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

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 genewide 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.

A Genome-wide Association Study Identifies Novel Genetic Variants Associated with Neck or Shoulder Pain in the UK Biobank (N = 441,757)

“…In a previous GWAS analysis, FOXP2 has been confirmed to be associated with neck or shoulder pain, and multi-site chronic pain (Johnston et al 2019; Meng et al 2020). In addition, FOXP2 has been found to be associated with the development of attention deficit hyperactivity disorder and psychological disorders (Wendt et al 2018; Meyer et al 2023). The identified brain regions, including the hypothalamus, are known to play crucial roles in central neuroendocrine and hormone secretion (Markakis 2002).…”

Investigation of the forkhead box protein P2 gene by the next-generation sequence analysis method in children diagnosed with specific learning disorder

“…The rs5886709 SNP selected from FOXP2 gene was associated with ADHD risk in a GWAS meta-analysis (Demontis et al , 2019). In another GWAS study conducted with adults with ADHD, it was reported to be associated with impulse control and decision-making mechanisms, although it was not specifically associated with ADHD status (Meyer et al , 2022). As far as we know, there has been no study comparing the specific cognitive functions for both psychopathologies of ADHD and SLD, including the studies mentioned above.…”

FOXP2-immunoreactive, corticothalamic pyramidal cells in neocortical layers 6a and 6b are tightly regulated by neuromodulatory systems

“…Additionally, in humans, FOXP2 has been implicated in various neuropsychiatric disorders such as autism spectrum disorder, attentiondeficit hyperactivity disorder (ADHD), and schizophrenia (e.g. Co et al, 2020;Demontis et al, 2019;Konopka and Roberts, 2016;Li and Pozzo-Miller, 2020;Meyer et al, 2022;Mukamel et al, 2011;Walker et al, 2012). These disorders may result from dysfunctional neuronal networks caused by disruptions in the interaction between FOXP2 and its transcription targets.. FOXP2 regulates the transcription of numerous downstream target genes (den Hoed et al, 2021;Konopka et al, 2012;Spiteri et al, 2007).…”