This work was funded by Vita Genomics, Inc., Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW103-TDU-B-212-113002), and China Medical University Hospital, Taiwan (CMU 101-AWARD-13, DMR-100-117 and DMR-100-119). The funding organizations played no role in the writing of this review. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
References
Papers of special note have been highlighted as:
* of interest
** of considerable interest
[1] Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002
to 2030. PLoS Med. 3(11), e442 (2006).
[2] Lin E, Chen PS. Pharmacogenomics with antidepressants in the STAR*D study.
Pharmacogenomics 9(7), 935-46 (2008).
* Review on pharmacogenomics of antidepressants based on the literature up to 2008.
[3] Murphy E, McMahon FJ. Pharmacogenetics of antidepressants, mood stabilizers, and
antipsychotics in diverse human populations. Discov. Med. 16(87), 113-22 (2013).
[4] Fabbri C, Porcelli S, Serretti A. From pharmacogenetics to pharmacogenomics: the way toward the personalization of antidepressant treatment. Can. J. Psychiatry 59(2), 62-75
(2014).
[5] Johnson AD, O'Donnell CJ. An open access database of genome-wide association
results. BMC Med. Genet. 10(6), (2009).
[6] Christensen K, Murray JC. What genome-wide association studies can do for medicine.
N. Engl. J. Med. 356(11), 1094–1097 (2007).
* Review on GWAS.
[7] Need AC, Goldstein DB. Whole genome association studies in complex diseases: where
do we stand? Dialogues Clin. Neurosci. 12(1), 37-46 (2010).
[8] Pearson TA, Manolio TA. How to interpret a genome-wide association study. JAMA
299(11), 1335–1344 (2008).
[9] Goldstein DB. Common genetic variation and human traits. N. Engl. J. Med. 360(17),
1696-1698 (2009).
[10] Rosenberg NA, Huang L, Jewett EM, Szpiech ZA, Jankovic I, Boehnke M.
Genome-wide association studies in diverse populations. Nat. Rev. Genet. 11(5), 356-66 (2010).
[11] Elbers CC, van Eijk KR, Franke L et al. Using genome-wide pathway analysis to
unravel the etiology of complex diseases. Genet. Epidemiol. 33(5), 419-31 (2009).
[12] Cantor RM, Lange K, Sinsheimer JS. Prioritizing GWAS results: A review of statistical methods and recommendations for their application. Am. J. Hum. Genet.
86(1), 6-22 (2010).
[13] Ising M, Lucae S, Binder EB et al. A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression. Arch. Gen.
Psychiatry 66(9), 966-75 (2009).
** First GWAS in pharmacogenomics of antidepressants.
[14] Zhu R, Wong KF, Lee NP, Lee KF, Luk JM. HNF1α and CDX2 transcriptional factors bind to cadherin-17 (CDH17) gene promoter and modulate its expression in
hepatocellular carcinoma. J. Cell Biochem. 111(3), 618-26 (2010).
[15] Panarelli NC, Yantiss RK, Yeh MM, Liu Y, Chen YT. Tissue-specific cadherin CDH17 is a useful marker of gastrointestinal adenocarcinomas with higher sensitivity
than CDX2. Am. J. Clin. Pathol. 138(2), 211-22 (2012).
[16] Ikeda M, Aleksic B, Kinoshita Y et al. Genome-wide association study of
schizophrenia in a Japanese population. Biol. Psychiatry 69(5), 472-8 (2011).
[17] Sullivan PF, Lin D, Tzeng JY et al. Genomewide association for schizophrenia in the
CATIE study: results of stage 1. Mol. Psychiatry 13(6), 570-84 (2008).
[18] Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M. Strong association of de novo copy number mutations with sporadic schizophrenia, Nat. Genet.
40(7), 880-5 (2008).
[19] Kushima I, Nakamura Y, Aleksic B et al. Resequencing and association analysis of the KALRN and EPHB1 genes and their contribution to schizophrenia susceptibility.
Schizophr. Bull. 38(3), 552-60 (2012).
