Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project

N. Perroud; R. Uher; M. Y.M. Ng; M. Guipponi; J. Hauser; N. Henigsberg; W. Maier; O. Mors; M. Gennarelli; M. Rietschel; D. Souery; M. Z. Dernovsek; A. S. Stamp; M. Lathrop; A. Farmer; G. Breen; K. J. Aitchison; C. M. Lewis; I. W. Craig; P. McGuffin

doi:10.1038/tpj.2010.70

Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project

N. Perroud, R. Uher, M. Y.M. Ng, M. Guipponi, J. Hauser, N. Henigsberg, W. Maier, O. Mors, M. Gennarelli, M. Rietschel, D. Souery, M. Z. Dernovsek, A. S. Stamp, M. Lathrop, A. Farmer, G. Breen, K. J. Aitchison, C. M. Lewis, I. W. Craig, P. McGuffin

Research output: Contribution to journal › Article › peer-review

78 Citations (Scopus)

Abstract

Suicidal thoughts during antidepressant treatment have been the focus of several candidate gene association studies. The aim of the present genome-wide association study was to identify additional genetic variants involved in increasing suicidal ideation during escitalopram and nortriptyline treatment. A total of 706 adult participants of European ancestry, treated for major depression with escitalopram or nortriptyline over 12 weeks in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study were genotyped with Illumina Human 610-Quad Beadchips (Illumina, San Diego, CA, USA). A total of 244 subjects experienced an increase in suicidal ideation during follow-up. The genetic marker most significantly associated with increasing suicidality (8.28 × 10 7) was a single-nucleotide polymorphism (SNP; rs11143230) located 30 kb downstream of a gene encoding guanine deaminase (GDA) on chromosome 9q21.13. Two suggestive drug-specific associations within KCNIP4 (Kv channel-interacting protein 4; chromosome 4p15.31) and near ELP3 (elongation protein 3 homolog; chromosome 8p21.1) were found in subjects treated with escitalopram. Suggestive drug by gene interactions for two SNPs near structural variants on chromosome 4q12, one SNP in the apolipoprotein O (APOO) gene on chromosome Xp22.11 and one on chromosome 11q24.3 were found. The most significant association within a set of 33 candidate genes was in the neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene. Finally, we also found trend for an association within genes previously associated with psychiatric phenotypes indirectly linked to suicidal behavior, that is, GRIP1, NXPH1 and ANK3. The results suggest novel pathways involved in increasing suicidal ideation during antidepressant treatment and should help to target treatment to reduce the risk of this dramatic adverse event. Limited power precludes definitive conclusions and replication in larger sample is warranted.

Original language	English
Pages (from-to)	68-77
Number of pages	10
Journal	Pharmacogenomics Journal
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/tpj.2010.70
Publication status	Published - Feb 2012
Externally published	Yes

Bibliographical note

Funding Information:
We acknowledge the contribution of Maja Bajs, Mara Barreto, Cristian Bonvicini, Desmond Campbell, Elzbieta Cegielska, Monika Dmitrzak-Weglarz, Amanda Elkin, Caterina Giovannini, Joanna M Gray, Cerisse Gunasinghe, Bhanu Gupta, Sudhir Kumar, Susanne Höfels, Petra Kalember, Pawe" Kapelski, Zrnka Kovacic, Dejan Kozel, Anna Leszczynska-Rodziewicz, Sylvie Linotte, Andrej Marusic, Julien Mendlewicz, Metka Paragi, Laura Pedrini, Jorge Perez, Ute Pfeiffer, Aleksandra Rajewska-Rager, Luciana Rillosi, Christine Schmäl, Anna Schuhmacher, Maria Skibiñska, Rebecca Smith, Farzana Hoda, Jana Strohmaier, Jerneja Sveticic, Aleksandra Szczepankiewicz, Alenka Tancic, Sandra Weber, Thomas Schulze, Piotr Czerski and Richard J Williamson. The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref: LSHB-CT-2003-503428. Lundbeck provided both nortriptyline and escitalopram free of charge for the GENDEP study. GlaxoSmithKline, the Medical Research Council and the Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King’s College London and South London and Maudsley NHS Foundation Trust (funded by the National Institute for Health Research, Department of Health, UK) contributed by funding add-on projects in the London center. The genotyping was funded by joint grant from the Medical Research Council, UK and GlaxoSmithKline (G0701420). The fund providers had no role in the design and conduct of the study, in data collection, analysis, interpretation or writing the report.

