A functional variant in SLC1A3 influences ADHD risk by disrupting a hsa-miR-3171 binding site: A two-stage association study

Attention-deficit hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders in children and adolescents with high heritability. Evidence is accumulating that SLC1A3 may play a role in ADHD etiology. Therefore, a two-stage case-control study was conducted on 752 cases and 774 controls to explore the role of SLC1A3 in ADHD. Bioinformatic annotations and functional experiments were applied to reveal the potential biological mechanisms. Finally, SLC1A3 rs1049522 showed significant association with ADHD risk in two stages with CA genotype vs AA genotype, odds ratio (OR) = 0.694 (95% confidence interval, CI = 0.570-0.844) and dominant model, OR = 0.749 (95% CI = 0.621-0.904) in the combined stage. Besides, rs1049522 was found to be related to ADHD hyperactive/impulsive symptom, and rs1049522-C showed increased SLC1A3 mRNA expression in the cerebellar cortex. Dual-luciferase reporter assay further indicated that rs1049522-C allele enhanced SLC1A3 expression by disrupting the hsa-miR-3171 binding site. In conclusion, SLC1A3 variant rs1049522 was implicated in ADHD susceptibility in a Chinese Han population probably by enhancing the SLC1A3 expression in a miRNA-mediated manner.