Posttraumatic Brain Injury Cognitive Performance Is Moderated by Variation Within ANKK1 and DRD2 Genes

Abstract

Objective: As dopamine neurotransmission impacts cognition, we hypothesized that variants in the linked dopamine D2 receptor (DRD2) and ankyrin repeat and kinase domain (ANKK1) genes might account for some individual variability in cognitive recovery following traumatic brain injury (TBI).

Participants: Prospective cohort of 108 survivors of severe TBI, recruited consecutively from a level 1 trauma center.

Design: We examined relationships between DRD2 genetic variation and functional recovery at 6 and 12 months post-TBI.

Main measures: Cognitive performance was evaluated using 8 neuropsychological tests targeting different cognitive domains. An overall cognitive composite was developed using normative data. We also assessed functional cognition, depression status, and global outcome. Subjects were genotyped for 6 DRD2 tagging single-nucleotide polymorphisms and Taq1A within ANKK1.

Results: ANKK1 Taq1A heterozygotes performed better than homozygotes across several cognitive domains at both time points postinjury. When adjusting for age, Glasgow Coma Scale score, and education, the Taq1A (ANKK1) and rs6279 (DRD2) variants were associated with overall composite scores at 6 months post-TBI (P = .0453 and P = .0452, respectively). At 12 months, only Taq1A remained a significant genetic predictor of cognition (P = .0128). Following multiple-comparisons correction, there were no significant associations between examined genetic variants and functional cognition, depression status, and global outcome.

Conclusion: These data suggest that genetic variation within DRD2 influences cognitive recovery post-TBI. Understanding genetic influences on dopaminergic systems post-TBI may impact current treatment paradigms.

Figure 1

Targeted single nucleotide polymorphisms (SNPs) within ANKK1 and DRD2 shown here, lie within their respective genes as marked in the gray rectangles, and consecutively along the genome as mapped on the white rectangle. Linkage disequilibrium (LD) between the 7 SNPs examined (calculated LDs using Haploview v.4.2) is represented as the numbers in each square between each pair of SNPs (D’). Red squares indicate high LD and white squares indicate low LD based on algorithms calculated within Haploview. The bold black line around Block 1 indicates a haploblock that contains rs7131056 and rs4630328. In our sample, there is relatively low LD between rs1800497 and SNPs in DRD2.

Figure 2

Overall and domain specific cognitive composite scores at 6 and 12 months post-injury show rs1800497 (Taq1A) heterozygotes exhibit better cognitive recovery compared to homozygotes. Error bars represent SEM. *p<0.05, #p<0.10.

Figure 3

Overall and domain specific cognitive composite scores at 6 and 12 months post-injury show rs6279 C-homozygotes exhibit better cognitive recovery compared to G-carriers. Error bars represent SEM. *p<0.05, #p<0.10.