Attention-deficit hyperactivity disorder associated gene variants and their impact on neuroanatomy

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder characterized by complex genetic and neurobiological underpinnings, with heritability estimates suggesting that genetic factors account for up to 75% of the risk. Neuroimaging studies have consistently demonstrated structural and functional alterations in brain regions such as the frontal cortex, striatum, and cingulate areas among affected individuals. This narrative review synthesizes evidence from genome-wide association studies (GWAS), molecular genetic analyses, and neuroimaging research published between 2005 and 2023 to elucidate the associations between ADHD-related genetic variants and neuroanatomical or functional brain changes. Key genes implicated include DRD4, SLC6A3, COMT, CDH13, and ADGRL3, whose polymorphisms—such as the DRD4 7-repeat allele, SLC6A3 9R/10R variants, and COMT Val158Met—have been linked to altered dopaminergic signaling, reduced gray matter volume, cortical thinning, and disrupted connectivity in fronto-striatal and fronto-parietal networks. Subtype-specific neuroimaging findings further reveal that individuals with the combined subtype exhibit decreased pallidum volume and cingulate cortical thinning, whereas those with the Inattentive subtype demonstrate occipital thinning and insular abnormalities. Collectively, these findings reinforce that ADHD is a polygenic disorder with distinct neuroanatomical correlates underlying its phenotypic heterogeneity and variable treatment responses. Despite progress, inconsistencies in methodology, small effect sizes, and limited population diversity constrain current insights, underscoring the need for longitudinal, multimodal research to refine genotype–phenotype mapping and support precision medicine approaches in ADHD.