Expression profile of the ADHD risk gene <i>ADGRL3</i> during human neurodevelopment and the effects of genetic variation

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, with symptoms including hyperactivity, inattention and impulsivity. Moreover, ADHD persists into adulthood in ∼50% cases, significantly affecting quality of life. Currently, the complex aetiology of ADHD remains unclear. Single nucleotide polymorphisms (SNPs) in the adhesion G protein-coupled receptor isoform L3 gene (<i>ADGRL3</i>) have been associated with ADHD development, with the rs1397547 SNP found associated with altered <i>ADGRL3</i> transcription in fibroblast cells. However, ADGRL3 function has not been investigated in human neurodevelopment. We used human induced pluripotent stem cell (hiPSC)-derived cortical neurons to characterise ADGRL3 expression during human neurogenesis and investigated the effects of the rs1397547 SNP on gene expression. We found that <i>ADGRL3</i> expression peaks early in neurodevelopment. ADGRL3 protein was found primarily expressed in glutamatergic neurons, and localised to growth cone-like structures, supporting a role in neurite outgrowth and glutamatergic synapse development. We found rs1397547 was associated with significantly increased <i>ADGRL3</i> transcription in early neurodevelopmental stages. Moreover, single-cell RNA sequencing of maturing cortical neurons revealed a unique transcriptional profile in SNP carriers. Our results further implicate ADGRL3 in ADHD development and suggest that genetic variation may result in dysregulated glutamatergic neuron development.