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Dissecting the cross-trait effects of the FOXP2 GWAS hit on clinical and brain phenotypes in adults with ADHD

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Abstract

The Forkhead box P2 (FOXP2) encodes for a transcription factor with a broad role in embryonic development. It is especially represented among GWAS hits for neurodevelopmental disorders and related traits, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, neuroticism, and risk-taking behaviors. While several functional studies are underway to understand the consequences of FOXP2 variation, this study aims to expand previous findings to clinically and genetically related phenotypes and neuroanatomical features among subjects with ADHD. The sample included 407 adults with ADHD and 463 controls. Genotyping was performed on the Infinium PsychArray-24 BeadChip, and the FOXP2 gene region was extracted. A gene-wide approach was adopted to evaluate the combined effects of FOXP2 variants (n = 311) on ADHD status, severity, comorbidities, and personality traits. Independent risk variants presenting potential functional effects were further tested for association with cortical surface areas in a subsample of cases (n = 87). The gene-wide analyses within the ADHD sample showed a significant association of the FOXP2 gene with harm avoidance (P = 0.001; PFDR = 0.015) and nominal associations with hyperactivity symptoms (P = 0.026; PFDR = 0.130) and antisocial personality disorder (P = 0.026; PFDR = 0.130). An insertion/deletion variant (rs79622555) located downstream of FOXP2 was associated with the three outcomes and nominally with the surface area of superior parietal and anterior cingulate cortices. Our results extend and refine previous GWAS findings pointing to a role of FOXP2 in several neurodevelopment-related phenotypes, mainly those involving underlying symptomatic domains of self-regulation and inhibitory control. Taken together, the available evidence may constitute promising insights into the puzzle of the FOXP2-related pathophysiology.

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Acknowledgements

We are thankful to the staff of the participating institutions for all their support with data collection, including ProDAH-A team and all the subjects who kindly agreed to participate in the research.

Funding

This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq—476529/2012-3, 466722/2014-1, and 424041/2016-2), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES—Finance Code 001 and FIPE-HCPA 160600), and the Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (PqG-19/2551–0001731-6, PqG-19/2551–001668-9).

Author information

Author notes

  1. Gabriela P. Meyer and Bruna S. da Silva contributed equally to this work.

Authors and Affiliations

  1. Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Gabriela Pessin Meyer, Bruna Santos da Silva, Cibele Edom Bandeira, Maria Eduarda Araujo Tavares, Eduarda Pereira Oliveira & Claiton Henrique Dotto Bau

  2. ADHD Outpatient Program, Clinical Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil

    Bruna Santos da Silva, Cibele Edom Bandeira, Maria Eduarda Araujo Tavares, Diana Müller, Stefania Pigatto Teche, Eduardo Schneider Vitola, Luis Augusto Rohde, Eugenio Horacio Grevet & Claiton Henrique Dotto Bau

  3. Developmental Psychiatry Program, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil

    Bruna Santos da Silva, Cibele Edom Bandeira, Maria Eduarda Araujo Tavares, Diana Müller, Luis Augusto Rohde, Eugenio Horacio Grevet & Claiton Henrique Dotto Bau

  4. Department of Genetics, Institute of Biosciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Bruna Santos da Silva, Cibele Edom Bandeira, Maria Eduarda Araujo Tavares & Claiton Henrique Dotto Bau

  5. Department of Psychiatry, University of Vermont, Burlington, VT, USA

    Renata Basso Cupertino

  6. Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales

    Djenifer B. Kappel

  7. Department of Psychiatry, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Stefania Pigatto Teche, Eduardo Schneider Vitola & Eugenio Horacio Grevet

  8. Departamento de Fisiologia e Biofisica, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, São Paulo, Brazil

    Diego Luiz Rovaris

Authors
  1. Gabriela Pessin Meyer
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  2. Bruna Santos da Silva
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  3. Cibele Edom Bandeira
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  4. Maria Eduarda Araujo Tavares
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  5. Renata Basso Cupertino
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  6. Eduarda Pereira Oliveira
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  7. Diana Müller
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  8. Djenifer B. Kappel
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  9. Stefania Pigatto Teche
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  10. Eduardo Schneider Vitola
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  11. Luis Augusto Rohde
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  12. Diego Luiz Rovaris
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  13. Eugenio Horacio Grevet
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  14. Claiton Henrique Dotto Bau
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Contributions

GPM and BSS designed the study, performed the data analysis, and prepared the first drafts of the manuscript. CEB, MEAT, and RBC collected and processed the neuroimaging data, providing essential contributions to these analyses. EPO, DM, and DBK provided substantial contributions to data acquisition, analyses, and interpretation of the results. SPT and ESV were responsible for the clinical assessment of the patients and helped with the evaluation of the clinical outcomes. DLR, LAR, and EHG provided critical discussion and insights into the intellectual content of the manuscript. CHDB contributed to the conception and design of the study and participated in all its stages of its preparation. All authors carefully revised and approved the final version of this manuscript.

Corresponding author

Correspondence to Claiton Henrique Dotto Bau.

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Conflict of interest

LAR has received honoraria, has been on the speakers’ bureau/advisory board, and/or has acted as a consultant for Medicine, Novartis/Sandoz, and Shire/Takeda in the last two years; and receives authorship royalties from OxfordPress and ArtMed. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by him have received unrestricted educational and research support from the following pharmaceutical companies in the last three years: Janssen-Cilag, Novartis/Sandoz, and Shire/Takeda. EHG has served as a speakers’ bureau/advisory board for Novartis and Shire Pharmaceuticals in the past three years; and has received travel awards from Novartis and Shire for taking part in psychiatric meetings. The other authors declare no conflicts of interest.

Non-financial interests

The authors have no relevant nonfinancial interests to disclose.

Ethical statement

This project was carried out following the Declaration of Helsinki. All subjects signed an informed consent form that was previously approved by the Research Ethics Committees of the participating institutions.

Supplementary Information

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Supplementary file1 (DOCX 610 KB)

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Meyer, G.P., da Silva, B.S., Bandeira, C.E. et al. Dissecting the cross-trait effects of the FOXP2 GWAS hit on clinical and brain phenotypes in adults with ADHD. Eur Arch Psychiatry Clin Neurosci 273, 15–24 (2023). https://doi.org/10.1007/s00406-022-01388-7

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  • DOI: https://doi.org/10.1007/s00406-022-01388-7

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