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Genome-Wide Association Study of Increasing Suicidal Ideation During Antidepressant Treatment in the GENDEP Project

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Genome-Wide Association Study of Increasing Suicidal Ideation During Antidepressant Treatment in the GENDEP Project The Pharmacogenomics Journal (2012) 12, 68–77 & 2012 Macmillan Publishers Limited. All rights reserved 1470-269X/12 www.nature.com/tpj ORIGINAL ARTICLE Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project NPerroud1,2,3,RUher1, Suicidal thoughts during antidepressant treatment have been the focus of 1 2,3,4 several candidate gene association studies. The aim of the present genome- MYM Ng , M Guipponi , wide association study was to identify additional genetic variants involved in 5 6 JHauser, N Henigsberg , increasing suicidal ideation during escitalopram and nortriptyline treatment. WMaier7,OMors8, A total of 706 adult participants of European ancestry, treated for major M Gennarelli9, M Rietschel10, depression with escitalopram or nortriptyline over 12 weeks in the Genome- DSouery11, MZ Dernovsek12, Based Therapeutic Drugs for Depression (GENDEP) study were genotyped 13 14 with Illumina Human 610-Quad Beadchips (Illumina, San Diego, CA, USA). AS Stamp ,MLathrop , A total of 244 subjects experienced an increase in suicidal ideation AFarmer1, G Breen1,KJAitchison1, during follow-up. The genetic marker most significantly associated with CM Lewis1,IWCraig1 increasing suicidality (8.28 Â 10À7) was a single-nucleotide polymorphism and P McGuffin1 (SNP; rs11143230) located 30 kb downstream of a gene encoding guanine deaminase (GDA) on chromosome 9q21.13. Two suggestive drug-specific 1MRC Social, Genetic and Developmental Psychiatry associations within KCNIP4 (Kv channel-interacting protein 4; chromosome Centre, Institute of Psychiatry, King’s College 4p15.31) and near ELP3 (elongation protein 3 homolog; chromosome London, London, UK; 2Department of Psychiatry, 8p21.1) were found in subjects treated with escitalopram. Suggestive drug University of Geneva Medical School, Geneva, by gene interactions for two SNPs near structural variants on chromosome Switzerland; 3University Hospitals of Geneva, Geneva, Switzerland; 4Department of Genetic 4q12, one SNP in the apolipoprotein O (APOO) gene on chromosome Medicine and Development, University of Geneva Xp22.11 and one on chromosome 11q24.3 were found. The most significant Medical School, Geneva, Switzerland; 5Laboratory of association within a set of 33 candidate genes was in the neurotrophic Psychiatric Genetics, Department of Psychiatry, tyrosine kinase receptor type 2 (NTRK2) gene. Finally, we also found trend for Poznan University of Medical Sciences, Poznan, Poland; 6Croatian Institute for Brain Research, an association within genes previously associated with psychiatric pheno- Medical School, University of Zagreb, Zagreb, types indirectly linked to suicidal behavior, that is, GRIP1, NXPH1 and ANK3. Croatia; 7Department of Psychiatry, University of The results suggest novel pathways involved in increasing suicidal ideation 8 Bonn, Bonn, Germany; Centre for Psychiatric during antidepressant treatment and should help to target treatment to Research, Aarhus University Hospital, Risskov, Denmark; 9Biological Psychiatry Unit and Dual reduce the risk of this dramatic adverse event. Limited power precludes Diagnosis ward IRCCS, Centro San Giovanni di Dio, definitive conclusions and replication in larger sample is warranted. FBF, Brescia, Italy; 10Division of Genetic Epidemiology The Pharmacogenomics Journal (2012) 12, 68–77; doi:10.1038/tpj.2010.70; in Psychiatry, Central Institute of Mental Health, published online 28 September 2010 Mannheim, Germany; 11Laboratoire de Psychologie Me´dicale, Universite´ LibredeBruxellesandPsy Pluriel—Centre Europe´en de Psychologie Me´dicale, Keywords: suicidal ideation; antidepressants; genome-wide association; suicidality; Brussels, Belgium; 12Institute of Public Health of the escitalopram; nortriptyline Republic of Slovenia, Ljubljana, Slovenia; 13Regionspsykiatrien Silkeborg, Aarhus University Hospital, Aarhus, Denmark and 14Centre National de Ge´notypage, Evry Cedex, France Correspondence: Introduction Dr N Perroud, MRC Social, Genetic and Develop- mental Psychiatry Centre, Institute of Psychiatry, Since the issuing of a ‘black box warning’ by the regulatory bodies in the US and King’s College London, Internal PO80, 16 De 1,2 Crespigny Park, Denmark Hill, London SE5 8AF, UK. Europe, there has been an ongoing controversy about the issue of emergence E-mail: [email protected] and/or worsening of suicidal ideation during antidepressant treatment. In an attempt to predict and reduce the risk of these adverse events, several teams of Received 28 February 2010; revised 21 June 2010; accepted 5 August 2010; researchers have sought to identify subjects at risk of