title: Genetic Variation in the Vesicular Monoamine Transporter: Preliminary Associations With Cognitive Outcomes After Severe Traumatic Brain Injury.
abstract: Traumatic brain injury (TBI) frequently results in impaired cognition, a function that can be modulated by monoaminergic signaling. Genetic variation among monoaminergic genes may affect post-TBI cognitive performance. The vesicular monoamine transporter-2 (VMAT2) gene may be a novel source of genetic variation important for cognitive outcomes post-TBI given VMAT2's role in monoaminergic neurotransmission.
  
  
  
  To evaluate associations between VMAT2 variability and cognitive outcomes post-TBI.
  
  
  
  We evaluated 136 white adults with severe TBI for variation in VMAT2 using a tagging single nucleotide polymorphism (tSNP) approach (rs363223, rs363226, rs363251, and rs363341). We show genetic variation interacts with assessed cognitive impairment (cognitive composite [Comp-Cog] T-scores) to influence functional cognition (functional independence measure cognitive [FIM-Cog] subscale] 6 and 12 months postinjury.
  
  
  
  Multivariate analyses at 6 months postinjury showed rs363226 genotype was associated with Comp-Cog (P = .040) and interacted with Comp-Cog to influence functional cognition (P < .001). G-homozygotes had the largest cognitive impairment, and their cognitive impairment had the greatest adverse effect on functional cognition.
  
  
  
