A novel cis-regulatory variant modulating TIE1 expression associated with attention deficit hyperactivity disorder in Han Chinese children.

ABSTRACT

BACKGROUND: The genetic factors of attention deficit hyperactivity disorder (ADHD) are far from fully elucidated. This study aims to get additional insight into the genetic structure of ADHD. METHODS: First, a transcriptome-wide association study and summary data-based Mendelian randomization analysis were performed to identify ADHD susceptibility genes. Then, genetic variants influencing the expression of the identified susceptibility genes were tested for association with ADHD risk in a sample of Han Chinese children (543 cases and 560 controls). Dual-luciferase reporter gene assays and electrophoretic mobility shift assays were performed to verify the transcriptional regulatory functions of the identified ADHD-associated variants. Additionally, real-time quantitative polymerase chain reaction was applied to quantify the expression levels of target genes in blood samples. RESULTS: Both TIE1 and MED8 were identified as ADHD susceptibility genes. Furthermore, we first found the G allele of rs3768046 was significantly associated with an increased risk of ADHD (recessive model GG vs AA+AG, OR= 1.659, 95% CI= (1.262, 2.181); additive model GG vs GA vs AA, OR= 1.493, 95% CI= (1.179, 1.890)). Additionally, in vitro functional experiments revealed that rs3768046 might alter TIE1 expression by affecting the binding sites of transcription factors. Moreover, the expression level of TIE1 in the blood samples of patients was significantly higher than that of controls. LIMITATIONS: Given the moderate statistical power of this study, it is necessary to verify our findings in other larger samples. CONCLUSIONS: Together, this study presents the first systematic evidence of TIE1 with potential implications for the genetic basis of ADHD.