suicidality during published online 28 September 2010 antidepressant treatment based on clinical and demographic data.3–5 More GWAS of treatment-increasing suicidal ideation N Perroud et al 69 recently, there has been a focus on genetic markers in order controlled trials ISRCTN03693000 (http://www.controlled- to explain the susceptibility to treatment-related emergence trials.com). and worsening of suicidal ideation.6–9 Recently, in the Genome-Based Therapeutic Drugs for Depression (GENDEP) Phenotype definition study, which comprises subjects treated with escitalopram As previously described,3 suicidal ideation was assessed and nortriptyline, we have reported an association between using the third item of the HDRS-17, the ninth item of the treatment-increasing suicidal ideation and two candidate Beck Depression Inventory and the tenth item of the genes, namely, the brain-derived neurotrophic factor Montgomery–Asberg Depression Rating Scale. Item response (BDNF) and its receptor (neurotrophic tyrosine kinase theory was used to calculate a composite score allowing the receptor type 2, NTRK2) genes.9 Other candidate genes such use of all available data and providing unbiased estimates in as the cyclic adenosine monophosphate response element- the presence of missing values.15 An increase of at least 0.5 binding (CREB1) gene and the glutamate receptor (GRIA3 standard deviation (s.d.) and reaching a level of at least 1 s.d. and GRIK2) genes have also been reported to be associated above the minimum score on the standardized item with treatment-emergent suicidal ideation (TESI) in citalo- response theory-derived suicidality scale was considered as pram-treated subjects.7,8 In addition, Laje et al.,6 in the first increasing suicidal ideation. Individuals with either emer- genome-wide association study of TESI, found evidence of gence or worsening of suicidal ideation at any time point in association with markers within PAPLN, encoding papilin, the 12 weeks of follow-up were considered as cases.3 and IL28RA, encoding an interleukin receptor. Controls were those without increasing suicidal ideation Despite significant advances in our understanding of the during this period. To compare our results with previously genetic etiology of TESI, the genetic determinants under- published studies,6 we also considered, in a secondary lying this complex trait are mostly unknown. The GENDEP analysis, individuals with only TESI (N ¼ 48), compared study offers a unique opportunity to search, on a genome- with individuals without suicidal ideation either at baseline wide basis, for genetic variants involved in increasing or during treatment (N ¼ 230). suicidal ideation during antidepressant treatment and to identity whether common and/or drug-specific pathways Genotyping are involved in this phenomenon. Genotyping was performed as previously described.12 Briefly, DNA was extracted from blood collected in EDTA provided by 795 participants, and 727 samples available in sufficient quantity and quality were sent to the Centre Materials and methods National de Ge´notypage, France and genotyped using the Illumina Human610-quad bead chip (Illumina). Study design and sample A total of 811 adult patients of European ethnicity, suffering Quality control and population stratification from unipolar depression of at least moderate severity Quality control procedures on the 727 genotyped samples according to ICD-10 (International Classification of Dis- using PLINK16 have previously been described in detail in eases, 10th revision) or DSM-IV (Diagnostic and Statistical Uher et al.12 Markers were retained if they had a minor allele Manual of Mental Disorders, Fourth Edition) criteria, frequency (MAF) of X0.01, a genotyping completeness of established in the semi-structured Schedules for Clinical 99% and no significant departures from Hardy–Weinberg Assessment in Neuropsychiatry interview10 and aged be- equilibrium (P40.0001). A total of 539 199 single-nucleo- tween 19 and 72 years, were recruited in nine European tide polymorphism (SNP) markers were retained for the centers.11 Exclusion criteria have been described pre- analyses. At the individual level, samples with ambiguous viously.12 GENDEP is a partially randomized multicenter sex (N ¼ 3), outliers on autosomal heterozygosity (N ¼ 3) and clinical and pharmacogenomic study. Participants with no one of each pair of related individuals ascertained through contraindications were randomly allocated to receive, for 12 estimation of identity by descent (N ¼ 6) were excluded. weeks, either escitalopram (10–30 mg daily), a selective Finally, genotyping completeness was assessed for each inhibitor of the serotonin transporter,13 or nortriptyline individual, and outliers with genotyping completeness (50–150 mg daily), a tricyclic antidepressant with a hundred o95% were excluded from further analyses (N ¼ 4). times higher
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