title: COMT Val158Met polymorphism is associated with post-traumatic stress disorder and functional outcome following mild traumatic brain injury.
abstract: Mild traumatic brain injury (mTBI) results in variable clinical trajectories and outcomes. The source of variability remains unclear, but may involve genetic variations, such as single nucleotide polymorphisms (SNPs). A SNP in catechol-o-methyltransferase (COMT) is suggested to influence development of post-traumatic stress disorder (PTSD), but its role in TBI remains unclear. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val158Met polymorphism is associated with PTSD and global functional outcome as measured by the PTSD Checklist - Civilian Version and Glasgow Outcome Scale Extended (GOSE), respectively. Results in 93 predominately Caucasian subjects with mTBI show that the COMT Met158allele is associated with lower incidence of PTSD (univariate odds ratio (OR) of 0.25, 95% CI [0.09-0.69]) and higher GOSE scores (univariate OR 2.87, 95% CI [1.20-6.86]) 6-months following injury. The COMT Val158Met genotype and PTSD association persists after controlling for race (multivariable OR of 0.29, 95% CI [0.10-0.83]) and pre-existing psychiatric disorders/substance abuse (multivariable OR of 0.32, 95% CI [0.11-0.97]). PTSD emerged as a strong predictor of poorer outcome on GOSE (multivariable OR 0.09, 95% CI [0.03-0.26]), which persists after controlling for age, GCS, and race. When accounting for PTSD in multivariable analysis, the association of COMT genotype and GOSE did not remain significant (multivariable OR 1.73, 95% CI [0.69-4.35]). Whether COMT genotype indirectly influences global functional outcome through PTSD remains to be determined and larger studies in more diverse populations are needed to confirm these findings.
authors: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Brain and Spinal Injury Center, San Francisco General Hospital, San Francisco, CA, USA.
authors: Ethan A
authors: EA
authors: Winkler
authors: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Brain and Spinal Injury Center, San Francisco General Hospital, San Francisco, CA, USA.
authors: John K
authors: JK
authors: Yue
authors: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Brain and Spinal Injury Center, San Francisco General Hospital, San Francisco, CA, USA.
authors: Adam R
authors: AR
authors: Ferguson
authors: Department of Neurological Surgery and Biostatistics, University of Washington, Seattle, WA, USA.
authors: Nancy R
authors: NR
authors: Temkin
authors: Department of Psychiatry, University of California, San Diego, San Diego, CA, USA; Department of Family and Preventative Medicine, University of California, San Diego, San Diego, CA, USA.
authors: Murray B
authors: MB
authors: Stein
authors: Department of Neurological Surgery and Biostatistics, University of Washington, Seattle, WA, USA.
authors: Jason
authors: J
authors: Barber
authors: Brain and Spinal Injury Center, San Francisco General Hospital, San Francisco, CA, USA; Department of Radiology, University of California, San Francisco, San Francisco, CA, USA.
authors: Esther L
authors: EL
authors: Yuh
authors: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Brain and Spinal Injury Center, San Francisco General Hospital, San Francisco, CA, USA.
authors: Sourabh
authors: S
authors: Sharma
authors: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Brain and Spinal Injury Center, San Francisco General Hospital, San Francisco, CA, USA.
authors: Gabriela G
authors: GG
authors: Satris
authors: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: Thomas W
authors: TW
authors: McAllister
authors: Department of Neurology, Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors: Jonathan
authors: J
authors: Rosand
authors: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Brain and Spinal Injury Center, San Francisco General Hospital, San Francisco, CA, USA.
authors: Marco D
authors: MD
authors: Sorani
authors: Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Hester F
authors: HF
authors: Lingsma
authors: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Brain and Spinal Injury Center, San Francisco General Hospital, San Francisco, CA, USA.
authors: Phiroz E
authors: PE
authors: Tarapore
authors: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
authors: Esteban G
authors: EG
authors: Burchard
authors: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
authors: Donglei
authors: D
authors: Hu
authors: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
authors: Celeste
authors: C
authors: Eng
authors: Center for Neuroproteomics and Biomarkers Research, Departments of Psychiatry and Neuroscience, University of Florida, Gainesville, FL, USA.
authors: Kevin K W
authors: KK
authors: Wang
authors: Brain and Spinal Injury Center, San Francisco General Hospital, San Francisco, CA, USA; Department of Radiology, University of California, San Francisco, San Francisco, CA, USA.
authors: Pratik
authors: P
authors: Mukherjee
authors: Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors: David O
authors: DO
authors: Okonkwo
authors: Department of Neurology, Uniformed Services University of the Health Sciences, and Center for Neuroscience and Regenerative Medicine, Bethesda, MD, USA.
authors: Ramon
authors: R
authors: Diaz-Arrastia
authors: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Brain and Spinal Injury Center, San Francisco General Hospital, San Francisco, CA, USA. Electronic address: manleyg@neurosurg.ucsf.edu.
authors: Geoffrey T
authors: GT
authors: Manley
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000070642:Brain Injuries, Traumatic / Q000150:complications* / Q000235:genetics*; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D005006:Ethnicity; D005260:Female; D015600:Glasgow Coma Scale; D023261:Glasgow Outcome Scale; D006801:Humans; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D013313:Stress Disorders, Post-Traumatic / Q000209:etiology* / Q000235:genetics*; D019966:Substance-Related Disorders / Q000150:complications / Q000453:epidemiology; D014633:Valine / Q000235:genetics
chemical_list: D008715:Methionine; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase; D014633:Valine
keywords: Genetic factors; Human studies; Outcome measures; PTSD; Traumatic brain injury