title: A Dopamine Pathway Gene Risk Score for Cognitive Recovery Following Traumatic Brain Injury: Methodological Considerations, Preliminary Findings, and Interactions With Sex.
abstract: 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.
  
  
  
  Adult survivors of severe TBI (n = 193) consecutively recruited from a level 1 trauma center.
  
  
  
  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.
  
  
  
  A cognitive composite score generated from 8 standardized neuropsychological tests targeting multiple cognitive domains.
  
  
  
  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.
  
  
  
  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.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).
authors.forename: John M
authors.initials: JM
authors.lastname: Myrga
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Failla
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Ricker
authors.forename: C Edward
authors.initials: CE
authors.lastname: Dixon
authors.forename: Yvette P
authors.initials: YP
authors.lastname: Conley
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Arenth
authors.forename: Amy K
authors.initials: AK
authors.lastname: Wagner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000070642:Brain Injuries, Traumatic / Q000235:genetics* / Q000503:physiopathology; D002394:Catechol O-Methyltransferase / Q000235:genetics; D003071:Cognition; D004298:Dopamine / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009483:Neuropsychological Tests; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000235:genetics; D012307:Risk Factors; D012737:Sex Factors; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: C581293:DRD2 protein, human; D017448:Receptors, Dopamine D2; C493449:SLC18A1 protein, human; D050493:Vesicular Monoamine Transport Proteins; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase; C489948:ANKK1 protein, human; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine