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Objective Genetic variations in the dopamine (DA) system are associated with cortical-striatal behavior in multiple populations. This study assessed associations of functional polymorphisms in the ankyrin repeat and kinase domain (ANKK1; Taq1a) and catechol-o-methyltransferase (COMT; Val158Met) genes with behavioral dysfunction following traumatic brain injury (TBI). Participants Prospective study of 90 survivors of severe TBI recruited from a level 1 trauma center. Main Measures The Frontal Systems Behavior Scale, a self or family report questionnaire evaluating behavior associated with frontal lobe dysfunction, was completed 6 and 12-months post-injury. Depression was measured concurrently with the Patient Health Questionnaire-9. Study participants were genotyped for Val158Met and Taq1a polymorphisms. Results No statistically significant behavioral differences were observed by Taq1a or Val158Met genotype alone. At 12-months, among those with depression, Met-homozygotes (Val158Met) self-reported worse behavior than Val-carriers (p=0.015) and A2-homozygotes (Taq1a) self-reported worse behavior than A1-carriers (p=0.028) in bivariable analysis. Multivariable models suggest an interaction between depression and genetic variation with behavior at 12-months post-TBI, and descriptive analysis suggests that carriage of both risk alleles may contribute to worse behavioral performance than carriage of either risk allele alone. Conclusion In the context of depression, Val158Met and Taq1a polymorphisms are individually associated with behavioral dysfunction 12-months following severe TBI with preliminary evidence suggesting cumulative, or perhaps epistatic, effects of COMT and ANKK1 on behavioral dysfunction.

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A sex-specific DA-pathway GRS may be a valuable tool when predicting cognitive recovery post-TBI. Future work should validate these findings and explore how DA-pathway genetics may guide therapeutic intervention.

Timely treatment of depression and behavioral dysfunction after moderate-to-severe traumatic brain injury (TBI) could improve health, function, and quality of life. We hypothesized 6-month depression would be the stronger contributor to later depression and behavioral dysfunction in a sample of n=88 adults with moderate-to-severe TBI. A structural equation modeling cross-lagged panel analysis, adjusting for all 6-month predictors, revealed 6-month depression had a stronger relationship to 12-month depression (βstand=.55, p=.002) and behavioral dysfunction (βstand=.41, p=.004) than did 6-month behavior behavioral dysfunction (βstand=.17, p=.270, βstand=.30, p=.035). Depression may be in the developmental pathway to behavioral dysfunction, triggering a cycle of reciprocal causality.