title: Genotype-based ancestral background consistently predicts efficacy and side effects across treatments in CATIE and STAR*D.
abstract: Only a subset of patients will typically respond to any given prescribed drug. The time it takes clinicians to declare a treatment ineffective leaves the patient in an impaired state and at unnecessary risk for adverse drug effects. Thus, diagnostic tests robustly predicting the most effective and safe medication for each patient prior to starting pharmacotherapy would have tremendous clinical value. In this article, we evaluated the use of genetic markers to estimate ancestry as a predictive component of such diagnostic tests. We first estimated each patient's unique mosaic of ancestral backgrounds using genome-wide SNP data collected in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) (n = 765) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) (n = 1892). Next, we performed multiple regression analyses to estimate the predictive power of these ancestral dimensions. For 136/89 treatment-outcome combinations tested in CATIE/STAR*D, results indicated 1.67/1.84 times higher median test statistics than expected under the null hypothesis assuming no predictive power (p<0.01, both samples). Thus, ancestry showed robust and pervasive correlations with drug efficacy and side effects in both CATIE and STAR*D. Comparison of the marginal predictive power of MDS ancestral dimensions and self-reported race indicated significant improvements to model fit with the inclusion of MDS dimensions, but mixed evidence for self-reported race. Knowledge of each patient's unique mosaic of ancestral backgrounds provides a potent immediate starting point for developing algorithms identifying the most effective and safe medication for a wide variety of drug-treatment response combinations. As relatively few new psychiatric drugs are currently under development, such personalized medicine offers a promising approach toward optimizing pharmacotherapy for psychiatric conditions.
authors: Center for Biomarker Research and Personalized Medicine, School of Pharmacy, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA.
authors: Daniel E
authors: DE
authors: Adkins
authors: Renan P
authors: RP
authors: Souza
authors: Karolina
authors: K
authors: Aberg
authors: Shaunna L
authors: SL
authors: Clark
authors: Joseph L
authors: JL
authors: McClay
authors: Patrick F
authors: PF
authors: Sullivan
authors: Edwin J C G
authors: EJ
authors: van den Oord
mesh_terms: D005819:Genetic Markers / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods*; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D057285:Precision Medicine / Q000379:methods*; D055553:Prescription Drugs / Q000009:adverse effects* / Q000627:therapeutic use*; D057566:Self Report; D016896:Treatment Outcome
chemical_list: D005819:Genetic Markers; D055553:Prescription Drugs
references: Am J Psychiatry. 2008 Aug;165(8):952-5
references: 18676598
references: Mol Psychiatry. 2008 Jun;13(6):570-84
references: 18347602
references: Arch Gen Psychiatry. 2009 Aug;66(8):848-56
references: 19652124
references: Schizophr Bull. 2003;29(1):15-31
references: 12908658
references: Arch Gen Psychiatry. 2001 Apr;58(4):395-401
references: 11296101
references: Biol Psychiatry. 2010 Jan 15;67(2):133-8
references: 19846067
references: PLoS Genet. 2008 Jan;4(1):e236
references: 18208327
references: Am J Psychiatry. 2006 Jan;163(1):28-40
references: 16390886
references: Schizophr Res. 2011 Nov;132(2-3):114-20
references: 21872442
references: Psychol Med. 2012 Jun;42(6):1151-62
references: 22041458
references: Am J Hum Genet. 2007 Jun;80(6):1014-23
references: 17557415
references: Neuropsychopharmacology. 2011 Feb;36(3):616-26
references: 21107309
references: Biol Psychiatry. 2010 Feb 1;67(3):279-82
references: 19875103
references: N Engl J Med. 2005 Sep 22;353(12):1209-23
references: 16172203
references: Biol Psychiatry. 2010 Sep 15;68(6):e25-7
references: 20619826
references: Science. 2008 Jan 18;319(5861):274-7
references: 18202268
references: Schizophr Res. 2012 Mar;135(1-3):200-1
references: 22099390
references: Mol Psychiatry. 2011 Jan;16(1):76-85
references: 19721433
references: Schizophr Res. 2009 Jan;107(1):13-21
references: 18930379
references: Am J Hum Genet. 2006 Oct;79(4):640-9
references: 16960800
references: Control Clin Trials. 2004 Feb;25(1):119-42
references: 15061154
references: Hum Mol Genet. 2008 Oct 15;17(R2):R143-50
references: 18852203
references: Transl Psychiatry. 2012 Jul 03;2:e129
references: 22760553
references: Nat Protoc. 2010 Sep;5(9):1564-73
references: 21085122
references: Pharmacogenomics J. 2012 Apr;12(2):165-72
references: 20921969
references: Int J Epidemiol. 2003 Feb;32(1):26-8
references: 12690000
references: J Health Soc Behav. 2010;51 Suppl:S15-27
references: 20943580
references: Nat Genet. 2001 Nov;29(3):265-9
references: 11685208
references: Mol Psychiatry. 2011 Mar;16(3):321-32
references: 20195266
references: Nat Genet. 2004 Nov;36(11 Suppl):S48-53
references: 15508003
references: Psychol Methods. 2002 Mar;7(1):19-40
references: 11928888
references: Hum Mol Genet. 2008 Oct 15;17(R2):R122-8
references: 18852200
references: Lancet. 2010 May 1;375(9725):1525-35
references: 20435227
references: Science. 2003 Oct 24;302(5645):594-6
references: 14576420
references: Am J Hum Genet. 2007 Sep;81(3):559-75
references: 17701901
references: Nat Genet. 2006 Aug;38(8):904-9
references: 16862161
references: Pharmacogenomics. 2009 Feb;10(2):161-3
references: 19207016