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Choline transporter gene variation is associated with attention-deficit hyperactivity disorder

The neurotransmitter acetylcholine (ACh) plays a critical role in brain circuits mediating motor control, attention, learning and memory. Cholinergic dysfunction is associated with multiple brain disorders including Alzheimer’s Disease, addiction, schizophrenia and Attention-Deficit Hyperactivity Di...

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Autores principales: English, Brett A., Hahn, Maureen K., Gizer, Ian R., Mazei-Robison, Michelle, Steele, Angela, Kurnik, Daniel M., Stein, Mark A., Waldman, Irwin D., Blakely, Randy D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164006/
https://www.ncbi.nlm.nih.gov/pubmed/21547719
http://dx.doi.org/10.1007/s11689-009-9033-8
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author English, Brett A.
Hahn, Maureen K.
Gizer, Ian R.
Mazei-Robison, Michelle
Steele, Angela
Kurnik, Daniel M.
Stein, Mark A.
Waldman, Irwin D.
Blakely, Randy D.
author_facet English, Brett A.
Hahn, Maureen K.
Gizer, Ian R.
Mazei-Robison, Michelle
Steele, Angela
Kurnik, Daniel M.
Stein, Mark A.
Waldman, Irwin D.
Blakely, Randy D.
author_sort English, Brett A.
collection PubMed
description The neurotransmitter acetylcholine (ACh) plays a critical role in brain circuits mediating motor control, attention, learning and memory. Cholinergic dysfunction is associated with multiple brain disorders including Alzheimer’s Disease, addiction, schizophrenia and Attention-Deficit Hyperactivity Disorder (ADHD). The presynaptic choline transporter (CHT, SLC5A7) is the major, rate-limiting determinant of ACh production in the brain and periphery and is consequently upregulated during tasks that require sustained attention. Given the contribution of central cholinergic circuits to the control of movement and attention, we hypothesized that functional CHT gene variants might impact risk for ADHD. We performed a case-control study, followed by family-based association tests on a separate cohort, of two purportedly functional CHT polymorphisms (coding variant Ile89Val (rs1013940) and a genomic SNP 3’ of the CHT gene (rs333229), affording both a replication sample and opportunities to reduce potential population stratification biases. Initial genotyping of pediatric ADHD subjects for two purportedly functional CHT alleles revealed a 2–3 fold elevation of the Val89 allele (n = 100; P = 0.02) relative to healthy controls, as well as a significant decrease of the 3’SNP minor allele in Caucasian male subjects (n = 60; P = 0.004). In family based association tests, we found significant overtransmission of the Val89 variant to children with a Combined subtype diagnosis (OR = 3.16; P = 0.01), with an increased Odds Ratio for a haplotype comprising both minor alleles. These studies show evidence of cholinergic deficits in ADHD, particularly for subjects with the Combined subtype, and, if replicated, may encourage further consideration of cholinergic agonist therapy in the disorder. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11689-009-9033-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-31640062011-10-18 Choline transporter gene variation is associated with attention-deficit hyperactivity disorder English, Brett A. Hahn, Maureen K. Gizer, Ian R. Mazei-Robison, Michelle Steele, Angela Kurnik, Daniel M. Stein, Mark A. Waldman, Irwin D. Blakely, Randy D. J Neurodev Disord Article The neurotransmitter acetylcholine (ACh) plays a critical role in brain circuits mediating motor control, attention, learning and memory. Cholinergic dysfunction is associated with multiple brain disorders including Alzheimer’s Disease, addiction, schizophrenia and Attention-Deficit Hyperactivity Disorder (ADHD). The presynaptic choline transporter (CHT, SLC5A7) is the major, rate-limiting determinant of ACh production in the brain and periphery and is consequently upregulated during tasks that require sustained attention. Given the contribution of central cholinergic circuits to the control of movement and attention, we hypothesized that functional CHT gene variants might impact risk for ADHD. We performed a case-control study, followed by family-based association tests on a separate cohort, of two purportedly functional CHT polymorphisms (coding variant Ile89Val (rs1013940) and a genomic SNP 3’ of the CHT gene (rs333229), affording both a replication sample and opportunities to reduce potential population stratification biases. Initial genotyping of pediatric ADHD subjects for two purportedly functional CHT alleles revealed a 2–3 fold elevation of the Val89 allele (n = 100; P = 0.02) relative to healthy controls, as well as a significant decrease of the 3’SNP minor allele in Caucasian male subjects (n = 60; P = 0.004). In family based association tests, we found significant overtransmission of the Val89 variant to children with a Combined subtype diagnosis (OR = 3.16; P = 0.01), with an increased Odds Ratio for a haplotype comprising both minor alleles. These studies show evidence of cholinergic deficits in ADHD, particularly for subjects with the Combined subtype, and, if replicated, may encourage further consideration of cholinergic agonist therapy in the disorder. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11689-009-9033-8) contains supplementary material, which is available to authorized users. Springer US 2009-08-28 2009-12 /pmc/articles/PMC3164006/ /pubmed/21547719 http://dx.doi.org/10.1007/s11689-009-9033-8 Text en © Springer Science+Business Media, LLC 2009
spellingShingle Article
English, Brett A.
Hahn, Maureen K.
Gizer, Ian R.
Mazei-Robison, Michelle
Steele, Angela
Kurnik, Daniel M.
Stein, Mark A.
Waldman, Irwin D.
Blakely, Randy D.
Choline transporter gene variation is associated with attention-deficit hyperactivity disorder
title Choline transporter gene variation is associated with attention-deficit hyperactivity disorder
title_full Choline transporter gene variation is associated with attention-deficit hyperactivity disorder
title_fullStr Choline transporter gene variation is associated with attention-deficit hyperactivity disorder
title_full_unstemmed Choline transporter gene variation is associated with attention-deficit hyperactivity disorder
title_short Choline transporter gene variation is associated with attention-deficit hyperactivity disorder
title_sort choline transporter gene variation is associated with attention-deficit hyperactivity disorder
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164006/
https://www.ncbi.nlm.nih.gov/pubmed/21547719
http://dx.doi.org/10.1007/s11689-009-9033-8
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