• John M Myrga, Michelle D Failla, Joseph H Ricker, C Edward Dixon, Yvette P Conley, Patricia M Arenth, and Amy K Wagner.
• Department of Physical Medicine & Rehabilitation (Mr Myrga and Drs Failla, Dixon, Arenth, and Wagner), Center for Neuroscience (Drs Failla, Dixon, and Wagner), University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania; Department of Rehabilitation Medicine, New York University, School of Medicine, New York (Dr Ricker); Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, Pennsylvania (Dr Dixon); Department of Human Genetics, University of Pittsburgh, School of Public Health, Pittsburgh, Pennsylvania (Dr Conley); Health Promotion & Development, University of Pittsburgh, School of Nursing, Pittsburgh, Pennsylvania (Dr Conley); and Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Dixon, Conley, and Wagner).
• J Head Trauma Rehabil. 2016 Sep 1; 31 (5): E15-29.

ObjectivesWith evidence of sexual dimorphism involving the dopamine (DA)-pathway, and the importance of DA pathways in traumatic brain injury (TBI) recovery, we hypothesized that sex × DA-gene interactions may influence cognition post-TBI.ParticipantsAdult survivors of severe TBI (n = 193) consecutively recruited from a level 1 trauma center.DesignRisk allele assignments were made for multiple DA pathway genes using a sex-specific stratified approach. Genetic risk alleles, and their impacts on cognition, were assessed at 6 and 12 months postinjury using unweighted, semiweighted, and weighted gene risk score (GRS) approaches.Main MeasuresA cognitive composite score generated from 8 standardized neuropsychological tests targeting multiple cognitive domains.ResultsA significant sex × gene interaction was observed at 6 and 12 months for ANKK1 rs1800497 (6M: P = .002, 12M: P = .001) and COMT rs4680 (6M: P = .048; 12M: P = .004); DRD2 rs6279 (P = .001) and VMAT rs363226 (P = .043) genotypes were independently associated with cognition at 6 months, with trends for a sex × gene interaction at 12 months. All GRS methods were significant predictors of cognitive performance in multivariable models. Weighted GRS multivariate models captured the greatest variance in cognition: R = 0.344 (6 months); R = 0.441 (12 months), significantly increasing the variance captured from the base prediction models.ConclusionsA 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.

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