Association of methylation status of CpG islands in DAT1 and DRD4 genes with attention deficit hyperactivity disorder

Abstract

Objective To explore the difference of methylation status of CpG island in promoter region of DAT1 and DRD4 genes between children with attention deficit hyperactivity disorder (ADHD) and normal controls, and further understand the pathogenesis of ADHD from a epigenetics point of view. Methods 111 ADHD patients and 118 normal controls were enrolled in the present study. The demographic data and peripheral venous blood were collected from both groups. Bisulfite genomic sequencing (BGS) was used to confirm the methylation status of every CpG site in promoter region of DAT1 and DRD4 genes. Results No significant differences were found between ADHD patients and normal controls on percentage of methylated CpG sites in total CpG islands for both DAT1 and DRD4 (P>0.05). However, the percentage of methylation in No. 17 CpG site for DAT1 and No. 8 CpG site for DRD4 was higher in ADHD patients (23.42% and 64.86% respectively)compared with that in normal controls(11.86% and 47.46% respectively)(P<0.05). In all samples, the percentage of methylated CpG site in total CpG island for DAT1 was higher in males compared with that in females(P<0.05), whereas that for DRD4 was higher in females compared with that in males (P<0.05); the same gender difference on methylation level for DAT1 was also found in ADHD patients and for DRD4 in normal controls(P<0.05). In all samples and in ADHD patients, percentage of methylated CpG site in total CpG island for DAT1 was higher in individuals over 7 years old compared with that in individuals younger than or equal to 7 years old(P<0.05). Conclusions Methylation status of CpG island in DAT1 and DRD4 genes promoter region might correlate with ADHD susceptibility.Methylation status of CpG island in DAT1 and DRD4 genes show differences in different age span and sex. Key words: Attention deficit hyperactivity disorder; Epigenetics; DNA methylation; Dopamine transporter gene (DAT1/SLC6A3); Dopamine receptor D4 gene (DRD4)