  We provide the first evidence that genetic variation within VMAT2 is associated with cognitive outcomes after TBI. Further work is needed to validate this finding and elucidate mechanisms by which genetic variation affects monoaminergic signaling, mediating differences in cognitive outcomes.
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania (Drs Markos, Failla, Ritter, Dixon, Arenth, Juengst, and Wagner); Department of Neuroscience, University of Pittsburgh, Pittsburgh Pennsylvania (Dr Wagner); Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania (Drs Dixon and Wagner); Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania (Drs Dixon and Wagner); Pittsburgh VA Healthcare System, and Department of Neurological Surgery, School of Medicine, University of Pittsburgh (Dr Dixon); Department of Rehabilitation Medicine, New York University, School of Medicine, New York, New York (Dr Ricker); and Department of Human Genetics, University of Pittsburgh, School of Public Health, and Health Promotion and Development, University of Pittsburgh, School of Nursing, Pittsburgh, Pennsylvania (Dr Conley).
authors.forename: Steven M
authors.initials: SM
authors.lastname: Markos
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Failla
authors.forename: Anne C
authors.initials: AC
authors.lastname: Ritter
authors.forename: C Edward
authors.initials: CE
authors.lastname: Dixon
authors.forename: Yvette P
authors.initials: YP
authors.lastname: Conley
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Ricker
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Arenth
authors.forename: Shannon B
authors.initials: SB
authors.lastname: Juengst
authors.forename: Amy K
authors.initials: AK
authors.lastname: Wagner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000070642:Brain Injuries, Traumatic / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D015600:Glasgow Coma Scale; D006801:Humans; D015601:Injury Severity Score; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012189:Retrospective Studies; D018570:Risk Assessment; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: C493452:SLC18A2 protein, human; D050493:Vesicular Monoamine Transport Proteins
references.citation: Schizophr Res. 2010 Jul;120(1-3):191-8
references.pmid: 20493663
references.citation: J Head Trauma Rehabil. 2006 Sep-Oct;21(5):375-8
references.pmid: 16983222
references.citation: Am J Phys Med Rehabil. 2000 May-Jun;79(3):235-42
references.pmid: 10821308
references.citation: J Gen Intern Med. 2001 Sep;16(9):606-13
references.pmid: 11556941
references.citation: Eur J Phys Rehabil Med. 2010 Dec;46(4):549-56
references.pmid: 21224787
references.citation: J Neurosci. 2005 May 18;25(20):5038-45
references.pmid: 15901785
references.citation: Handb Clin Neurol. 2015;128:579-611
references.pmid: 25701909
references.citation: J Head Trauma Rehabil. 2010 Jan-Feb;25(1):61-7
references.pmid: 20051895
references.citation: Fed Proc. 1978 Feb;37(2):131-6
references.pmid: 414936
references.citation: J Neurotrauma. 2012 Nov 20;29(17):2613-24
references.pmid: 22994879
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D930-4
references.pmid: 22064851
references.citation: Neuroreport. 2001 Aug 8;12(11):2323-7
references.pmid: 11496104
references.citation: J Trauma. 2002 May;52(5):907-11
references.pmid: 11988658
references.citation: Ann N Y Acad Sci. 2004 Oct;1025:146-50
references.pmid: 15542712
references.citation: Mol Psychiatry. 2007 Apr;12(4):331-59
references.pmid: 17389902
references.citation: J Head Trauma Rehabil. 2008 Jan-Feb;23(1):25-32
references.pmid: 18219232
references.citation: Arch Phys Med Rehabil. 2005 May;86(5):851-6
references.pmid: 15895327
references.citation: Psychopharmacology (Berl). 2006 Jul;187(1):30-5
references.pmid: 16767413
references.citation: J Biol Chem. 2010 Jan 15;285(3):1957-66
references.pmid: 19903816
references.citation: J Neural Transm (Vienna). 2013 Aug;120(8):1161-9
references.pmid: 23504072
references.citation: Neurobiol Aging. 2008 Nov;29(11):1702-11
references.pmid: 17582657
references.citation: Parkinsons Dis. 2015;2015:903164
references.pmid: 26246935
references.citation: NeuroRehabilitation. 2013;32(4):803-15
references.pmid: 23867406
references.citation: Nucleic Acids Res. 1988 Feb 11;16(3):1215
references.pmid: 3344216
references.citation: Neurology. 1985 Jan;35(1):16-24
references.pmid: 3871249
references.citation: J Head Trauma Rehabil. 2016 Nov/Dec;31(6):E62-E73
references.pmid: 26828711
references.citation: Stud Health Technol Inform. 2013;191:38-42
references.pmid: 23792839
references.citation: J Neurosurg. 1989 Apr;70(4):509-13
references.pmid: 2926490
references.citation: Mol Genet Metab. 2000 Sep-Oct;71(1-2):19-31
references.pmid: 11001792
references.citation: Neuropsychiatry Neuropsychol Behav Neurol. 2002 Sep;15(3):184-91
references.pmid: 12218711
references.citation: J Trauma. 2004 May;56(5):1084-9
references.pmid: 15179250
