Unraveling ADHD: genes, co-occurring traits, and developmental dynamics

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental condition with a high prevalence of co-occurring conditions, contributing to increased difficulty in long-term management. Genome-wide association studies have identified variants shared between ADHD and co-occurring psychiatric disorders; however, the genetic mechanisms are not fully understood. We integrated gene expression and spatial organization data into a two-sample Mendelian randomization study for putatively causal ADHD genes in fetal and adult cortical tissues. We identified four genes putatively causal for ADHD in cortical tissues (fetal: ST3GAL3, PTPRF, PIDD1; adult: ST3GAL3, TIE1). Protein-protein interaction databases seeded with the causal ADHD genes identified biological pathways linking these genes with conditions (e.g., rheumatoid arthritis) and biomarkers (e.g., lymphocyte counts) known to be associated with ADHD, but without previously shown genetic relationships. The analysis was repeated on adult liver tissue, where putatively causal ADHD gene ST3GAL3 was linked to cholesterol traits. This analysis provides insight into the tissue-dependent temporal relationships between ADHD, co-occurring traits, and biomarkers. Importantly, it delivers evidence for the genetic interplay between co-occurring conditions, both previously studied and unstudied, with ADHD.