[20] Garriock HA, Kraft JB, Shyn SI et al. A genomewide association study of citalopram response in major depressive disorder. Biol. Psychiatry 67(2), 133-8 (2010).
[21] Rush AJ, Fava M, Wisniewski SR et al. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Control Clin. Trials 25(1), 119–142
(2004).
[22] Trivedi MH, Rush AJ, Wisniewski SR et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical
practice, Am. J. Psychiatry 163(1), 28–40 (2006).
[23] McMahon FJ, Buervenich S, Charney D et al. Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment, Am. J.
Hum. Genet. 78(5), 804-14 (2006).
[24] Adkins DE, Aberg K, McClay JL et al. A genomewide association study of citalopram response in major depressive disorder-a psychometric approach. Biol. Psychiatry 68(6),
e25-7 (2010).
[25] Lee JS, Kim JH, Bae JS et al. Association analysis of UBE3C polymorphisms in Korean aspirin-intolerant asthmatic patients. Ann. Allergy Asthma Immunol. 105(4),
307-312 (2010).
[26] Pasaje CF, Kim JH, Park BL et al. UBE3C genetic variations as potent markers of nasal polyps in Korean asthma patients. J. Hum. Genet. 56(11), 797-800 (2011).
hepatocellular carcinoma revealed by exome sequencing. Hepatology 59(6), 2216-27
(2014).
[28] Ordway GA, Szebeni A, Chandley MJ et al. Low gene expression of bone morphogenetic protein 7 in brainstem astrocytes in major depression, Int. J.
Neuropsychopharmacol. 15(7), 855-68 (2012).
[29] Esaki K, Kondo K, Hatano M et al. Further evidence of an association between a genetic variant in BMP7 and treatment response to SSRIs in major depressive disorder.
J. Hum. Genet. 58(8), 568-9 (2013).
[30] Logue MW, Baldwin C, Guffanti G et al. A genome-wide association study of post-traumatic stress disorder identifies the retinoid-related orphan receptor alpha (RORA)
gene as a significant risk locus. Mol. Psychiatry 18(8), 937-42 (2013).
[31] Lavebratt C, Sjöholm LK, Partonen T, Schalling M, Forsell Y. PER2 variantion is associated with depression vulnerability. Am. J. Med. Genet. B Neuropsychiatr. Genet.
153B(2), 570-81 (2010).
[32] Terracciano A, Tanaka T, Sutin AR et al. Genome-wide association scan of trait
depression. Biol. Psychiatry 68(9), 811-7 (2010).
[33] Uher R, Perroud N, Ng MY et al. Genome-wide pharmacogenetics of antidepressant response in the GENDEP project. Am. J. Psychiatry 167(5), 555-64 (2010).
[34] Bovolenta P, Fernaud-Espinosa I. Nervous system proteoglycans as modulators of
neurite outgrowth. Prog. Neurobiol. 61(2), 113-32 (2000).
[35] Sulkava S, Ollila HM, Ahola K et al. Genome-wide scan of job-related exhaustion with three replication studies implicate a susceptibility variant at the UST gene locus.
Hum. Mol. Genet. 22(16), 3363-72 (2013).
[36] Rudge JS, Eaton MJ, Mather P, Lindsay RM, Whittemore SR. CNTF induces raphe neuronal precursors to switch from a serotonergic to a cholinergic phenotype in vitro.
Mol. Cell Neurosci. 7(3), 204-21 (1996).
[37] Powell TR, Schalkwyk LC, Heffernan AL et al. Tumor necrosis factor and its targets in the inflammatory cytokine pathway are identified as putative transcriptomic biomarkers for escitalopram response. Eur. Neuropsychopharmacol. 23(9), 1105-14
(2013).
[38] Powell TR, Smith RG, Hackinger S et al. NA methylation in interleukin-11 predicts
clinical response to antidepressants in GENDEP. Transl. Psychiatry 3, e300 (2013).
[39] Hunter AM, Leuchter AF, Power RA et al. A genome-wide association study of a sustained pattern of antidepressant response. J. Psychiatr. Res. 47(9), 1157-65 (2013).
