GENETIC VARIATION IN CHT 1 AND HUMAN ATTENTION 3 Contributions of Variation in CHT 1 to Human Attention

This study examined the contributions of genetic variation to individual differences in ability to pay attention. Specifically, we examined a subcapacity version (Ile89Val) of the high affinity choline transporter, a protein important in regulating the brain’s acetylcholine levels, and tested the hypothesis that it would influence the ability to modulate attention. In Experiment 1, subjects were genotyped for this mutation, and completed questionnaires addressing attentional capacity. In Experiment 2, a subset of subjects heterozygous for the Ile89Val mutation and homozygous wild-type controls were brought back to complete the Attention Network Task. Results revealed a significant effect of genotype on self-reported tendency towards lapses of attention (as measured by the Distractibility measure of the Short Imaginal Processes Inventory). Moreover, genotype played a significant role in determining the magnitude of a subject’s alerting effect on the ANT. Our results suggest that even a single nucleotide change in CHT1 may be important for determining an individual’s attentional ability. GENETIC VARIATION IN CHT1 AND HUMAN ATTENTION 3 Contributions of Variation in CHT1 to Human Attention Everyone experiences some degree of mind wandering and inattention from day to day, but individuals differ in their ability to control these tendencies. Part of this diversity may be attributable to genetic variation. Several studies have identified specific genetic components that contribute to pathologies of attention. For example, attention-deficit hyperactivity disorder has been linked to genes involved in the regulation of both norepinephrine and dopamine (Bobb et al., 2005; Kim et al., 2006; Roman et al., 2002). However, comparatively little work has been done to investigate the specific impact on human attentional capacity of another major neurotransmitter, acetylcholine. In the present study, we used a community sample to examine whether variation in a gene thought to regulate the efficiency of the cholinergic system may be related to variation in attention and mind-wandering. Although the gene in question has not been identified as a direct cause of any clinical disorders, it may contribute to normal variation in attentional control and increase the risk for disorders of attention including attention-deficit hyperactivity disorder. The high-affinity choline transporter gene (CHT1) is involved in the regulation of acetylcholine (ACh), which is one of the primary neurotransmitters involved in modulating cognitive functions such as attention, memory, and optimization of task performance. Disruption of the cholinergic system may be implicated in disorders like schizophrenia and ADHD (Sarter, Nelson, & Bruno, 2005). Animal studies have shown that tasks demanding high levels of attention for sustained periods lead to increased release of ACh (Arnold, Burk, Hodgson, Sarter, & Bruno, 2002; Himmelheber, Sarter, & Bruno, 2000; Sarter, Hasselmo, Bruno, & Givens, 2005); thus, decreases in ACh regulation should be associated with inattention. GENETIC VARIATION IN CHT1 AND HUMAN ATTENTION 4 CHT1 may influence ACh function by affecting the rate at which the neurotransmitter can be produced. After ACh is released into the synapse, it is degraded into inactive metabolites – choline and acetate – by acetylcholinesterase. Choline is then taken back up into the cell, and recycled to synthesize new ACh in a reaction catalyzed by choline acyltransferase. The ratelimiting step in this process is thought to be the uptake of choline through the CHT1 protein (Okuda, Okamura, Kaitsuka, Haga, & Gurwitz, 2002). As a result, the rate of transport through CHT1 should be closely tied to the capacity of the cortical cholinergic system in mediating attention. In the present study, we examine the impact that a single nucleotide polymorphism of the CHT1 gene (Ile89Val; identified by Okuda et al., 2002) may have on attentional function. This polymorphism is thought to decrease the rate of choline transport in mammalian cells by 4050%. Possessing this sub-capacity CHT1 variant may decrease a human subject’s ability to maintain elevated levels of ACh, thus potentially impairing performance in situations demanding high attentional control. This research will compare the performance of subjects possessing a copy of the Ile89Val polymorphism to those who are homozygous for the wild type allele (Ile/Ile) in order to determine the overall functional significance of variation in CHT1 on human attentional capacity.