title: Multivariate analysis of subjective responses to d-amphetamine in healthy volunteers finds novel genetic pathway associations.
abstract: BACKGROUND
  Researchers studying behavioral and physiologic effects of d-amphetamine have explored individual response differences to the drug. Concurrently, genome-wide analyses have identified several single-nucleotide polymorphisms (SNPs) associated with these traits. Univariate methods can identify SNPs associated with behavioral and physiological traits, but multivariate analyses allow identification of clusters of related biologically relevant SNPs and behavioral components.
  
  
  OBJECTIVE
  The aim of the study was to identify clusters of related biologically relevant SNPs and behavioral components in the responses of healthy individuals to d-amphetamine using multivariate analysis.
  
  
  METHODS
  Individuals (N = 375) without substance abuse histories completed surveys and detailed cardiovascular monitoring during randomized, blinded sessions: d-amphetamine (10 and 20 mg) and placebo. We applied parallel independent component analysis (Para-ICA) to data previously analyzed with univariate approaches, revealing new associations between genes and behavioral responses to d-amphetamine.
  
  
  RESULTS
  Three significantly associated (p < .001) phenotype-genotype pairs emerged. The first component included physiologic measures of systolic and diastolic blood pressure (BP) and mean arterial pressure (MAP) along with SNPs in calcium and glutamatergic signaling pathways. The second associated components included the "Anger" items from the Profile of Mood States (POMS) questionnaire and the marijuana effects from the Addiction Research Center Inventory (Cuyas, Verdejo-Garcia et al.), with enriched genetic pathways involved in cardiomyopathy and MAPK signaling. The final pair included "Anxious," "Fatigue," and "Confusion" items from the POMS questionnaire, plus functional pathways related to cardiac muscle contraction and cardiomyopathy.
  
  
  CONCLUSIONS
  Multifactorial genetic networks related to calcium signaling, glutamatergic and dopaminergic synapse function, and amphetamine addiction appear to mediate common behavioral and cardiovascular responses to d-amphetamine.
authors.affiliation: Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, 200 Retreat Avenue, Hartford, CT, 06102, USA.
authors.forename: Haley L
authors.initials: HL
authors.lastname: Yarosh
authors.forename: Shashwath A
authors.initials: SA
authors.lastname: Meda
authors.forename: Harriet
authors.initials: H
authors.lastname: de Wit
authors.forename: Amy B
authors.initials: AB
authors.lastname: Hart
authors.forename: Godfrey D
authors.initials: GD
authors.lastname: Pearlson
mesh_terms: D019969:Amphetamine-Related Disorders / Q000235:genetics*; D000786:Anger / Q000187:drug effects*; D001007:Anxiety / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects* / Q000235:genetics; D003913:Dextroamphetamine / Q000494:pharmacology*; D005260:Female; D055106:Genome-Wide Association Study; D064368:Healthy Volunteers; D006801:Humans; D007206:Individuality; D008297:Male; D015999:Multivariate Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D003913:Dextroamphetamine
references.citation: Arch Gen Psychiatry. 2008 Mar;65(3):345-55
references.pmid: 18316681
references.citation: Psychopharmacology (Berl). 2001 Aug;157(1):20-30
references.pmid: 11512039
references.citation: Psychiatry Res. 2013 Mar 30;206(1):122-3
references.pmid: 22985546
references.citation: Genes Brain Behav. 2009 Nov;8(8):785-94
references.pmid: 19694819
references.citation: Addiction. 2009 Jul;104(7):1085-99
references.pmid: 19426289
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: Neuropathol Appl Neurobiol. 2010 Feb;36(1):17-24
references.pmid: 19627511
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):27-30