[40] Watkins PA, Maiguel D, Jia Z, Pevsner J. Evidence for 26 distinct acyl-coenzyme A
[41] Murphy E, Hou L, Maher BS et al. Race, genetic ancestry and response to antidepressant treatment for major depression. Neuropsychopharmacology 38(13),
2598-606 (2013).
[42] Clark SL, Adkins DE, Aberg K et al. Pharmacogenomic study of side-effects for
antidepressant treatment options in STAR*D. Psychol. Med. 42(6), 1151-62 (2012).
[43] Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA
292(3), 338-343 (2004).
[44] Licinio J, Wong ML. Depression, antidepressants, and suicidality: a critical appraisal.
Nat. Rev. Drug Discov. 4(2), 165–171 (2005).
[45] Perroud N, Uher R, Ng MY et al. Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project.
Pharmacogenomics J. 12(1), 68-77 (2012).
[46] Martins-de-Souza D, Maccarrone G, Wobrock T et al. Proteome analysis of the thalamus and cerebrospinal fluid reveals glycolysis dysfunction and potential
biomarkers candidates for schizophrenia. J. Psychiatr. Res. 44(16), 1176-89 (2010).
[47] Ward LD, Kellis M. Interpreting noncoding genetic variation in complex traits and human disease. Nat. Biotechnol. 30(11), 1095-106 (2012).
[48] Nebert DW, Zhang G, Vesell ES. From human genetics and genomics to
pharmacogenetics and pharmacogenomics: past lessons, future directions. Drug Metab.
Rev. 40(2), 187-224 (2008).
[49] Spencer CC, Su Z, Donnelly P, Marchini J. Designing genome-wide association studies: sample size, power, imputation, and the choice of genotyping chip. PLoS
Genet. 5(5), e1000477 (2009).
[50] Perlis RH, Moorjani P, Fagerness J et al. Pharmacogenetic analysis of genes implicated in rodent models of antidepressant response: association of TREK1 and treatment resistance in the STAR(*)D study. Neuropsychopharmacology 33(12),
2810-9 (2008).
[51] Manolio TA, Collins FS, Cox NJ et al. Finding the missing heritability of complex
diseases. Nature 461(7265), 747-53 (2009).
[52] Cirulli ET, Goldstein DB. Uncovering the roles of rare variants in common disease
through whole-genome sequencing. Nat. Rev. Genet. 11(6), 415-25 (2010).
[53] Wheeler DA, Srinivasan M, Egholm M et al. The complete genome of an individual
by massively parallel DNA sequencing. Nature 452(7189), 872-6 (2008).
[54] Bamshad MJ, Ng SB, Bigham AW et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat. Rev. Genet. 12(11), 745-55 (2011).
[55] Bell JT, Wallace C, Dobson R et al. Two-dimensional genome-scan identifies novel
epistatic loci for essential hypertension. Hum. Mol. Genet. 15(8), 1365-1374 (2006).
[56] Carlborg O, Haley CS. Epistasis: too often neglected in complex trait studies Nature
5(8), 618-625 (2004).
[57] Lin E, Hwang Y, Chen EY. Gene-gene and gene-environment interactions in
interferon therapy for chronic hepatitis C. Pharmacogenomics 8(10), 1327-1335 (2007).
[58] Lin E, Hwang Y, Liang KH, Chen EY. Pattern-recognition techniques with haplotype
analysis in pharmacogenomics. Pharmacogenomics 8(1), 75-83 (2007).
[59] Lin E, Tsai SJ. Gene-gene interactions in a context of individual variability in antipsychotic drug pharmacogenomics. Curr. Pharmacogenomics Person. Med. 9(4),
323-331 (2011).
[60] Lin E, Tsai SJ. Novel diagnostics R&D for public health and personalized medicine in Taiwan: current state, challenges and opportunities. Curr. Pharmacogenomics Person.
Med. 10(3), 239-246 (2012).
[61] Lin E. Novel drug therapies and diagnostics for personalized medicine and nanomedicine in genome science, nanoscience, and molecular engineering.
Pharmaceutical Regulatory Affairs: Open Access 1, e116 (2012).
[62] Autry AE, Adachi M, Nosyreva E et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475(7354), 91-5 (2011).
