Examining Differences in the Genetic and Functional Architecture of Attention-Deficit/Hyperactivity Disorder Diagnosed in Childhood and Adulthood

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is diagnosed when symptoms begin in childhood. We investigate whether individuals diagnosed as children differ from those diagnosed in adulthood with respect to shared and unique architecture at the genome-wide and gene expression level of analysis. We utilize Genomic Structural Equation Modeling (SEM) to investigate differences in genetic correlations (rg) of childhood (Ncases=14,878) and adulthood (Ncases=6,961) diagnosed ADHD with 98 behavioral, psychiatric, cognitive, and health outcomes. We go on to apply Transcriptome-wide SEM (T-SEM) to identify functional annotations and patterns of gene expression associated with genetic risk sharing or divergence across the ADHD subgroups. Relative to the childhood subgroup, adulthood diagnosed ADHD exhibited a significantly larger negative rg with educational attainment, the noncognitive skills of educational attainment, and age at first sexual intercourse. We observe a larger positive rg for adulthood diagnosed ADHD with major depression, suicidal ideation, and a latent internalizing factor. At the gene expression level, T-SEM analyses revealed 22 genes that were significantly associated with shared genetic risk across the subtypes that reflected a mixture of coding and non-coding genes and included 15 novel genes relative to the ADHD subgroups. This study demonstrates that ADHD diagnosed later in life shows much stronger genetic overlap with internalizing disorders and related traits. This may indicate the potential clinical relevance of distinguishing these subgroups or increased misdiagnosis for those diagnosed later in life. Top T-SEM results implicated genes related to neuronal function and clinical characteristics (e.g., sleep).