Article

Journal of Neurodevelopmental Disorders

, Volume 1, Issue 4, pp 252-263

Open Access This content is freely available online to anyone, anywhere at any time.

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

  • Brett A. EnglishAffiliated withDepartment of Pharmacology, Vanderbilt University School of Medicine
  • , Maureen K. HahnAffiliated withDepartment of Pharmacology, Vanderbilt University School of MedicineDepartment of Medicine, Vanderbilt University School of MedicineCenter for Molecular Neuroscience, Vanderbilt University School of Medicine
  • , Ian R. GizerAffiliated withDepartment of Psychology, Emory University
  • , Michelle Mazei-RobisonAffiliated withDepartment of Pharmacology, Vanderbilt University School of Medicine
  • , Angela SteeleAffiliated withDepartment of Pharmacology, Vanderbilt University School of Medicine
  • , Daniel M. KurnikAffiliated withDepartment of Pharmacology, Vanderbilt University School of MedicineDepartment of Medicine, Vanderbilt University School of Medicine
  • , Mark A. SteinAffiliated withDepartment of Psychiatry, University of Illinois-Chicago
  • , Irwin D. WaldmanAffiliated withDepartment of Psychology, Emory University
  • , Randy D. BlakelyAffiliated withDepartment of Pharmacology, Vanderbilt University School of MedicineDepartment of Psychiatry, Vanderbilt University School of MedicineCenter for Molecular Neuroscience, Vanderbilt University School of Medicine Email author 

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, 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.

Keywords

Choline Transporter SLC5A7 Attention-deficit hyperactivity disorder Polymorphism