Expression Of The Adult Adhd-Associated Geneadgrl3is Dysregulated By Risk Variants And Environmental Risk Factors

Objectives ADGRL3is a well-replicated risk gene for adult ADHD, encoding the G protein-coupled receptor latrophilin-3 (LPHN3). However, LPHN3's potential role in pathogenesis is unclear. We aimed to determine whether ADGRL3 expression could be dysregulated by genetic risk variants and/or ADHD-associated environmental risk factors. Methods Eighteen adult ADHD patients and healthy controls were genotyped for rs734644, rs1397547, rs1397548, rs2271338, rs2305339, rs2345039 and rs6551665ADGRL3SNPs, and fibroblast cells were derived from skin punches. The environmental ADHD risk factors 'low birthweight' and 'maternal smoking' were modelled in fibroblast cell culture using starvation and nicotine exposure, respectively. Quantitative real-time PCR and western blotting were performed to quantify ADGRL3 gene and protein expression under control, starvation and nicotine-exposed conditions. Results Starvation was found to significantly decrease ADGRL3 expression, whereas nicotine exposure significantly increased ADGRL3 expression. rs1397547 significantly elevatedADGRL3transcription and protein expression. rs6551665 and rs2345039 interacted with environment to modulateADGRL3transcription.ADGRL3SNPs were significantly able to predict its transcription under both baseline and starvation conditions, and rs1397547 was identified as a significant independent predictor. Conclusions ADGRL3SNPs and environmental risk factors can regulate ADGRL3 expression, providing a potential functional mechanism by which LPHN3 may play a role in ADHD pathogenesis.