Advertisement

Rare Copy Number Variation in Treatment-Resistant Major Depressive Disorder

      Background

      While antidepressant treatment response appears to be partially heritable, no consistent genetic associations have been identified. Large, rare copy number variants (CNVs) play a role in other neuropsychiatric diseases, so we assessed their association with treatment-resistant depression (TRD).

      Methods

      We analyzed data from two genome-wide association studies comprising 1263 Caucasian patients with major depressive disorder. One was drawn from a large health system by applying natural language processing to electronic health records (i2b2 cohort). The second consisted of a multicenter study of sequential antidepressant treatments, Sequenced Treatment Alternatives to Relieve Depression. The Birdsuite package was used to identify rare deletions and duplications. Individuals without symptomatic remission, despite two antidepressant treatment trials, were contrasted with those who remitted with a first treatment trial.

      Results

      CNV data were derived for 778 subjects in the i2b2 cohort, including 300 subjects (37%) with TRD, and 485 subjects in Sequenced Treatment Alternatives to Relieve Depression cohort, including 152 (31%) with TRD. CNV burden analyses identified modest enrichment of duplications in cases (empirical p = .04 for duplications of 100–200 kilobase) and a particular deletion region spanning gene PABPC4L (empirical p = .02, 6 cases: 0 controls). Pathway analysis suggested enrichment of CNVs intersecting genes regulating actin cytoskeleton. However, none of these associations survived genome-wide correction.

      Conclusions

      Contribution of rare CNVs to TRD appears to be modest, individually or in aggregate. The electronic health record-based methodology demonstrated here should facilitate collection of larger TRD cohorts necessary to further characterize these effects.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Rush A.J.
        • Trivedi M.H.
        • Wisniewski S.R.
        • Nierenberg A.A.
        • Stewart J.W.
        • Warden D.
        • et al.
        Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report.
        Am J Psychiatry. 2006; 163: 1905-1917
        • Gibson T.B.
        • Jing Y.
        • Smith Carls G.
        • Kim E.
        • Bagalman J.E.
        • Burton W.N.
        • et al.
        Cost burden of treatment resistance in patients with depression.
        Am J Manag Care. 2010; 16: 370-377
        • Perlis R.H.
        A clinical risk stratification tool for predicting treatment resistance in major depressive disorder.
        Biol Psychiatry. 2013; 74: 7-14
        • Garriock H.A.
        • Kraft J.B.
        • Shyn S.I.
        • Peters E.J.
        • Yokoyama J.S.
        • Jenkins G.D.
        • et al.
        A genomewide association study of citalopram response in major depressive disorder.
        Biol Psychiatry. 2010; 67: 133-138
        • Ising M.
        • Lucae S.
        • Binder E.B.
        • Bettecken T.
        • Uhr M.
        • Ripke S.
        • et al.
        A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression.
        Arch Gen Psychiatry. 2009; 66: 966-975
      1. GENDEP investigators, MARS investigators, STAR*D investigators (2013): Common genetic variation and antidepressant efficacy in major depressive disorder: A meta-analysis of three genome-wide pharmacogenetic studies. Am J Psychiatry 170:207–217

