John M Myrga1, Michelle D Failla, Joseph H Ricker, C Edward Dixon, Yvette P Conley, Patricia M Arenth, Amy K Wagner. 1. 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).
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.
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 ANKK1rs1800497 (6M: P = .002, 12M: P = .001) and COMTrs4680 (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.
Authors: Solomon M Adams; Yvette P Conley; Amy K Wagner; Ruchira M Jha; Robert Sb Clark; Samuel M Poloyac; Patrick M Kochanek; Philip E Empey Journal: Pharmacogenomics Date: 2017-10-04 Impact factor: 2.533
Authors: Steven M Markos; Michelle D Failla; Anne C Ritter; C Edward Dixon; Yvette P Conley; Joseph H Ricker; Patricia M Arenth; Shannon B Juengst; Amy K Wagner Journal: J Head Trauma Rehabil Date: 2017 Mar/Apr Impact factor: 2.710