references.pmid: 10592173
references.citation: Toxicol Lett. 2009 Sep 10;189(2):152-8
references.pmid: 19481142
references.citation: PLoS Comput Biol. 2008 Jan;4(1):e2
references.pmid: 18179280
references.citation: J Cell Physiol. 1996 Nov;169(2):358-63
references.pmid: 8908203
references.citation: Proc Natl Acad Sci U S A. 2003 May 13;100(10):6186-91
references.pmid: 12716966
references.citation: Neurobiol Learn Mem. 2008 Sep;90(2):472-4
references.pmid: 18583162
references.citation: Neurosci Biobehav Rev. 2014 May;42:9-34
references.pmid: 24486722
references.citation: BMC Med Genet. 2013;14:119
references.pmid: 24252324
references.citation: Genes Brain Behav. 2013 Feb;12(1):13-20
references.pmid: 23231539
references.citation: Neuron. 2009 Jul 30;63(2):230-43
references.pmid: 19640481
references.citation: Chang Gung Med J. 2009 Mar-Apr;32(2):148-54
references.pmid: 19403004
references.citation: Alcohol Clin Exp Res. 2004 Jan;28(1):4-9
references.pmid: 14745296
references.citation: PLoS Comput Biol. 2012;8(2):e1002375
references.pmid: 22383865
references.citation: Neurology. 2013 Jun 4;80(23):2106-11
references.pmid: 23658386
references.citation: Alcohol Clin Exp Res. 2013 Jun;37(6):896-904
references.pmid: 23278386
references.citation: Eur J Neurosci. 2007 Nov;26(10):2713-8
references.pmid: 17970718
references.citation: FASEB J. 2013 Dec;27(12):4877-89
references.pmid: 24005908
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2013 Jan 10;40:347-52
references.pmid: 23153507
references.citation: Dev Biol. 2008 Oct 1;322(1):95-108
references.pmid: 18675265
references.citation: Neurosci Biobehav Rev. 2012 Jul;36(6):1565-76
references.pmid: 22542906
references.citation: Eur J Med Genet. 2014 Jan;57(1):32-6
references.pmid: 24211661
references.citation: IEEE Signal Process Lett. 2008 Jan 1;15:413-416
references.pmid: 19834575
references.citation: Neurobiol Aging. 2011 Jan;32(1):157-67
references.pmid: 19233512
references.citation: Cell Tissue Res. 2006 Apr;324(1):17-24
references.pmid: 16374620
references.citation: BMC Psychiatry. 2012;12:221
references.pmid: 23216941
references.citation: Am J Pathol. 2013 Apr;182(4):1322-36
references.pmid: 23416161
references.citation: Acta Genet Med Gemellol (Roma). 1983;32(2):139-49
references.pmid: 6685963
references.citation: J Neurosci Res. 2013 Oct;91(10):1338-48
references.pmid: 23913674
references.citation: Neuropsychopharmacology. 2006 Mar;31(3):572-84
references.pmid: 16123759
references.citation: Hum Mol Genet. 2012 Oct 15;21(R1):R97-110
references.pmid: 22914737
references.citation: AAPS J. 2005;7(1):E259-65
references.pmid: 16146347
references.citation: Neurobiol Dis. 2011 Oct;44(1):84-91
references.pmid: 21726646
references.citation: Genet Epidemiol. 2008 Apr;32(3):215-26
references.pmid: 18161052
references.citation: Mol Psychiatry. 2013 Aug;18(8):937-42
references.pmid: 22869035
references.citation: J Clin Endocrinol Metab. 2010 May;95(5):2418-25
references.pmid: 20215397
references.citation: Psychopharmacology (Berl). 1980;71(3):275-9
references.pmid: 6779335
references.citation: Prenat Diagn. 2013 Jan;33(1):75-80
references.pmid: 23161355
references.citation: BMC Neurosci. 2010;11:128
references.pmid: 20939929
references.citation: Hum Brain Mapp. 2001 Nov;14(3):140-51
references.pmid: 11559959
references.citation: Nat Genet. 2003 Jul;34(3):267-73
references.pmid: 12808457
references.citation: J Neurosci. 2002 Nov 15;22(22):9905-11
references.pmid: 12427847
references.citation: Rinsho Shinkeigaku. 2008 Nov;48(11):892-5
references.pmid: 19198108
references.citation: Psychopharmacology (Berl). 1985;86(3):307-12
references.pmid: 3929301
references.citation: Eur J Oral Sci. 2009 Jun;117(3):218-23
references.pmid: 19583747
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D277-80
references.pmid: 14681412
references.citation: PLoS One. 2013;8(1):e53301