        • International Schizophrenia Consortium
        Rare chromosomal deletions and duplications increase risk of schizophrenia.
        Nature. 2008; 455: 237-241
        • Stefansson H.
        • Rujescu D.
        • Cichon S.
        • Pietilainen O.P.
        • Ingason A.
        • Steinberg S.
        • et al.
        Large recurrent microdeletions associated with schizophrenia.
        Nature. 2008; 455: 232-236
        • Elia J.
        • Gai X.
        • Xie H.M.
        • Perin J.C.
        • Geiger E.
        • Glessner J.T.
        • et al.
        Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes.
        Mol Psychiatry. 2010; 15: 637-646
        • Malhotra D.
        • Sebat J.
        CNVs: Harbingers of a rare variant revolution in psychiatric genetics.
        Cell. 2012; 148: 1223-1241
        • Bergen S.E.
        • O’Dushlaine C.T.
        • Ripke S.
        • Lee P.H.
        • Ruderfer D.M.
        • Akterin S.
        • et al.
        Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder.
        Mol Psychiatry. 2012; 17: 880-886
        • Rucker J.J.
        • Breen G.
        • Pinto D.
        • Pedroso I.
        • Lewis C.M.
        • Cohen-Woods S.
        • et al.
        Genome-wide association analysis of copy number variation in recurrent depressive disorder.
        Mol Psychiatry. 2013; 18: 183-189
        • Degenhardt F.
        • Priebe L.
        • Herms S.
        • Mattheisen M.
        • Muhleisen T.W.
        • Meier S.
        • et al.
        Association between copy number variants in 16p11.2 and major depressive disorder in a German case-control sample.
        Am J Med Genet B Neuropsychiatr Genet. 2012; 159B: 263-273
        • Glessner J.T.
        • Wang K.
        • Sleiman P.M.
        • Zhang H.
        • Kim C.E.
        • Flory J.H.
        • et al.
        Duplication of the SLIT3 locus on 5q35.1 predisposes to major depressive disorder.
        PLoS One. 2010; 5: e15463
        • Rasmussen H.B.
        • Dahmcke C.M.
        Genome-wide identification of structural variants in genes encoding drug targets: Possible implications for individualized drug therapy.
        Pharmacogenet Genomics. 2012; 22: 471-483
        • Perlis R.H.
        • Iosifescu D.V.
        • Castro V.M.
        • Murphy S.N.
        • Gainer V.S.
        • Minnier J.
        • et al.
        Using electronic medical records to enable large-scale studies in psychiatry: Treatment resistant depression as a model.
        Psychol Med. 2011; 42: 41-50
        • Gallagher P.J.
        • Castro V.
        • Fava M.
        • Weilburg J.B.
        • Murphy S.N.
        • Gainer V.S.
        • et al.
        Antidepressant response in individuals with major depressive disorder exposed to NSAIDs: A pharmacovigilance study.
        Am J Psychiatry. 2012; 169: 1065-1072
        • Rush A.J.
        • Fava M.
        • Wisniewski S.R.
        • Lavori P.W.
        • Trivedi M.H.
        • Sackeim H.A.
        • et al.
        Sequenced Treatment Alternatives to Relieve Depression (STAR*D): Rationale and design.
        Control Clin Trials. 2004; 25: 119-142
        • Rush A.J.
        • Trivedi M.H.
        • Ibrahim H.M.
        • Carmody T.J.
        • Arnow B.
        • Klein D.N.
        • et al.
        The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): A psychometric evaluation in patients with chronic major depression.
        Biol Psychiatry. 2003; 54: 573-583
        • Korn J.M.
        • Kuruvilla F.G.
        • McCarroll S.A.
        • Wysoker A.
        • Nemesh J.
        • Cawley S.
        • et al.
        Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs.
        Nat Genet. 2008; 40: 1253-1260
        • Zhang D
        • Qian Y
        • Akula N
        • Alliey-Rodriguez N
        • Tang J
        • Bipolar Genome Study
        • et al.
        Accuracy of CNV detection from GWAS data.
        PLoS One. 2011; 6: e14511
        • International Scizophrenia Consortium
        • Purcell S.M.
        • Wray N.R.
        • Stone J.L.
        • Visscher P.M.
        • O’Donovan M.C.
        • et al.
        Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.
        Nature. 2009; 460: 748-752
        • Raychaudhuri S.
        • Korn J.M.
        • McCarroll S.A.
        • International Schizophrenia Consortium
        • Altshuler D.
        • Sklar P.
        • et al.
        Accurately assessing the risk of schizophrenia conferred by rare copy-number variation affecting genes with brain function.
        PLoS Genet. 2010; 6: e1001097
        • Purcell S.
        • Neale B.
        • Todd-Brown K.
        • Thomas L.
        • Ferreira M.A.
        • Bender D.
        • et al.
        PLINK: A tool set for whole-genome association and population-based linkage analyses.
        Am J Hum Genet. 2007; 81: 559-575
        • Kim W.
        • Bennett E.J.
        • Huttlin E.L.
        • Guo A.
        • Li J.
        • Possemato A.
        • et al.
        Systematic and quantitative assessment of the ubiquitin-modified proteome.
        Mol Cell. 2011; 44: 325-340
        • Cross-Disorder Group of the Psychiatric Genomics Consortium, Genetic Risk Outcome of Psychosis (GROUP) Consortium
        Identification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis.
        Lancet. 2013; 381: 1371-1379
        • Chang J.C.
        • Tomlinson I.D.
        • Warnement M.R.
        • Ustione A.
        • Carneiro A.M.
        • Piston D.W.
        • et al.
        Single molecule analysis of serotonin transporter regulation using antagonist-conjugated quantum dots reveals restricted, p38 MAPK-dependent mobilization underlying uptake activation.
        J Neurosci. 2012; 32: 8919-8929
        • Durand C.M.
        • Perroy J.
        • Loll F.
        • Perrais D.
        • Fagni L.
        • Bourgeron T.
        • et al.
        SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism.
        Mol Psychiatry. 2012; 17: 71-84
        • Piubelli C.
        • Gruber S.
        • El Khoury A.
        • Mathe A.A.
        • Domenici E.
        • Carboni L.
        Nortriptyline influences protein pathways involved in carbohydrate metabolism and actin-related processes in a rat gene-environment model of depression.
        Eur Neuropsychopharmacol. 2011; 21: 545-562
        • Gallagher P.J.
        • Castro V.
        • Fava M.
        • Weilburg J.B.
        • Murphy S.N.
        • Gainer V.S.
        • et al.
        Antidepressant response in patients with major depression exposed to NSAIDs: A pharmacovigilance study.
        Am J Psychiatry. 2012; 169: 1065-1072
        • Peters E.J.
        • Slager S.L.
        • Kraft J.B.
        • Jenkins G.D.
        • Reinalda M.S.
        • McGrath P.J.
        • Hamilton S.P.
        Pharmacokinetic genes do not influence response or tolerance to citalopram in the STAR*D sample.
        PLoS One. 2008; 3: e1872
        • Wray N.R.
        • Pergadia M.L.
        • Blackwood D.H.
        • Penninx B.W.
        • Gordon S.D.
        • Nyholt D.R.
        • et al.
        Genome-wide association study of major depressive disorder: New results, meta-analysis, and lessons learned.
        Mol Psychiatry. 2012; 17: 36-48
        • Psychiatric GWAS Consortium Bipolar Disorder Working Group
        Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.
        Nat Genet. 2011; 43: 977-983