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Association of a common genetic variant within ANKK1 with six-month cognitive performance after traumatic brain injury

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Abstract

Genetic association analyses suggest that certain common single nucleotide polymorphisms (SNPs) may adversely impact recovery from traumatic brain injury (TBI). Delineating their causal relationship may aid in development of novel interventions and in identifying patients likely to respond to targeted therapies. We examined the influence of the (C/T) SNP rs1800497 of ANKK1 on post-TBI outcome using data from two prospective multicenter studies: the Citicoline Brain Injury Treatment (COBRIT) trial and Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot). We included patients with ANKK1 genotyping results and cognitive outcomes at six months post-TBI (n = 492: COBRIT n = 272, TRACK-TBI Pilot n = 220). Using the California Verbal Learning Test Second Edition (CVLT-II) Trial 1-5 Standard Score, we found a dose-dependent effect for the T allele, with T/T homozygotes scoring lowest on the CVLT-II Trial 1-5 Standard Score (T/T 45.1, C/T 51.1, C/C 52.1, ANOVA, p = 0.008). Post hoc testing with multiple comparison-correction indicated that T/T patients performed significantly worse than C/T and C/C patients. Similar effects were observed in a test of non-verbal processing (Wechsler Adult Intelligence Scale, Processing Speed Index). Our findings extend those of previous studies reporting a negative relationship of the ANKK1 T allele with cognitive performance after TBI. In this study, we demonstrate the value of pooling shared clinical, biomarker, and outcome variables from two large datasets applying the NIH TBI Common Data Elements. The results have implications for future multicenter investigations to further elucidate the role of ANKK1 in post-TBI outcome.

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Acknowledgments

The authors would like to thank the COBRIT and TRACK-TBI Investigators, without whom this work would not have been possible. 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: General Peter Chiarelli, U.S. Army (Ret.), and Garen Staglin; and Thomson Reuters: Sirimon O’Charoen, PhD. This work was supported by the following Grant Numbers: NIH U01 HD42652, NIH R01 HD48179 (to R.D.-A.), and NIH RC2 NS0694909, DOD USAMRAA W81XWH-13-1-0441 (to G.T.M.).

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Disclosure of Potential Conflicts of Interest

The authors declare that they have no conflicts of interest.

Research Involving Human Participants

All procedures performed in the 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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Authors and Affiliations

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

    John K. Yue, Adam R. Ferguson, Sourabh Sharma, Marco D. Sorani, Ethan A. Winkler, Shelly R. Cooper & Geoffrey T. Manley

  2. Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA

    John K. Yue, Adam R. Ferguson, Sourabh Sharma, Marco D. Sorani, Ethan A. Winkler, Shelly R. Cooper & Geoffrey T. Manley

  3. Department of Neurology, Uniformed Services University of the Health Sciences, and Center for Neuroscience and Regenerative Medicine, Bethesda, MD, USA

    Angela M. Pronger & Ramon Diaz-Arrastia

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

    Nancy R. Temkin & Jason Barber

  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 Psychiatry, University of Indiana, Indianapolis, IN, USA

    Thomas W. McAllister

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

    Esteban G. Burchard & Donglei Hu

  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

    Shelly R. Cooper

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

    Ava M. Puccio & David O. Okonkwo

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  1. John K. Yue
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The COBRIT Investigators

The TRACK-TBI Investigators

Corresponding author

Correspondence to Geoffrey T. Manley.

Additional information

John K. Yue and Angela M. Pronger contributed equally to the manuscript

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

Registry: ClinicalTrials.gov Identifier NCT01565551

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Appendix

Appendix

COBRIT investigators

The following are COBRIT investigators: Howard M. Eisenberg, MD (Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD), Jack Jallo, MD, PhD (Temple University Hospital and Moss Rehabilitation Research Institute, Philadelphia, PA; Division of Neurotrauma and Critical Care, Thomas Jefferson University, Philadelphia, PA), Randall E. Merchant, PhD (Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA), Thomas A. Novack, PhD (Department of Physical Medicine and Rehabilitation, University of Alabama at Birmingham, Birmingham, AL), Joseph H. Ricker, PhD (University of Pittsburgh School of Medicine, Pittsburgh, PA), Shelly D. Timmons, MD, PhD (Department of Neurosurgery, Geisinger Medical Center, Danville, PA; University of Tennessee Health Science Center, Memphis, TN), and Ross D. Zafonte, DO (Department of Physical Medicine and Rehabilitation, Harvard Medical School and Massachusetts General Hospital, Boston, MA).

TRACK-TBI investigators

The following are TRACK-TBI investigators: 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 Neurological Surgery, 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), Diane J. Morabito, RN, MPH (Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA), Pratik Mukherjee, MD, PhD (Department of Radiology, University of California, San Francisco, San Francisco, CA), David M. Schnyer, PhD (Department of Psychology, University of Texas at Austin, Austin, TX), Alex B. Valadka, MD (Seton Brain and Spine Institute, Austin, TX), Mary J. Vassar, RN, MS (Department of Neurosurgery, University of California, San Francisco, San Francisco, CA), and Esther L. Yuh, MD, PhD (Department of Radiology, University of California, San Francisco, San Francisco, CA).

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Yue, J.K., Pronger, A.M., Ferguson, A.R. et al. Association of a common genetic variant within ANKK1 with six-month cognitive performance after traumatic brain injury. Neurogenetics 16, 169–180 (2015). https://doi.org/10.1007/s10048-015-0437-1

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