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

doi:10.1007/s00406-022-01388-7

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

Eur Arch Psychiatry Clin Neurosci. 2023 Feb;273(1):15-24. doi: 10.1007/s00406-022-01388-7. Epub 2022 Mar 12.

Authors

Gabriela Pessin Meyer^#¹, Bruna Santos da Silva^#^{1

2

3

4}, Cibele Edom Bandeira^{1

2

3

4}, Maria Eduarda Araujo Tavares^{1

2

3

4}, Renata Basso Cupertino⁵, Eduarda Pereira Oliveira¹, Diana Müller^{2

3}, Djenifer B Kappel⁶, Stefania Pigatto Teche^{2

7}, Eduardo Schneider Vitola^{2

7}, Luis Augusto Rohde^{2

3}, Diego Luiz Rovaris⁸, Eugenio Horacio Grevet^{2

3

7}, Claiton Henrique Dotto Bau^{9

10

11

12}

Affiliations

¹ Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
² ADHD Outpatient Program, Clinical Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
³ Developmental Psychiatry Program, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
⁴ Department of Genetics, Institute of Biosciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
⁵ Department of Psychiatry, University of Vermont, Burlington, VT, USA.
⁶ Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales.
⁷ Department of Psychiatry, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
⁸ Departamento de Fisiologia e Biofisica, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, São Paulo, Brazil.
⁹ Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. claiton.bau@ufrgs.br.
¹⁰ ADHD Outpatient Program, Clinical Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. claiton.bau@ufrgs.br.
¹¹ Developmental Psychiatry Program, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. claiton.bau@ufrgs.br.
¹² Department of Genetics, Institute of Biosciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. claiton.bau@ufrgs.br.

^# Contributed equally.

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

MeSH terms

Attention Deficit Disorder with Hyperactivity* / diagnosis
Autism Spectrum Disorder* / complications
Brain
Forkhead Transcription Factors / genetics
Genome-Wide Association Study
Humans
Phenotype

Substances

FOXP2 protein, human
Forkhead Transcription Factors

Abstract

MeSH terms

Substances

Grants and funding