Exogenous visual orienting is associated with specific neurotransmitter genetic markers: a population-based genetic association study

Abstract

Background: Currently, there is a sense that the spatial orienting of attention is related to genotypic variations in cholinergic genes but not to variations in dopaminergic genes. However, reexamination of associations with both cholinergic and dopaminergic genes is warranted because previous studies used endogenous rather than exogenous cues and costs and benefits were not analyzed separately. Examining costs (increases in response time following an invalid pre-cue) and benefits (decreases in response time following a valid pre-cue) separately could be important if dopaminergic genes (implicated in disorders such as attention deficit disorder) independently influence the different processes of orienting (e.g., disengage, move, engage).

Methodology/principal findings: We tested normal subjects (N = 161) between 18 and 61 years. Participants completed a computer task in which pre-cues preceded the presence of a target. Subjects responded (with a key press) to the location of the target (right versus left of fixation). The cues could be valid (i.e., appear where the target would appear) or invalid (appear contralateral to where the target would appear). DNA sequencing assays were performed on buccal cells to genotype known genetic markers and these were examined for association with task scores. Here we show significant associations between visual orienting and genetic markers (on COMT, DAT1, and APOE; R(2)s from 4% to 9%).

Conclusions/significance: One measure in particular--the response time cost of a single dim, invalid cue - was associated with dopaminergic markers on COMT and DAT1. Additionally, variations of APOE genotypes based on the ε2/ε3/ε4 alleles were also associated with response time differences produced by simultaneous cues with unequal luminances. We conclude that individual differences in visual orienting are related to several dopaminergic markers as well as to a cholinergic marker. These results challenge the view that orienting is not associated with genotypic variation in dopaminergic genes.

Figure 1. Mean cost dim difference scores by DAT1 genotype.

Note that the 5R/5R genotype group had only 6 subjects and the mean may, therefore, not be reliable. This graph represents the mean after adjustment for ethnicity. Error bars are +/−1 SEM.

Figure 2. Mean cost dim benefit dim, and dual asymmetric cost dim difference scores by COMT genotype.

This graph represents means after each measure was adjusted for ethnicity. Error bars are +/−1 SEM.

Figure 3. Mean congruence benefit and alert bright difference scores by APOE genotype.

With two SNPs contributing to APOE status, there are six possible groups. We organized these into groupings as did others , however we modified the groups by eliminating subjects who had one risk allele (e4) and one protective factor (e2) (n = 2) since a hypothesis for the outcome in such individuals was unclear . The sample size for the e2/e3 genotype is relatively small, but represents a naturally occurring group with a putative protective factor. The e2 allele is relatively rare. For example, in a sample of 5000 alleles from 2500 subjects only 7.65% of the alleles were e2 . This graph represents means after adjustment for ethnicity. Error bars are +/−1 SEM.

Figure 4. Mean cost dim, benefit dim, and alert bright difference scores by DRD4 genotype.

This graph represents means after adjustment for ethnicity. Error bars are +/−1 SEM.

Figure 5. Illustration of stimuli: The fixation cross was visible throughout a trial.

A pre-cue condition appeared for 67 msec. Conditions a) no cue and b) dual cues of a single luminance were used as baseline conditions for the calculations of derived measures as described in Table 1. Otherwise, either one or two cues of different luminances appeared. A single target as in condition c) could appear on either the left or right side with 50% probability and could be either bright or dim (50% probability each). The target that followed could appear near where the pre-cue had appeared or contralaterally. If two cues appeared as in condition d) then the bright cue would appear on the left side for 50% of these trials. After the cue condition disappeared, a single target followed and could appear near the dim or the bright cue.

Figure 6. Derived measures by ethnicity.

Overall, patterns are similar and statistical decisions were unchanged whether or not ethnicity was used as a factor in the ANOVA. Note that some ethnicities do differ significantly from other ethnicities on particular outcome measures. AB = Alert Bright; AD = Alert Dim; BB = Benefit Bright; BD = Benefit Dim; CB = Cost Bright; CD = Cost dim; DACB = Dual Asymmetric Cost Bright; DACD = Dual Asymmetric Cost dim; CongB = Congruence Benefit; DTBN = Dim Better Than Nothing. Error bars are +/−1 SEM.