Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
neurogenetics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Faul M, Xu L, Wald MM, Coronado VG (2010) Traumatic brain injury in the United States: emergency department visits, hospitalizations and deaths, 2002–2006. Centers for Disease Control and Prevention, National Center for Injury.

  2. Maas AI, Stocchetti N, Bullock R (2008) Moderate and severe traumatic brain injury in adults. Lancet Neurol 7:728–741

    Article  PubMed  Google Scholar 

  3. Teasdale G, Maas A, Lecky F, Manley G, Stocchetti N, Murray G (2014) The Glasgow Coma Scale at 40 years: standing the test of time. Lancet Neurol 13:844–854

    Article  PubMed  Google Scholar 

  4. Ponsford J, Draper K, Schonberger M (2008) Functional outcome 10 years after traumatic brain injury: its relationship with demographic, injury severity, and cognitive and emotional status. J Int Neuropsychol Soc 14:233–242

    Article  PubMed  Google Scholar 

  5. Langlois JA, Rutland-Brown W, Wald MM (2006) The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil 21:375–378

    Article  PubMed  Google Scholar 

  6. McAllister TW (2008) Neurobehavioral sequelae of traumatic brain injury: evaluation and management. World Psychiatry 7:3–10

    Article  PubMed  PubMed Central  Google Scholar 

  7. Manley GT, Maas AI (2013) Traumatic brain injury: an international knowledge-based approach. JAMA 310:473–474

    Article  CAS  PubMed  Google Scholar 

  8. Dardiotis E, Fountas KN, Dardioti M, Xiromerisiou G, Kapsalaki E, Tasiou A, Hadjigeorgiou GM (2010) Genetic association studies in patients with traumatic brain injury. Neurosurg Focus 28:E9

    Article  PubMed  Google Scholar 

  9. Davidson J, Cusimano MD, Bendena WG (2014) Post-traumatic brain injury: genetic susceptibility to outcome. Neuroscientist.

  10. Diaz-Arrastia R, Baxter VK (2006) Genetic factors in outcome after traumatic brain injury: what the human genome project can teach us about brain trauma. J Head Trauma Rehabil 21:361–374

    Article  PubMed  Google Scholar 

  11. Jordan BD (2007) Genetic influences on outcome following traumatic brain injury. Neurochem Res 32:905–915

    Article  CAS  PubMed  Google Scholar 

  12. McAllister TW (2009) Polymorphisms in genes modulating the dopamine system: do they influence outcome and response to medication after traumatic brain injury? J Head Trauma Rehabil 24:65–68

    Article  PubMed  PubMed Central  Google Scholar 

  13. McAllister TW, Flashman LA, Harker Rhodes C, Tyler AL, Moore JH, Saykin AJ, McDonald BC, Tosteson TD, Tsongalis GJ (2008) Single nucleotide polymorphisms in ANKK1 and the dopamine D2 receptor gene affect cognitive outcome shortly after traumatic brain injury: a replication and extension study. Brain Inj 22:705–714

    Article  PubMed  PubMed Central  Google Scholar 

  14. Levey AI, Hersch SM, Rye DB, Sunahara RK, Niznik HB, Kitt CA, Price DL, Maggio R, Brann MR, Ciliax BJ (1993) Localization of D1 and D2 dopamine receptors in brain with subtype-specific antibodies. Proc Natl Acad Sci U S A 90:8861–8865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Voisey J, Swagell CD, Hughes IP, Morris CP, van Daal A, Noble EP, Kann B, Heslop KA, Young RM, Lawford BR (2009) The DRD2 gene 957C>T polymorphism is associated with posttraumatic stress disorder in war veterans. Depress Anxiety 26:28–33

    Article  CAS  PubMed  Google Scholar 

  16. Wise RA (2004) Dopamine, learning and motivation. Nat Rev Neurosci 5:483–494

    Article  CAS  PubMed  Google Scholar 

  17. White NM, Viaud M (1991) Localized intracaudate dopamine D2 receptor activation during the post-training period improves memory for visual or olfactory conditioned emotional responses in rats. Behav Neural Biol 55:255–269

    Article  CAS  PubMed  Google Scholar 

  18. McAllister TW, Rhodes CH, Flashman LA, McDonald BC, Belloni D, Saykin AJ (2005) Effect of the dopamine D2 receptor T allele on response latency after mild traumatic brain injury. Am J Psychiatry 162:1749–1751

    Article  PubMed  Google Scholar 

  19. Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, Gejman PV (2003) Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet 12:205–216

