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Feb, 2023;273 (1): 15-24.

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

Gabriela Pessin Meyer, Bruna Santos da Silva, Cibele Edom Bandeira, Maria Eduarda Araujo Tavares, Renata Basso Cupertino, Eduarda Pereira Oliveira, Diana Müller, Djenifer B Kappel, Stefania Pigatto Teche, Eduardo Schneider Vitola, Luis Augusto Rohde, Diego Luiz Rovaris, Eugenio Horacio Grevet, Claiton Henrique Dotto Bau
Author Information
  1. Gabriela Pessin Meyer: Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
  2. Bruna Santos da Silva: Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
  3. Cibele Edom Bandeira: Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
  4. Maria Eduarda Araujo Tavares: Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
  5. Renata Basso Cupertino: Department of Psychiatry, University of Vermont, Burlington, VT, USA.
  6. Eduarda Pereira Oliveira: Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
  7. Diana Müller: ADHD Outpatient Program, Clinical Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
  8. Djenifer B Kappel: Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales.
  9. Stefania Pigatto Teche: ADHD Outpatient Program, Clinical Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
  10. Eduardo Schneider Vitola: ADHD Outpatient Program, Clinical Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
  11. Luis Augusto Rohde: ADHD Outpatient Program, Clinical Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
  12. Diego Luiz Rovaris: Departamento de Fisiologia e Biofisica, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, São Paulo, Brazil.
  13. Eugenio Horacio Grevet: ADHD Outpatient Program, Clinical Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
  14. Claiton Henrique Dotto Bau: Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. claiton.bau@ufrgs.br. ORCID
PMID: 35279744 DOI: 10.1007/s00406-022-01388-7

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; P = 0.015) and nominal associations with hyperactivity symptoms (P = 0.026; P = 0.130) and antisocial personality disorder (P = 0.026; P = 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.

Keywords

ADHD FOXP2 Personality traits Psychiatric disorders Structural neuroimaging

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Grants

  1. 476529/2012-3/Conselho Nacional de Desenvolvimento Científico e Tecnológico
  2. 466722/2014-1/Conselho Nacional de Desenvolvimento Científico e Tecnológico
  3. 424041/2016-2/Conselho Nacional de Desenvolvimento Científico e Tecnológico
  4. finance code 001/Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
  5. FIPE-HCPA 160600/Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
  6. PqG-19/2551-0003731/Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul
  7. PqG-19/2551-001668-9/Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul

MeSH Term

Humans
Attention Deficit Disorder with Hyperactivity
Autism Spectrum Disorder
Genome-Wide Association Study
Phenotype
Brain
Forkhead Transcription Factors

Chemicals

FOXP2 protein, human
Forkhead Transcription Factors
Journal Article
Article has an altmetric score of 3

Word Cloud

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