Genetic Variation in the Vesicular Monoamine Transporter: Preliminary Associations With Cognitive Outcomes After Severe Traumatic Brain Injury

Abstract

Introduction: Traumatic brain injury (TBI) frequently results in impaired cognition, a function that can be modulated by monoaminergic signaling. Genetic variation among monoaminergic genes may affect post-TBI cognitive performance. The vesicular monoamine transporter-2 (VMAT2) gene may be a novel source of genetic variation important for cognitive outcomes post-TBI given VMAT2's role in monoaminergic neurotransmission.

Objective: To evaluate associations between VMAT2 variability and cognitive outcomes post-TBI.

Methods: We evaluated 136 white adults with severe TBI for variation in VMAT2 using a tagging single nucleotide polymorphism (tSNP) approach (rs363223, rs363226, rs363251, and rs363341). We show genetic variation interacts with assessed cognitive impairment (cognitive composite [Comp-Cog] T-scores) to influence functional cognition (functional independence measure cognitive [FIM-Cog] subscale] 6 and 12 months postinjury.

Results: Multivariate analyses at 6 months postinjury showed rs363226 genotype was associated with Comp-Cog (P = .040) and interacted with Comp-Cog to influence functional cognition (P < .001). G-homozygotes had the largest cognitive impairment, and their cognitive impairment had the greatest adverse effect on functional cognition.

Discussion: We provide the first evidence that genetic variation within VMAT2 is associated with cognitive outcomes after TBI. Further work is needed to validate this finding and elucidate mechanisms by which genetic variation affects monoaminergic signaling, mediating differences in cognitive outcomes.

Figure 1

Targeted single nucleotide polymorphisms (SNPs) within the VMAT2 gene on chromosome 10 are shown here as mapped on the white rectangle. Linkage disequilibrium (LD) between the 4 SNPs examined (calculated LDs using Haploview v.4.2) is represented as the numbers in each square between each pair of SNPs (D’). Grey squares indicate high LD and white squares indicate low LD based on algorithms calculated within Haploview. Significant SNP in multiple regression is outlined in black box

Figure 2. Adjusted Mean 6-Month Comp-Cog Score by rs363226 Genotype

Adjusted mean Comp-Cog scores are predicted values derived from the regression model (Table 3A), which controls for covariates. Standard error bars are shown. Mean (95% confidence interval) Comp-Cog scores for genotype groups were as follows: GG=35.2 (30.9, 39.5), CG=40.4 (38.1, 42.7), and CC=41.42 (39.4, 43.5). The GG group average was significantly different from the CG (p=0.036) and CC (p=0.012) group averages. CG and CC groups did not significantly differ (p=0.528)

Figure 3. 6-Month FIM-Cog vs Comp-Cog by rs363226 Genotype

Descriptive plot of individual 6-month FIM-Cog scores versus Comp-Cog score, labeled by rs363226 genotype. Best fit lines are shown for each genotype group, which have R² values of 0.722 (GG), 0.514 (CG), and 0.262 (CC). Vertical lines were added to denote an average Comp-Cog score (50) and one standard deviation below average (40), which marks the threshold for mild cognitive impairment.