Differential Genetic Effect of the Norepinephrine Transporter Promoter Polymorphisms on Attention Problems in Clinical and Non-clinical Samples.

Zsofia Nemoda,Maria Sasvari-Szekely,Zsanett Tarnok,Krisztina Lakatos,Judit Gervai,Nora Angyal,Emese Bognar,Emma Birkas

doi:10.3389/fnins.2018.01051

Abstract

Among the monoaminergic modulatory neurotransmitters, norepinephrine is involved in task orienting, hence noradrenergic genetic variants have been studied in connection to attentional processes. The role of this catecholamine system is also highlighted by the selective norepinephrine transporter blocking atomoxetine, which has proved to be effective in the pharmacological treatment of Attention Deficit Hyperactivity Disorder (ADHD). In the present genetic association study three single nucleotide polymorphisms (rs28386840, rs2242446, rs3785143 SNPs) were analyzed from the 5′ region of the norepinephrine transporter (NET, SLC6A2) gene, which have been linked to ADHD previously. Attention problems scores of the mother-rated Child Behavior Checklist (CBCL) were used in separate analyses of 88 preschoolers (59.1% male, 6 years of age) recruited from the general population and 120 child psychiatry patients with ADHD diagnosis (85.8% male, age: 9.8 ± 2.9). The NET SNPs showed associations with attention problems, but the direction was different in the two groups. Regarding the promoter variant rs28386840, which showed the most consistent association, the T-allele-carrier patients with ADHD had lower CBCL attention problems scores compared to patients with AA genotype (p = 0.023), whereas T-allele-carriers in the community sample had more attention problems (p = 0.042). Based on previous reports of lower NE levels in ADHD children and the inverted-U shape effect of NE on cognitive functions, we propose that rs28386840 (-3081) T-allele, which is associated with lower NET expression (and potentially higher synaptic NE level) would support attention processes among ADHD patients (similarly as atomoxetine increases NE levels), whereas it would hinder cortical functions in healthy children.

Highlights

Attention problems have gained increasing interest during the last decades, as the proportion of children with attention deficit hyperactivity disorder (ADHD) diagnosis has risen dramatically in many countries, creating social and scientific debates (Singh, 2008)
The effectiveness of the selective norepinephrine transporter inhibitor atomoxetine was shown in Attention Deficit Hyperactivity Disorder (ADHD) treatment (Hazell et al, 2011)
Since the availability of dopamine transporter is low in the cortex, but NET is relatively abundant and can take up extracellular dopamine (Moron et al, 2002), imbalances in NET expression may contribute to attention problems due to suboptimal cortical catecholamine functioning

Summary

Introduction

Attention problems have gained increasing interest during the last decades, as the proportion of children with attention deficit hyperactivity disorder (ADHD) diagnosis has risen dramatically in many countries, creating social and scientific debates (Singh, 2008). Identifying potential risk and protective factors at an early age could help developing preventive strategies. Since both ADHD diagnosis and attention problems show substantial genetic background with complex inheritance, searching for genetic markers has been in the center of many studies. Twin studies of children using parent or teacher ratings reported high heritability estimates (h2 ∼ 0.7) for attention problems (Chang et al, 2013; Kan et al, 2013). Our aim was to identify genetic factor(s) of attention problems using a mother-rated symptom scale in a community sample of children in addition to child psychiatry patients, because childhood is potentially the most sensitive period to detect genetic effects

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