Association analysis of norepinephrine transporter polymorphisms and methylphenidate response in ADHD patients

Angyal, Nóra; Horvath, Erzsebet; Tárnok, Zsanett; Richman, Mara J.; Bognar, Emese; Lakatos, Krisztina; Sasvári-Székely, Mária; Nemoda, Zsófia

doi:10.1016/j.pnpbp.2018.01.013

Cited by 16 publications

(23 citation statements)

References 41 publications

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“…Previously, we reported genetic associations between NET gene polymorphisms and inattention symptom severity on the ADHD-Rating Scale among ADHD patients (intronic rs3785143-T and promoter rs2242446-C allele carriers showed lower inattention scores, Angyal et al, 2018). Our haplotype analyses indicated that a combination of three SNPs from the 5′ end of the NET gene, namely the rs28386840-T∼rs2242446-C∼rs3785143-T haplotype group had significantly different score compared to the most common A-T-C haplotype group.…”

Section: Discussionmentioning

confidence: 95%

“…Polymorphisms from the 5′ end of the NET gene were chosen based on their previous associations with ADHD-related phenotypes in different ethnic groups (Joung et al, 2010; Sengupta et al, 2012; Hohmann et al, 2015). Importantly, these SNPs were in high (but not complete) linkage in the previously studied Hungarian population (Angyal et al, 2018). The promoter SNPs rs28386840 (-3081 A/T) and rs2242446 (-182 T/C) can potentially influence gene expression (Zill et al, 2002; Kim et al, 2006; Sigurdardottir et al, 2016), hence can have functional consequences.…”

Section: Introductionmentioning

confidence: 81%

“…The participating parents (mostly mothers) provided written informed consent. The two samples and genotyping methods are described in details by Angyal et al (2018) and Birkas et al (2006). Briefly, DNA was isolated from buccal swabs, and NET SNPs were genotyped with pre-designed TaqMan probes (rs28386840: C__60398891_10, rs2242446: C__26354911_10, rs3785143: C__27481932_10) on 7300 Real-Time PCR System (Applied BioSystem).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we have reported genetic associations of single nucleotide polymorphisms (SNPs) of the norepinephrine transporter gene ( NET, SLC6A2 ) with ADHD symptom severity but not with ADHD diagnosis per se (Angyal et al, 2018). In the present study, we wanted to test if this genetic association could be extended to a non-clinical range of inattention.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, we conducted the symptom-scale based genetic association analyses separately in the clinical and community samples. Case-control analyses were not run for these samples, because larger ADHD and control groups were compared earlier in our meta-analysis of NET polymorphisms (Angyal et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 81%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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Evaluation of SLC6A2 and CYP2D6 polymorphisms’ effects on atomoxetine treatment in attention deficit and hyperactivity disorder

Kole,

Vural,

Yurdacan

et al. 2024

Eur J Clin Pharmacol

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Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review

2022

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Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental disorder characterised by persistent inattention, hyperactivity and impulsivity. Moreover, ADHD is commonly associated with other comorbid diseases (depression, anxiety, bipolar disorder, etc.). The ADHD symptomatology interferes with subject function and development. The treatment of ADHD requires a multidisciplinary approach based on a combination of non-pharmacological and pharmacological treatments with the aim of ameliorating the symptomatology; among first-line pharmacological treatments are stimulants [such as methylphenidate (MPH) and lisdexamfetamine dimesylate (LDX)]. In this review we explored recent ADHD- and stimulants-related literature, with the aim of compiling available descriptions of molecular pathways altered in ADHD, and molecular mechanisms of current first-line stimulants MPH and LDX. While conducting the narrative review, we applied structured search strategies covering PubMed/MEDLINE database and performed handsearching of reference lists on the results of those searches. The aetiology and pathophysiology of ADHD are incompletely understood; both genetic and environmental factors have been associated with the disorder and its grade of burden, and also the relationship between the molecular mechanisms of pharmacological treatments and their clinical implications. The lack of comprehensive understanding of the underlying molecular pathology makes both the diagnosis and treatment difficult. Few published studies evaluating molecular data on the mechanism of action (MoA) of MPH and LDX on ADHD are available and most of them are based on animal models. Further studies are necessary to improve the knowledge of ADHD pathophysiology and how the MoAs of MPH and LDX differentially modulate ADHD pathophysiology and control ADHD symptomatology.

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Association analysis of norepinephrine transporter polymorphisms and methylphenidate response in ADHD patients

Cited by 16 publications

References 41 publications

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

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

Evaluation of SLC6A2 and CYP2D6 polymorphisms’ effects on atomoxetine treatment in attention deficit and hyperactivity disorder

Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review

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