    Article  CAS  PubMed  Google Scholar 

  20. Grandy DK, Litt M, Allen L, Bunzow JR, Marchionni M, Makam H, Reed L, Magenis RE, Civelli O (1989) The human dopamine D2 receptor gene is located on chromosome 11 at q22-q23 and identifies a TaqI RFLP. Am J Hum Genet 45:778–785

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Doll BB, Hutchison KE, Frank MJ (2011) Dopaminergic genes predict individual differences in susceptibility to confirmation bias. J Neurosci 31:6188–6198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chien YL, Hwu HG, Fann CS, Chang CC, Tsuang MT, Liu CM (2013) DRD2 haplotype associated with negative symptoms and sustained attention deficits in Han Chinese with schizophrenia in Taiwan. J Hum Genet 58:229–232

    Article  CAS  PubMed  Google Scholar 

  23. Kane JM, Cornblatt B, Correll CU, Goldberg T, Lencz T, Malhotra AK, Robinson D, Szeszko P (2012) The field of schizophrenia: strengths, weaknesses, opportunities, and threats. Schizophr Bull 38:1–4

    Article  PubMed  Google Scholar 

  24. Ramsay H, Barnett JH, Miettunen J, Mukkala S, Maki P, Liuhanen J, Murray GK, Jarvelin MR, Ollila H, Paunio T, Veijola J (2015) Association between dopamine receptor D2 (DRD2) variations rs6277 and rs1800497 and cognitive performance according to risk type for psychosis: a nested case control study in a Finnish population sample. PLoS One 10:e0127602

    Article  PubMed  PubMed Central  Google Scholar 

  25. Swagell CD, Lawford BR, Hughes IP, Voisey J, Feeney GF, van Daal A, Connor JP, Noble EP, Morris CP, Young RM (2012) DRD2 C957T and TaqIA genotyping reveals gender effects and unique low-risk and high-risk genotypes in alcohol dependence. Alcohol Alcohol 47:397–403

    Article  CAS  PubMed  Google Scholar 

  26. Yue JK, Vassar MJ, Lingsma HF, Cooper SR, Okonkwo DO, Valadka AB, Gordon WA, Maas AI, Mukherjee P, Yuh EL, Puccio AM, Schnyer DM, Manley GT, Investigators TRACK-TBI (2013) Transforming research and clinical knowledge in traumatic brain injury pilot: multicenter implementation of the common data elements for traumatic brain injury. J Neurotrauma 30:1831–1844

    Article  PubMed  PubMed Central  Google Scholar 

  27. Duhaime AC, Gean AD, Haacke EM, Hicks R, Wintermark M, Mukherjee P, Brody D, Latour L, Riedy G (2010) Common data elements in radiologic imaging of traumatic brain injury. Arch Phys Med Rehabil 91:1661–1666

    Article  PubMed  Google Scholar 

  28. Maas AI, Harrison-Felix CL, Menon D, Adelson PD, Balkin T, Bullock R, Engel DC, Gordon W, Orman JL, Lew HL, Robertson C, Temkin N, Valadka A, Verfaellie M, Wainwright M, Wright DW, Schwab K (2010) Common data elements for traumatic brain injury: recommendations from the interagency working group on demographics and clinical assessment. Arch Phys Med Rehabil 91:1641–1649

    Article  PubMed  Google Scholar 

  29. Manley GT, Diaz-Arrastia R, Brophy M, Engel D, Goodman C, Gwinn K, Veenstra TD, Ling G, Ottens AK, Tortella F, Hayes RL (2010) Common data elements for traumatic brain injury: recommendations from the biospecimens and biomarkers working group. Arch Phys Med Rehabil 91:1667–1672

    Article  PubMed  Google Scholar 

  30. Wilde EA, Whiteneck GG, Bogner J, Bushnik T, Cifu DX, Dikmen S, French L, Giacino JT, Hart T, Malec JF, Millis SR, Novack TA, Sherer M, Tulsky DS, Vanderploeg RD, von Steinbuechel N (2010) Recommendations for the use of common outcome measures in traumatic brain injury research. Arch Phys Med Rehabil 91(1650–1660):e1617

    Google Scholar 

  31. Okonkwo DO, Yue JK, Puccio AM, Panczykowski DM, Inoue T, McMahon PJ, Sorani MD, Yuh EL, Lingsma HF, Maas AI, Valadka AB, Manley GT (2013) GFAP-BDP as an acute diagnostic marker in traumatic brain injury: results from the prospective transforming research and clinical knowledge in traumatic brain injury study. J Neurotrauma 30:1490–1497

    Article  PubMed  PubMed Central  Google Scholar 

  32. Stallings G, Boake C, Sherer M (1995) Comparison of the California Verbal Learning Test and the Rey Auditory Verbal Learning Test in head-injured patients. J Clin Exp Neuropsychol 17:706–712

    Article  CAS  PubMed  Google Scholar 

  33. Delis DC, Kramer JH, Kaplan E, Ober BA (2000) California Verbal Learning Test, Second Edition. Psychological Corporation: San Antonio, TX.