[63] Krystal JH, Sanacora G, Duman RS. Rapid-acting glutamatergic antidepressants: the
path to ketamine and beyond. Biol. Psychiatry 73(12), 1133-41 (2013).
[64] Flight MH. Mood disorders: targeting protein synthesis for fast antidepressant action.
Nat. Rev. Drug Discov. 10(8), 577 (2011).
[65] Huang CC, Wei IH, Huang CL et al. Inhibition of glycine transporter-I as a novel
mechanism for the treatment of depression. Biol. Psychiatry 74(10), 734-41 (2013).
[66] Swen JJ, Huizinga TW, Gelderblom H et al. Translating pharmacogenomics:
challenges on the road to the clinic. PLoS Med. 4(8), e209 (2007).
[67] Bartlett G, Zgheib N, Manamperi A et al. Pharmacogenomics in primary care: a crucial entry point for global personalized medicine? Curr. Pharmacogenomics Person.
Med. 10(2), 101-105 (2012).
[68] Smits KM, Smits LJ, Schouten JS, Peeters FP, Prins MH. Does pretreatment testing for serotonin transporter polymorphisms lead to earlier effects of drug treatment in patients with major depression? A decision-analytic model. Clin. Ther. 29(4), 691-702
(2007).
[69] Couzin J. Science and commerce. Gene tests for psychiatric risk polarize researchers.
Science 319(5861), 274-7 (2008).
[70] Pate HN, Ursan ID, Zueger PM, Cavallari LH, Pickard AS. Stakeholder views on
pharmacogenomic testing. Pharmacotherapy 34(2), 151-65 (2014).
[71] Shifman S, Bhomra A, Smiley S et al. A whole genome association study of
neuroticism using DNA pooling. Mol. Psychiatry 13(3), 302-12 (2008).
[72] Heck A, Lieb R, Unschuld PG et al. Evidence for associations between PDE4D
polymorphisms and a subtype of neuroticism. Mol. Psychiatry 13(9), 831-2 (2008).
[73] Serretti A, Kato M, Kennedy JL. Pharmacogenetic studies in depression: a proposal for
methodologic guidelines. Pharmacogenomics J. 8(2), 90-100 (2008).
[74] Lin E, Hwang Y, Wang SC, Gu ZJ, Chen EY. An artificial neural network approach to
the drug efficacy of interferon treatments. Pharmacogenomics 7(7), 1017-1024 (2006).
[75] Serretti A, Smerald E. Neural network analysis in pharmacogenetics of mood
disorders. BMC Medical Genetics 5, 27 (2004).
[76] Lin E, Hsu SY. A Bayesian approach to gene-gene and gene-environment interactions in chronic fatigue syndrome. Pharmacogenomics 10(1), 35-42 (2009).
Table 1. Genes and SNPs in GWAS studies.
Reference Study Gene Polymorphism p-value Results
Ising and colleagues [13]
MARS CDH17 rs6989467 7.6 × 10(-7) Association with early partial response
EPHB1 rs1502174 8.5 × 10(-5) Association with early partial, response and remission
Hunter and STAR* ACSS3 rs10492002 4.5×10(-6) Association with response status
GENDE
NA NA NA Genetic ancestry as a predictor for
treatment response
rs2245705 4.98 ×
ACSS3: acyl-CoA synthetase short-chain family member 3; BMP7: Bone morphogenic protein 7; CDH17: cadherin-17;
EPHB1: Ephrin type-B receptor 1; GDA: guanine deaminase; GENDEP: Genome-based Therapeutic Drugs for Depression;
GWAS: genome-wide association study; IL11: interleukin-11; MARS: Munich Antidepressant Response Signature; NA: not available; RORA: RAR-related orphan receptor alpha; SACM1L: SAC1 suppressor of actin mutations 1-like; SNP: single
nucleotide polymorphism; STAR*D: Sequenced Treatment Alternatives to Relieve Depression; UBE3C: Ubiquitin protein ligase E3C; USP44: ubiquitin specific peptidase 44; UST : uronyl 2-sulphotransferase.