references.pmid: 23326410
references.citation: PLoS One. 2012;7(8):e42646
references.pmid: 22952603
references.citation: J Neural Transm (Vienna). 2014 Apr;121(4):353-6
references.pmid: 24253235
references.citation: Psychiatr Genet. 2012 Feb;22(1):31-41
references.pmid: 22064162
references.citation: Addict Biol. 2006 Sep;11(3-4):386-96
references.pmid: 16961766
references.citation: Nat Rev Neurosci. 2009 Aug;10(8):561-72
references.pmid: 19571793
references.citation: Mov Disord. 2013 Jan;28(1):14-23
references.pmid: 23389780
references.citation: Neuroreport. 2012 Jul 11;23(10):611-5
references.pmid: 22627700
references.citation: Psychiatr Genet. 2010 Jun;20(3):85-92
references.pmid: 20414144
references.citation: Mol Aspects Med. 2013 Apr-Jun;34(2-3):220-35
references.pmid: 23506867
references.citation: Annu Rev Med. 2014;65:245-61
references.pmid: 24111888
references.citation: Eur J Neurosci. 2008 Apr;27(8):2156-64
references.pmid: 18371075
references.citation: Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7406-11
references.pmid: 12773616
references.citation: Eur J Pharmacol. 2011 Dec 5;671(1-3):70-8
references.pmid: 21978834
references.citation: Hum Brain Mapp. 2009 Jan;30(1):241-55
references.pmid: 18072279
references.citation: Neurosci Lett. 2001 Aug 31;309(3):145-8
references.pmid: 11514062
references.citation: Emerg Med Australas. 2008 Oct;20(5):391-402
references.pmid: 18973636
references.citation: Biochem Biophys Res Commun. 2010 Nov 12;402(2):272-9
references.pmid: 20937252
references.citation: Clin Toxicol (Phila). 2010 Aug;48(7):675-94
references.pmid: 20849327
references.citation: Br Med Bull. 2003;65:259-70
references.pmid: 12697630
references.citation: Mol Psychiatry. 2014 Jun;19(6):717-23
references.pmid: 23958962
references.citation: Ann N Y Acad Sci. 2001 Jun;937:93-120
references.pmid: 11458542
references.citation: J Neurosci Res. 2010 Nov 15;88(15):3243-56
references.pmid: 20882566
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):868-73
references.pmid: 15644446
references.citation: Clin Pharmacol Ther. 1971 Mar-Apr;12(2):245-58
references.pmid: 5554941
references.citation: Biol Psychiatry. 2009 Nov 15;66(10):926-34
references.pmid: 19733838
references.citation: Mol Neurobiol. 2011 Dec;44(3):269-86
references.pmid: 21922273
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Transl Psychiatry. 2011;1:e49
references.pmid: 22833195
references.citation: Mol Cell Biol. 1999 Jun;19(6):4495-502
references.pmid: 10330188
references.citation: PLoS One. 2011;6(11):e27206
references.pmid: 22110616
references.citation: Neuroimage. 2012 Apr 15;60(3):1608-21
references.pmid: 22245343
references.citation: Proc Natl Acad Sci U S A. 2010 May 11;107(19):8695-700
references.pmid: 20421487
references.citation: Eur Neuropsychopharmacol. 2009 Feb;19(2):116-24
references.pmid: 19042106
references.citation: BMC Psychiatry. 2009;9:70
references.pmid: 19909500
references.citation: J Int Neuropsychol Soc. 2010 Sep;16(5):890-901
references.pmid: 20727252
references.citation: Neuroimage. 2009 Mar;45(1 Suppl):S163-72
references.pmid: 19059344
references.citation: Metab Brain Dis. 2014 Mar;29(1):131-8
references.pmid: 24048906
references.citation: Hypertens Res. 2012 Jun;35(6):585-91
references.pmid: 22297481
references.citation: Circ Res. 2000 Apr 14;86(7):795-801
references.pmid: 10764414
references.citation: PLoS Genet. 2010 Sep;6(9):e1001117
references.pmid: 20862358
references.citation: J Psychiatr Res. 2011 Feb;45(2):280-2
references.pmid: 20888579
references.citation: Addict Biol. 2014 May;19(3):343-53
references.pmid: 22780223
references.citation: Mol Autism. 2013 May 22;4(1):14
references.pmid: 23697635
references.citation: Neuropsychopharmacology. 2013 Apr;38(5):802-16
references.pmid: 23303064
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D199-205
references.pmid: 24214961