Expression profile of the ADHD risk gene ADGRL3 during human neurodevelopment and the effects of genetic variation

Objectives: 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 (ADGRL3) have been associated with ADHD development, with the rs1397547 SNP found associated with altered ADGRL3 transcription in fibroblast cells. However, ADGRL3 function has not been investigated in human neurodevelopment. Methods: 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. Results: We found that ADGRL3 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 ADGRL3 transcription in early neurodevelopmental stages. Moreover, single-cell RNA sequencing of maturing cortical neurons revealed a unique transcriptional profile in SNP carriers. Conclusions: Our results further implicate ADGRL3 in ADHD development and suggest that genetic variation may result in dysregulated glutamatergic neuron development.