Citation

Myrga JM, Failla MD, Ricker JH, Dixon CE, Conley YP, Arenth PM, Wagner AK. J. Head Trauma Rehabil. 2015; 31(5): E15-29.

Affiliation

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).

Copyright

(Copyright © 2015, Lippincott Williams and Wilkins)

DOI

10.1097/HTR.0000000000000199

PMID

26580694

Abstract

OBJECTIVES: With 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. PARTICIPANTS: Adult survivors of severe TBI (n = 193) consecutively recruited from a level 1 trauma center.

DESIGN: Risk 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 MEASURES: A cognitive composite score generated from 8 standardized neuropsychological tests targeting multiple cognitive domains.

RESULTS: A 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.

CONCLUSIONS: 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.

Language: en