DRD2 C957T polymorphism is associated with improved 6-month verbal learning following traumatic brain injury

John K Yue; Ethan A Winkler; Jonathan W Rick; John F Burke; Thomas W McAllister; Sam S Oh; Esteban G Burchard; Donglei Hu; Jonathan Rosand; Nancy R Temkin; Frederick K Korley; Marco D Sorani; Adam R Ferguson; Hester F Lingsma; Sourabh Sharma; Caitlin K Robinson; Esther L Yuh; Phiroz E Tarapore; Kevin K W Wang; Ava M Puccio; Pratik Mukherjee; Ramon Diaz-Arrastia; Wayne A Gordon; Alex B Valadka; David O Okonkwo; Geoffrey T Manley; TRACK-TBI Investigators

doi:10.1007/s10048-016-0500-6

DRD2 C957T polymorphism is associated with improved 6-month verbal learning following traumatic brain injury

Neurogenetics. 2017 Jan;18(1):29-38. doi: 10.1007/s10048-016-0500-6. Epub 2016 Nov 8.

Authors

John K Yue^{1

2}, Ethan A Winkler^{1

2}, Jonathan W Rick^{1

2}, John F Burke^{1

2}, Thomas W McAllister³, Sam S Oh⁴, Esteban G Burchard⁴, Donglei Hu⁴, Jonathan Rosand^{5

6}, Nancy R Temkin⁷, Frederick K Korley⁸, Marco D Sorani^{1

2}, Adam R Ferguson^{1

2}, Hester F Lingsma⁹, Sourabh Sharma^{1

2}, Caitlin K Robinson^{1

2}, Esther L Yuh^{1

10}, Phiroz E Tarapore^{1

2}, Kevin K W Wang¹¹, Ava M Puccio¹², Pratik Mukherjee^{1

10}, Ramon Diaz-Arrastia^{13

14}, Wayne A Gordon¹⁵, Alex B Valadka¹⁶, David O Okonkwo¹², Geoffrey T Manley^{17

18}; TRACK-TBI Investigators

Affiliations

¹ Department of Neurological Surgery, University of California, San Francisco, 1001 Potrero Avenue, Building 1, Room 101, San Francisco, CA, 94110, USA.
² Brain and Spinal Injury Center, San Francisco General Hospital, San Francisco, CA, USA.
³ Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
⁵ Department of Neurology, Harvard Medical School, Boston, MA, USA.
⁶ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁷ Department of Neurological Surgery and Biostatistics, University of Washington, Seattle, WA, USA.
⁸ Department of Emergency Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁹ Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands.
¹⁰ Department of Radiology, University of California, San Francisco, San Francisco, CA, USA.
¹¹ Center for Neuroproteomics and Biomarkers Research, Department of Psychiatry and Neuroscience, University of Florida, Gainesville, FL, USA.
¹² Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
¹³ Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
¹⁴ Center for Neuroscience and Regenerative Medicine, Bethesda, MD, USA.
¹⁵ Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁶ Department of Neurological Surgery, Virginia Commonwealth University, Richmond, VA, USA.
¹⁷ Department of Neurological Surgery, University of California, San Francisco, 1001 Potrero Avenue, Building 1, Room 101, San Francisco, CA, 94110, USA. [email protected].
¹⁸ Brain and Spinal Injury Center, San Francisco General Hospital, San Francisco, CA, USA. [email protected].

Abstract

Traumatic brain injury (TBI) often leads to heterogeneous clinical outcomes, which may be influenced by genetic variation. A single-nucleotide polymorphism (SNP) in the dopamine D2 receptor (DRD2) may influence cognitive deficits following TBI. However, part of the association with DRD2 has been attributed to genetic variability within the adjacent ankyrin repeat and kinase domain containing 1 protein (ANKK1). Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether a novel DRD2 C957T polymorphism (rs6277) influences outcome on a cognitive battery at 6 months following TBI-California Verbal Learning Test (CVLT-II), Wechsler Adult Intelligence Test Processing Speed Index Composite Score (WAIS-PSI), and Trail Making Test (TMT). Results in 128 Caucasian subjects show that the rs6277 T-allele associates with better verbal learning and recall on CVLT-II Trials 1-5 (T-allele carrier 52.8 ± 1.3 points, C/C 47.9 ± 1.7 points; mean increase 4.9 points, 95% confidence interval [0.9 to 8.8]; p = 0.018), Short-Delay Free Recall (T-carrier 10.9 ± 0.4 points, C/C 9.7 ± 0.5 points; mean increase 1.2 points [0.1 to 2.5]; p = 0.046), and Long-Delay Free Recall (T-carrier 11.5 ± 0.4 points, C/C 10.2 ± 0.5 points; mean increase 1.3 points [0.1 to 2.5]; p = 0.041) after adjusting for age, education years, Glasgow Coma Scale, presence of acute intracranial pathology on head computed tomography scan, and genotype of the ANKK1 SNP rs1800497 using multivariable regression. No association was found between DRD2 C947T and non-verbal processing speed (WAIS-PSI) or mental flexibility (TMT) at 6 months. Hence, DRD2 C947T (rs6277) may be associated with better performance on select cognitive domains independent of ANKK1 following TBI.

Trial registration: ClinicalTrials.gov NCT01565551.

Keywords: Cognition; Genetic factors; Human studies; Outcome measures; Traumatic brain injury.

Publication types

Multicenter Study
Observational Study

MeSH terms

Adult
Brain Injuries, Traumatic / genetics
Brain Injuries, Traumatic / psychology
Brain Injuries, Traumatic / rehabilitation*
Case-Control Studies
Female
Genetic Association Studies
Humans
Male
Middle Aged
Neuronal Plasticity / genetics*
Pilot Projects
Polymorphism, Single Nucleotide*
Receptors, Dopamine D2 / genetics*
Verbal Learning / physiology*

DRD2 C957T polymorphism is associated with improved 6-month verbal learning following traumatic brain injury

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