Comprehensive phenotype/genotype analyses of the norepinephrine transporter gene (SLC6A2) in ADHD: relation to maternal smoking during pregnancy.

Geeta A Thakur,Ridha Joober,Zia Choudhry,Sarojini M Sengupta,Natalie Grizenko

doi:10.1371/journal.pone.0049616

Abstract

ObjectiveDespite strong pharmacological evidence implicating the norepinephrine transporter in ADHD, genetic studies have yielded largely insignificant results. We tested the association between 30 tag SNPs within the SLC6A2 gene and ADHD, with stratification based on maternal smoking during pregnancy, an environmental factor strongly associated with ADHD.MethodsChildren (6–12 years old) diagnosed with ADHD according to DSM-IV criteria were comprehensively evaluated with regard to several behavioral and cognitive dimensions of ADHD as well as response to a fixed dose of methylphenidate (MPH) using a double-blind placebo controlled crossover trial. Family-based association tests (FBAT), including categorical and quantitative trait analyses, were conducted in 377 nuclear families.ResultsA highly significant association was observed with rs36021 (and linked SNPs) in the group where mothers smoked during pregnancy. Association was noted with categorical DSM-IV ADHD diagnosis (Z = 3.74, P = 0.0002), behavioral assessments by parents (CBCL, P = 0.00008), as well as restless-impulsive subscale scores on Conners’-teachers (P = 0.006) and parents (P = 0.006). In this subgroup, significant association was also observed with cognitive deficits, more specifically sustained attention, spatial working memory, planning, and response inhibition. The risk allele was associated with significant improvement of behavior as measured by research staff (Z = 3.28, P = 0.001), parents (Z = 2.62, P = 0.009), as well as evaluation in the simulated academic environment (Z = 3.58, P = 0.0003).ConclusionsBy using maternal smoking during pregnancy to index a putatively more homogeneous group of ADHD, highly significant associations were observed between tag SNPs within SLC6A2 and ADHD diagnosis, behavioral and cognitive measures relevant to ADHD and response to MPH. This comprehensive phenotype/genotype analysis may help to further understand this complex disorder and improve its treatment. Clinical trial registration information – Clinical and Pharmacogenetic Study of Attention Deficit with Hyperactivity Disorder (ADHD); www.clinicaltrials.gov; NCT00483106.

Highlights

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent psychiatric disorder, with rates ranging from 5.9–7.1% in children and adolescents [1]
[56] Nonperseverative errors are incorrect categorizations not related to perseveration, and usually arise from distractibility as well as deficits in updating and monitoring working memory. It appears that in the group where mothers smoked during pregnancy, children with the T allele at rs36021 exhibit executive function (EF) deficits, sustained attention, spatial working memory, planning, and response inhibition
Family-based association tests (FBAT) analysis in the group where mothers smoked during pregnancy showed significant association between other single nucleotide polymorphisms (SNPs) towards the 59end of SLC6A2 and one or more behavioral/ cognitive measures

Summary

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent psychiatric disorder, with rates ranging from 5.9–7.1% in children and adolescents [1]. It is heterogeneous in its clinical expression, with core symptoms of poor sustained attention, impulsivity, and hyperactivity. It is often associated with cognitive deficits, in executive function and sustained attention. Psychostimulants, mostly methylphenidate (MPH) [4] are the first-line of treatment for ADHD. These medications are known to block the dopamine (DA) and norepinephrine (NE) transporters, resulting in increased synaptic concentration of both neurotransmitters. These medications are known to block the dopamine (DA) and norepinephrine (NE) transporters, resulting in increased synaptic concentration of both neurotransmitters. [5,6,7] Short-term trials have concluded that MPH is efficacious in reducing ADHD symptoms in approximately 70% of affected children [4] and adults. [8] NE-specific pharmacological agents (including clonidine, guanfacine, desipramine, and atomoxetine) are effective in treating ADHD, thereby implicating this catecholamine as a major player in the pathophysiology of the disorder. [9] These studies reinforced the early evidence from neurochemical research that NE is involved in ADHD. [10,11] Neuroimaging [12] and animal studies [13] have provided further evidence for the role of NE in ADHD

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