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COMT Val 158 Met polymorphism is associated with nonverbal cognition following mild traumatic brain injury

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Abstract

Mild traumatic brain injury (mTBI) results in variable clinical outcomes, which may be influenced by genetic variation. A single-nucleotide polymorphism in catechol-o-methyltransferase (COMT), an enzyme which degrades catecholamine neurotransmitters, may influence cognitive deficits following moderate and/or severe head trauma. However, this has been disputed, and its role in mTBI has not been studied. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val 158 Met polymorphism influences outcome on a cognitive battery 6 months following mTBI—Wechsler Adult Intelligence Test Processing Speed Index Composite Score (WAIS-PSI), Trail Making Test (TMT) Trail B minus Trail A time, and California Verbal Learning Test, Second Edition Trial 1–5 Standard Score (CVLT-II). All patients had an emergency department Glasgow Coma Scale (GCS) of 13–15, no acute intracranial pathology on head CT, and no polytrauma as defined by an Abbreviated Injury Scale (AIS) score of ≥3 in any extracranial region. Results in 100 subjects aged 40.9 (SD 15.2) years (COMT Met 158/Met 158 29 %, Met 158/Val 158 47 %, Val 158/Val 158 24 %) show that the COMT Met 158 allele (mean 101.6 ± SE 2.1) associates with higher nonverbal processing speed on the WAIS-PSI when compared to Val 158/Val 158 homozygotes (93.8 ± SE 3.0) after controlling for demographics and injury severity (mean increase 7.9 points, 95 % CI [1.4 to 14.3], p = 0.017). The COMT Val 158 Met polymorphism did not associate with mental flexibility on the TMT or with verbal learning on the CVLT-II. Hence, COMT Val 158 Met may preferentially modulate nonverbal cognition following uncomplicated mTBI.

Registry: ClinicalTrials.gov Identifier NCT01565551

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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:

QuesGen Systems, Inc.: Vibeke Brinck, MS, and Michael Jarrett, MBA

One Mind for Research: General Peter Chiarelli, US Army (Ret.), and Garen Staglin, MBA

Thomson Reuters: Sirimon O’Charoen, PhD

This work was supported by the following grants: NIH RC2 NS069409, NIH RC2 NS069409-02S1, NIH U01 NS086090-01, DOD USAMRAA W81XWH-13-1-0441, DOD W81XWH-14-2-0176

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    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

      Ethan A. Winkler, John K. Yue, Adam R. Ferguson, John F. Burke, Marco D. Sorani, Phiroz E. Tarapore, Sourabh Sharma, Gabriela G. Satris & Geoffrey T. Manley

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

      Ethan A. Winkler, John K. Yue, Adam R. Ferguson, John F. Burke, Marco D. Sorani, Esther L. Yuh, Phiroz E. Tarapore, Sourabh Sharma, Gabriela G. Satris, Pratik Mukherjee & Geoffrey T. Manley

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

      Thomas W. McAllister

    4. Departments of Neurological Surgery and Biostatistics, University of Washington, Seattle, WA, USA

      Nancy R. Temkin & Jason Barber

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

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

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

      Hester F. Lingsma

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

      Jonathan Rosand & Raquel C. Gardner

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

      Jonathan Rosand

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

      Esther L. Yuh & Pratik Mukherjee

    10. Department of Neurology, San Francisco Veterans Administration Medical Center, San Francisco, CA, USA

      Raquel C. Gardner

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

      Ava M. Puccio & David O. Okonkwo

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

      Kevin K. W. Wang

    13. Seton Brain and Spine Institute, Austin, TX, USA

      Alex B. Valadka

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

      Ramon Diaz-Arrastia

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

      Ramon Diaz-Arrastia

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    Correspondence to Geoffrey T. Manley.

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    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.

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

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

    Ethan A. Winkler and John K. Yue contributed equally to this work.

    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), Wayne A. Gordon, 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, United Kingdom), 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).

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    Winkler, E.A., Yue, J.K., McAllister, T.W. et al. COMT Val 158 Met polymorphism is associated with nonverbal cognition following mild traumatic brain injury. Neurogenetics 17, 31–41 (2016). https://doi.org/10.1007/s10048-015-0467-8

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