Cargando…
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...
Autores principales: | , , , , , , , , |
---|---|
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 |
_version_ | 1782211002462371840 |
---|---|
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. |
format | Online Article Text |
id | pubmed-3164006 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT englishbretta cholinetransportergenevariationisassociatedwithattentiondeficithyperactivitydisorder AT hahnmaureenk cholinetransportergenevariationisassociatedwithattentiondeficithyperactivitydisorder AT gizerianr cholinetransportergenevariationisassociatedwithattentiondeficithyperactivitydisorder AT mazeirobisonmichelle cholinetransportergenevariationisassociatedwithattentiondeficithyperactivitydisorder AT steeleangela cholinetransportergenevariationisassociatedwithattentiondeficithyperactivitydisorder AT kurnikdanielm cholinetransportergenevariationisassociatedwithattentiondeficithyperactivitydisorder AT steinmarka cholinetransportergenevariationisassociatedwithattentiondeficithyperactivitydisorder AT waldmanirwind cholinetransportergenevariationisassociatedwithattentiondeficithyperactivitydisorder AT blakelyrandyd cholinetransportergenevariationisassociatedwithattentiondeficithyperactivitydisorder |