasevich  3   12 , Luciana Tovo-Rodrigues  3   4
Affiliations

Increasing specificity in ADHD genetic association studies during childhood: use of the oxytocin-vasopressin pathway in attentional processes suggests specific mechanism for endophenotypes in the 2004 Pelotas birth (Brazil) cohort

Laísa Camerini et al. Eur Arch Psychiatry Clin Neurosci. .

Abstract

Attentional executive functions, representing a set of self-regulatory cognitive skills, can be a potential Attention-Deficit/Hyperactivity Disorder (ADHD) endophenotype useful for exploring the huge heterogeneity associated to the disorder. Specific biological pathways like the oxytocin-vasopressin pathway (OT-AVP) can unreel ADHD polygenicity. Here, we test the association between genome-wide ADHD polygenic score (PGS) (ADHD-PGS) and both ADHD symptoms and attentional executive functions in the participants of the 2004 Pelotas (Brazil) birth cohort study (N = 4231). We also investigated whether the OT-AVP genomic pathway (OT/AVPADHD-PGS) is involved in the etiology of ADHD and whether it influences the specificity of attentional functions. ADHD symptoms were assessed through the Strength and Difficulties Questionnaire (SDQ) and the attentional executive functions were evaluated by the Test-of-Everyday-Attention-for-Children (TEA-Ch) at 11 years follow-up. The ADHD-PGS and OT/AVPADHD-PGS were constructed based on the most recent ADHD GWAS meta-analytic statistics. The OT/AVPADHD-PGS included only functional relevant genes for the pathway using KEGG repository. ADHD-PGS was associated with ADHD symptoms and attentional control/switching domain. OT/AVPADHD-PGS showed an enrichment for selective attention domain [number of targets (β = - 0.09, 95% CI = - 0.17; - 0.02, competitive-P = 0.025); attention score (β = 0.11, 95% CI = 0.001; 0.23, competitive-P = 0.050), and in attentional control/switching domain [verbal processing speed (β = 0.27, 95% CI = 0.05; 0.50, competitive-P = 0.041); attentional control (β = 0.42, 95% CI = 0.12; 0.73, competitive-P = 0.033). Our results show a specific role of the OT/AVP pathway in attentional executive functions and suggest that increasing both phenotypic and genetic specificity is of great value. These findings have clinical relevance since OT/AVP have a role in attention toward social cues and shared attentions, which are impaired in children with ADHD.

Keywords: ADHD; Attentional executive functions; Endophenotypes; Oxytocin/vasopressin signaling; Polygenic scores.

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Conflict of interest statement

Declarations. Conflict of interest: LAR has received grant or research support from, served as a consultant to, and served on the speakers’ bureau of Abdi-Ibrahim, Abbott, Aché, Adium, Aspen, Bial, Medice, Novartis/Sandoz, Pfizer/Upjohn, and Shire/Takeda in the last three years. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by LAR have received unrestricted educational and research support from the following pharmaceutical companies in the last three years: Novartis/Sandoz and Shire/Takeda. LAR has received authorship royalties from Oxford Press and ArtMed. The other authors declare that they have no conflict of interest. Ethical approval: The research protocol for all stages of the 2004 Pelotas Birth Cohort Study was approved by the Research Ethics Committee of the Faculty of Medicine at the Federal University of Pelotas and by the Ethics Committee for the Analysis of Research Projects of the University of São Paulo under the number of approvals 40602124 and 889,753. The Brazilian National Commission for Research Ethics also approved the use of genomic data for multifactorial characteristics. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. Consent to participate: Written informed consent was obtained from the mothers or legal guardians, and adolescents also signed an informed consent form.

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