Maulik Masaliya1 , Dielin Wang2 , Yashita Arora3 , Shuai Wang4 , Giulia Demo5 , Jamal B. Williams6

Background. ADHD is highly heritable, but case-control GWAS explain only a small fraction of that heritability. Genetic variants interacting with continuous behavioral traits may account for some missing heritability. We tested this using interaction-based GWAS across six ADHD phenotypes and structural MRI in a pediatric cohort. Methods. We used the ABCD Study (n up to 8,302 children, ages 9–11), stratified into five ancestry groups. Six phenotypes: hyperactivity, inattention, impulsivity, emotional dysregulation, CBCL Attention Problems T-scores, and Flanker inhibitory control. SNP × behavior interactions were modeled on 34 sMRI measures from the Desikan–Killiany atlas in PLINK and meta-analyzed across ancestries with METAL. Significant loci (p < 5×10−8 ) collapsed into 1 Mb windows. Results. We identified 589 genome-wide significant interaction loci — substantially exceeding prior ADHD GWAS of comparable sample size. rs56817477 (Chr 2) reached Z = −7.76 (p = 8.7×10−15) for 3rd ventricle volume independently in hyperactivity, emotional dysregulation, and inattention, with identical direction across all three analyses — within-study SNP-level replication not previously reported for a structural brain locus in ADHD. Precentral gyrus volume was significant across all five symptom composites, identifying primary motor cortex as a transdiagnostic neuroanatomical hub. Impulsivity yielded 18 independent white-matter hyperintensity loci across 13 chromosomes. Sixty-three ventricular clusters showed convergence across three or more phenotypes. Interaction effect directions reversed across phenotypes, revealing phenotype-specific genetic architectures. Conclusions. SNP-by-behavior interactions expose ADHD neurobiology invisible to case-control designs. Phenotype-specific pathways converge on ventricular, sensorimotor, and fronto-parietal systems. The chromosome 2 locus is the most robustly replicated structural brain locus in pediatric ADHD genetics to date.

Keywords: ADHD · interaction GWAS · structural MRI · SNP×behavior · Desikan–Killiany · ABCD Study · ventricular volume · precentral gyrus · white matter

1 Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 2Department of Psychiatry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 3Department of Pediatrics, University at Buffalo, Buffalo, NY 4Department of Psychiatry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 5Department of Psychiatry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 6Department of Psychiatry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY