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

• Type of Material: Article
• Authors: Brett A. English, Vanderbilt University School of Medicine; Maureen K. Hahn, Vanderbilt University School of Medicine; Ian R. Gizer, Emory University; Michelle Mazei-Robison, Vanderbilt University School of Medicine; Angela Steele, Vanderbilt University School of Medicine; Daniel M. Kurnik, Vanderbilt University School of Medicine; Mark A. Stein, University of Illinois at Chicago; Irwin Waldman, Emory University; Randy D. Blakely, Vanderbilt University School of Medicine
• Language: English
• Date: 2009-12-01
• Publisher: BMC (part of Springer Nature)
• Publication Version: Final Published Version
• Copyright Statement: © Springer Science + Business Media, LLC 2009
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1007/s11689-009-9033-8
• Title of Journal or Parent Work: Journal of Neurodevelopmental Disorders
• ISSN: 1866-1947
• Volume: 1
• Issue: 4
• Start Page: 252
• End Page: 263
• Grant/Funding Information: The studies described were supported by an American Heart Association Award 0715120B (B.A.E) and NIH Awards MH076018 (M.K.H.), MH072083 (I.R.G.), MH01818 (I.D.W.), K24MHO1823 (M.A.S), HL56693 (R.D.B.), and MH073159 (R.D.B.).
• Keywords: transporter; SLC5A7; choline; polymorphism; Attention-deficit/hyperactivity disorder
• Research Categories: Psychology, Cognitive

Abstract

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, ratelimiting 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.