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.