  34. Wechsler, D. (2008). Wechsler Adult Intelligence Scale—fourth edition. Pearson: Texas.

  35. Kennedy JE, Clement PF, Curtiss G (2003) WAIS-III processing speed index scores after TBI: the influence of working memory, psychomotor speed and perceptual processing. Clin Neuropsychol 17:303–307

    Article  PubMed  Google Scholar 

  36. Reitan RM (1958) Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills 8:271–276

    Article  Google Scholar 

  37. Sanchez-Cubillo I, Perianez JA, Adrover-Roig D, Rodriguez-Sanchez JM, Rios-Lago M, Tirapu J, Barcelo F (2009) Construct validity of the Trail Making Test: role of task-switching, working memory, inhibition/interference control, and visuomotor abilities. J Int Neuropsychol Soc 15:438–450

    Article  CAS  PubMed  Google Scholar 

  38. Voisey J, Swagell CD, Hughes IP, van Daal A, Noble EP, Lawford BR, Young RM, Morris CP (2012) A DRD2 and ANKK1 haplotype is associated with nicotine dependence. Psychiatry Res 196:285–289

    Article  CAS  PubMed  Google Scholar 

  39. Libon DJ, Bondi MW, Price CC, Lamar M, Eppig J, Wambach DM, Nieves C, Delano-Wood L, Giovannetti T, Lippa C, Kabasakalian A, Cosentino S, Swenson R, Penney DL (2011) Verbal serial list learning in mild cognitive impairment: a profile analysis of interference, forgetting, and errors. J Int Neuropsychol Soc 17:905–914

    Article  PubMed  PubMed Central  Google Scholar 

  40. Karr JE, Areshenkoff CN, Garcia-Barrera MA (2014) The neuropsychological outcomes of concussion: a systematic review of meta-analyses on the cognitive sequelae of mild traumatic brain injury. Neuropsychology 28:321–336

    Article  PubMed  Google Scholar 

  41. McCauley SR, Wilde EA, Miller ER, Frisby ML, Garza HM, Varghese R, Levin HS, Robertson CS, McCarthy JJ (2013) Preinjury resilience and mood as predictors of early outcome following mild traumatic brain injury. J Neurotrauma 30:642–652

    Article  PubMed  Google Scholar 

  42. Failla MD, Myrga JM, Ricker JH, Dixon CE, Conley YP, Wagner AK (2015) Posttraumatic brain injury cognitive performance is moderated by variation within ANKK1 and DRD2 genes. J Head Trauma Rehabil 30:E54–E66

    Article  PubMed  PubMed Central  Google Scholar 

  43. Frenette AJ, Kanji S, Rees L, Williamson DR, Perreault MM, Turgeon AF, Bernard F, Fergusson DA (2012) Efficacy and safety of dopamine agonists in traumatic brain injury: a systematic review of randomized controlled trials. J Neurotrauma 29:1–18

    Article  PubMed  Google Scholar 

  44. Yung KK, Bolam JP, Smith AD, Hersch SM, Ciliax BJ, Levey AI (1995) Immunocytochemical localization of D1 and D2 dopamine receptors in the basal ganglia of the rat: light and electron microscopy. Neuroscience 65:709–730

    Article  CAS  PubMed  Google Scholar 

  45. Packard MG, Knowlton BJ (2002) Learning and memory functions of the basal ganglia. Annu Rev Neurosci 25:563–593

    Article  CAS  PubMed  Google Scholar 

  46. Hirvonen MM, Laakso A, Nagren K, Rinne JO, Pohjalainen T, Hietala J (2009) C957T polymorphism of dopamine D2 receptor gene affects striatal DRD2 in vivo availability by changing the receptor affinity. Synapse 63:907–912

    Article  CAS  PubMed  Google Scholar 

  47. Bolton JL, Marioni RE, Deary IJ, Harris SE, Stewart MC, Murray GD, Fowkes FG, Price JF (2010) Association between polymorphisms of the dopamine receptor D2 and catechol-o-methyl transferase genes and cognitive function. Behav Genet 40:630–638

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the following contributors to the development of the TRACK-TBI database and repositories by organization and alphabetical order by last name—One Mind for Research: General Peter Chiarelli, US Army (Ret.), and Garen Staglin, MBA; QuesGen Systems, Inc.: Vibeke Brinck, MS, and Michael Jarrett, MBA; and Thomson Reuters: Sirimon O’Charoen, PhD.

