DLGAP1 and NMDA receptor-associated postsynaptic density protein genes influence executive function in attention deficit hyperactivity disorder.

Zili Fan,Ying Qian,Li Yang,Suhua Chang,Yufeng Wang,Qing Lu

doi:10.1002/brb3.914

Abstract

ObjectiveTo explore the association of DLGAP1 gene with executive function (EF) in attention deficit hyperactivity disorder (ADHD) children.MethodA total of 763 ADHD children and 140 healthy controls were enrolled. The difference of EF between ADHD and controls was analyzed using the analysis of covariance (ANCOVA), with IQ, sex, and age as covariates. Both the associations of SNPs with EF and three symptom traits of ADHD were conducted using an additive linear regression model by PLINK with the same covariates as ANCOVA.ResultsCompared with controls, children with ADHD showed poorer cognitive flexibility and inhibition. Two SNPs (rs2049161, p‐value = 5.08e‐7, adjusted p‐value = 1.63e‐4, rs16946051, p‐value = 5.18e‐7, adjusted p‐value = 1.66e‐4) survived multiple tests in Trail Making Test. Both SNPs also showed association with TOH (rs2049161, p = 6.82e‐4, rs16946051, p = 7.91e‐4). Set‐based analysis for gene DLGAP1 and its functional pathway DLGAP1‐DLG4‐NMDA showed they were associated with cognitive flexibility at both gene (p = .0057) and pathway level (p = .0321). Furthermore, the gene and pathway also showed association with ADHD symptom score. The associated SNPs and their LD proxies were related to the expression of DLGAP1 in medulla and frontal cortex.ConclusionChildren with ADHD showed deficit in EF, especially, cognitive flexibility and inhibition. DLGAP1 was associated with cognitive flexibility and plan, and the role of DLGAP1 might be implemented through the complex of DLGAP1‐DLG4‐NMDA.

Highlights

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in childhood, which is characterized by hyperactivity, impulsivity, and inattention
We firstly detected the deficit of cognitive flexibility and inhibition in our ADHD sample as expected, which had been consistently reported in previous studies (Paloscia et al, 2013)
We explored the association between DLGAP1 and executive function (EF) in children with ADHD

Summary

| INTRODUCTION

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in childhood, which is characterized by hyperactivity, impulsivity, and inattention. Children with ADHD often have executive function (EF) deficits (Barkley, 2010; Willcutt, Doyle, Nigg, Faraone, & Pennington, 2005), including impairment in inhibitory control, working memory, and cognitive flexibility. SAPAPs constitute the member of the N-methyl-d aspartate (NMDA) receptor-associated postsynaptic density proteins. The latter had been showed for potential association with ADHD for its significant role in prefrontal cortex activity and cognitive function (Chang, Lane, & Tsai, 2014; Lehohla, Kellaway, & Russell, 2004). For ADHD model of spontaneously hypertensive rat (SHR), impaired NMDA receptor function in the prefrontal cortex could result in cognitive deficits and an inability to sustaining attention (Lehohla et al, 2004). Set-based analyses for gene and gene-related pathway were performed to confirm the association

| MATERIALS AND METHODS

| Participants

Findings

| DISCUSSION