references.citation: BMC Neurosci. 2009 Dec 20;10:150
references.pmid: 20021692
references.citation: Neuroscientist. 2015 Aug;21(4):424-41
references.pmid: 25059577
references.citation: J Neurochem. 2005 Oct;95(1):89-98
references.pmid: 16181415
references.citation: J Neurotrauma. 2011 Jun;28(6):871-88
references.pmid: 21488721
references.citation: Heredity (Edinb). 2005 Sep;95(3):221-7
references.pmid: 16077740
references.citation: J Neurotrauma. 2012 Jul 1;29(10):1898-907
references.pmid: 22416854
references.citation: Injury. 2008 Jan;39(1):67-76
references.pmid: 18164301
references.citation: Brain Res. 2006 Jan 27;1070(1):31-4
references.pmid: 16406269
references.citation: Biochemistry. 2011 Aug 30;50(34):7295-310
references.pmid: 21797260
references.citation: Hum Mol Genet. 2005 May 15;14(10):1393-404
references.pmid: 15829504
references.citation: Arch Phys Med Rehabil. 2008 Dec;89(12 Suppl):S16-24
references.pmid: 19081437
references.citation: Brain Res. 2007 Dec 14;1185:18-32
references.pmid: 18028884
references.citation: Ann N Y Acad Sci. 2011 Jan;1216:86-98
references.pmid: 21272013
references.citation: Injury. 2009 Sep;40(9):973-7
references.pmid: 19540490
references.citation: J Head Trauma Rehabil. 2005 Nov-Dec;20(6):501-11
references.pmid: 16304487
references.citation: J Head Trauma Rehabil. 2016 Sep-Oct;31(5):E15-29
references.pmid: 26580694
references.citation: Bioinformatics. 2005 Jan 15;21(2):263-5
references.pmid: 15297300
references.citation: J Am Geriatr Soc. 2010 Jun;58(6):1090-6
references.pmid: 20487082
references.citation: Am J Psychiatry. 2005 Sep;162(9):1752-4
references.pmid: 16135641
references.citation: Neurobiol Aging. 2013 Jun;34(6):1712.e9-13
references.pmid: 23369548
references.citation: Arch Phys Med Rehabil. 1997 Feb;78(2):125-31
references.pmid: 9041891
references.citation: Curr Treat Options Neurol. 2002 Jan;4(1):43-57
references.pmid: 11734103
references.citation: J Head Trauma Rehabil. 2007 Sep-Oct;22(5):278-87
references.pmid: 17878769
references.citation: J Psychiatr Res. 2013 Nov;47(11):1760-5
references.pmid: 24018103
references.citation: FASEB J. 2010 Jul;24(7):2191-200
references.pmid: 20181938
references.citation: Neurosci Biobehav Rev. 2009 Jul;33(7):981-1003
references.pmid: 19580914
references.citation: J Neurosci. 2010 Oct 20;30(42):14205-12
references.pmid: 20962241
references.citation: Am J Psychiatry. 2012 Jan;169(1):55-63
references.pmid: 22193525
references.citation: Proc Natl Acad Sci U S A. 1996 May 14;93(10):5166-71
references.pmid: 8643547
references.citation: J Trauma. 2000 Sep;49(3):411-9
references.pmid: 11003316
references.citation: Brain Inj. 2012;26(11):1360-71
references.pmid: 22853194
references.citation: Neuropsychiatry Neuropsychol Behav Neurol. 2002 Jun;15(2):123-32
references.pmid: 12050475
references.citation: Brain Inj. 2013 Jun;27(6):696-706
references.pmid: 23672445
references.citation: Arch Gen Psychiatry. 2004 Jan;61(1):42-50
references.pmid: 14706943
references.citation: J Int Neuropsychol Soc. 2003 Jan;9(1):31-44
references.pmid: 12570356
references.citation: Brain Inj. 1998 Jul;12(7):537-53
references.pmid: 9653518
references.citation: Pharmacol Biochem Behav. 2014 Aug;123:45-54
references.pmid: 23978501
references.citation: J Neuropsychiatry Clin Neurosci. 2005 Winter;17(1):61-5
references.pmid: 15746484
references.citation: Hum Mol Genet. 2006 Jan 15;15(2):299-305
references.pmid: 16339215
references.citation: Arch Phys Med Rehabil. 2012 Aug;93(8):1343-9
references.pmid: 22840833
references.citation: J Invest Surg. 1997 Sep-Oct;10(5):281-6
references.pmid: 9361992
references.citation: Health Care Women Int. 2012;33(10):896-904
references.pmid: 22946592
references.citation: Epilepsy Res. 2013 Feb;103(2-3):180-94
references.pmid: 22840783
references.citation: Neurosurg Focus. 2000;8(1):e6
references.pmid: 16924776
references.citation: Brain Inj. 2012;26(10):1226-42
references.pmid: 22571223
references.citation: Can Fam Physician. 2012 Mar;58(3):257-67, e128-40
references.pmid: 22518895
references.citation: NeuroRehabilitation. 2002;17(4):333-44
references.pmid: 12547981
references.citation: J Cereb Blood Flow Metab. 2014 Aug;34(8):1328-39
references.pmid: 24849661
references.citation: Eur J Nucl Med. 2000 Sep;27(9):1410-4
references.pmid: 11007526
references.citation: Headache. 1994 Oct;34(9):503-7
references.pmid: 8002321
references.citation: J Neurosurg. 2007 Apr;106(4):538-47
references.pmid: 17432702
references.citation: J Head Trauma Rehabil. 1999 Dec;14(6):602-15
references.pmid: 10671706
references.citation: Adv Clin Rehabil. 1987;1:6-18
references.pmid: 3503663
references.citation: Med Res Rev. 2011 Jul;31(4):483-519
references.pmid: 20135628
references.citation: J Clin Exp Neuropsychol. 1995 Aug;17(4):536-47
references.pmid: 7593474
references.citation: JAMA. 2010 May 19;303(19):1938-45
references.pmid: 20483970
references.citation: J Cereb Blood Flow Metab. 2011 Sep;31(9):1886-96
references.pmid: 21448217