Author information

Authors and Affiliations

  1. Department of Neurological Surgery, University of California, San Francisco, 1001 Potrero Avenue, Building 1, Room 101, San Francisco, CA, 94110, USA

    John K. Yue, Ethan A. Winkler, Jonathan W. Rick, John F. Burke, Marco D. Sorani, Adam R. Ferguson, Sourabh Sharma, Caitlin K. Robinson, Esther L. Yuh, Phiroz E. Tarapore, Pratik Mukherjee & Geoffrey T. Manley

  2. Brain and Spinal Injury Center, San Francisco General Hospital, San Francisco, CA, USA

    John K. Yue, Ethan A. Winkler, Jonathan W. Rick, John F. Burke, Marco D. Sorani, Adam R. Ferguson, Sourabh Sharma, Caitlin K. Robinson, Phiroz E. Tarapore & Geoffrey T. Manley

  3. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA

    Thomas W. McAllister

  4. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA

    Sam S. Oh, Esteban G. Burchard & Donglei Hu

  5. Department of Neurology, Harvard Medical School, Boston, MA, USA

    Jonathan Rosand

  6. Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Jonathan Rosand

  7. Department of Neurological Surgery and Biostatistics, University of Washington, Seattle, WA, USA

    Nancy R. Temkin

  8. Department of Emergency Medicine, Johns Hopkins University, Baltimore, MD, USA

    Frederick K. Korley

  9. Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands

    Hester F. Lingsma

  10. Department of Radiology, University of California, San Francisco, San Francisco, CA, USA

    Esther L. Yuh & Pratik Mukherjee

  11. Center for Neuroproteomics and Biomarkers Research, Department of Psychiatry and Neuroscience, University of Florida, Gainesville, FL, USA

    Kevin K.W. Wang

  12. Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Ava M. Puccio & David O. Okonkwo

  13. Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    Ramon Diaz-Arrastia

  14. Center for Neuroscience and Regenerative Medicine, Bethesda, MD, USA

    Ramon Diaz-Arrastia

  15. Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Wayne A. Gordon

  16. Department of Neurological Surgery, Virginia Commonwealth University, Richmond, VA, USA

    Alex B. Valadka

Authors
  1. John K. Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ethan A. Winkler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jonathan W. Rick
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John F. Burke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas W. McAllister
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sam S. Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Esteban G. Burchard
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Donglei Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jonathan Rosand
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nancy R. Temkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Frederick K. Korley
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Marco D. Sorani
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Adam R. Ferguson
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hester F. Lingsma
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Sourabh Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Caitlin K. Robinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Esther L. Yuh
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Phiroz E. Tarapore
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Kevin K.W. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Ava M. Puccio
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Pratik Mukherjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Ramon Diaz-Arrastia
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Wayne A. Gordon
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Alex B. Valadka
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. David O. Okonkwo
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Geoffrey T. Manley
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

TRACK-TBI Investigators

Corresponding author

Correspondence to Geoffrey T. Manley.

Ethics declarations

Funding

This work was supported by the following grants: NIH RC2 NS069409, NIH RC2 NS069409-02S1, NIH U01 NS086090-01, DOD W81XWH-13-1-0441, and DOD W81XWH-14-2-0176 (to G.T.M.)

Conflict of interest

The authors declare that they have no conflicts of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Research involving human participants

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Additional information

Registry: ClinicalTrials.gov Identifier NCT01565551

John K. Yue and Ethan A. Winkler contributed equally to the manuscript

The TRACK-TBI Investigators are listed in the Appendix in alphabetical order by last name.

Appendix

Appendix

TRACK-TBI investigators

Shelly R. Cooper, BA (Department of Neurosurgery, University of California, San Francisco, San Francisco, CA), Kristen Dams-O’Connor, PhD (Department of Rehabilitation Medicine, Mount Sinai School of Medicine, New York, NY), Allison J. Hricik, MS (Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA), Andrew I. R. Maas, MD, PhD (Department of Neurosurgery, Antwerp University Hospital, Edegem, Belgium), David K. Menon, MD, PhD (Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK), David M. Schnyer, PhD (Department of Psychology, University of Texas at Austin, Austin, TX), and Mary J. Vassar, RN, MS (Department of Neurosurgery, University of California, San Francisco, San Francisco, CA).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yue, J.K., Winkler, E.A., Rick, J.W. et al. DRD2 C957T polymorphism is associated with improved 6-month verbal learning following traumatic brain injury. Neurogenetics 18, 29–38 (2017). https://doi.org/10.1007/s10048-016-0500-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10048-016-0500-6

Keywords

Search

Navigation