ASJC Scopus Subject Areas

Molecular Medicine
Genetics
Pharmacology

PubMed: MeSH publication types

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/tpj.2010.70

Cite this

Perroud, N., Uher, R., Ng, M. Y. M., Guipponi, M., Hauser, J., Henigsberg, N., Maier, W., Mors, O., Gennarelli, M., Rietschel, M., Souery, D., Dernovsek, M. Z., Stamp, A. S., Lathrop, M., Farmer, A., Breen, G., Aitchison, K. J., Lewis, C. M., Craig, I. W., & McGuffin, P. (2012). Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project. Pharmacogenomics Journal, 12(1), 68-77. https://doi.org/10.1038/tpj.2010.70

Perroud, N , Uher, R, Ng, MYM, Guipponi, M, Hauser, J, Henigsberg, N, Maier, W, Mors, O, Gennarelli, M, Rietschel, M, Souery, D, Dernovsek, MZ, Stamp, AS, Lathrop, M, Farmer, A, Breen, G, Aitchison, KJ, Lewis, CM, Craig, IW & McGuffin, P 2012, 'Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project', Pharmacogenomics Journal, vol. 12, no. 1, pp. 68-77. https://doi.org/10.1038/tpj.2010.70

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title = "Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project",

abstract = "Suicidal thoughts during antidepressant treatment have been the focus of several candidate gene association studies. The aim of the present genome-wide association study was to identify additional genetic variants involved in increasing suicidal ideation during escitalopram and nortriptyline treatment. A total of 706 adult participants of European ancestry, treated for major depression with escitalopram or nortriptyline over 12 weeks in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study were genotyped with Illumina Human 610-Quad Beadchips (Illumina, San Diego, CA, USA). A total of 244 subjects experienced an increase in suicidal ideation during follow-up. The genetic marker most significantly associated with increasing suicidality (8.28 × 10 7) was a single-nucleotide polymorphism (SNP; rs11143230) located 30 kb downstream of a gene encoding guanine deaminase (GDA) on chromosome 9q21.13. Two suggestive drug-specific associations within KCNIP4 (Kv channel-interacting protein 4; chromosome 4p15.31) and near ELP3 (elongation protein 3 homolog; chromosome 8p21.1) were found in subjects treated with escitalopram. Suggestive drug by gene interactions for two SNPs near structural variants on chromosome 4q12, one SNP in the apolipoprotein O (APOO) gene on chromosome Xp22.11 and one on chromosome 11q24.3 were found. The most significant association within a set of 33 candidate genes was in the neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene. Finally, we also found trend for an association within genes previously associated with psychiatric phenotypes indirectly linked to suicidal behavior, that is, GRIP1, NXPH1 and ANK3. The results suggest novel pathways involved in increasing suicidal ideation during antidepressant treatment and should help to target treatment to reduce the risk of this dramatic adverse event. Limited power precludes definitive conclusions and replication in larger sample is warranted.",

author = "N. Perroud and R. Uher and Ng, {M. Y.M.} and M. Guipponi and J. Hauser and N. Henigsberg and W. Maier and O. Mors and M. Gennarelli and M. Rietschel and D. Souery and Dernovsek, {M. Z.} and Stamp, {A. S.} and M. Lathrop and A. Farmer and G. Breen and Aitchison, {K. J.} and Lewis, {C. M.} and Craig, {I. W.} and P. McGuffin",

note = "Funding Information: We acknowledge the contribution of Maja Bajs, Mara Barreto, Cristian Bonvicini, Desmond Campbell, Elzbieta Cegielska, Monika Dmitrzak-Weglarz, Amanda Elkin, Caterina Giovannini, Joanna M Gray, Cerisse Gunasinghe, Bhanu Gupta, Sudhir Kumar, Susanne H{\"o}fels, Petra Kalember, Pawe{"} Kapelski, Zrnka Kovacic, Dejan Kozel, Anna Leszczynska-Rodziewicz, Sylvie Linotte, Andrej Marusic, Julien Mendlewicz, Metka Paragi, Laura Pedrini, Jorge Perez, Ute Pfeiffer, Aleksandra Rajewska-Rager, Luciana Rillosi, Christine Schm{\"a}l, Anna Schuhmacher, Maria Skibi{\~n}ska, Rebecca Smith, Farzana Hoda, Jana Strohmaier, Jerneja Sveticic, Aleksandra Szczepankiewicz, Alenka Tancic, Sandra Weber, Thomas Schulze, Piotr Czerski and Richard J Williamson. The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref: LSHB-CT-2003-503428. Lundbeck provided both nortriptyline and escitalopram free of charge for the GENDEP study. GlaxoSmithKline, the Medical Research Council and the Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King{\textquoteright}s College London and South London and Maudsley NHS Foundation Trust (funded by the National Institute for Health Research, Department of Health, UK) contributed by funding add-on projects in the London center. The genotyping was funded by joint grant from the Medical Research Council, UK and GlaxoSmithKline (G0701420). The fund providers had no role in the design and conduct of the study, in data collection, analysis, interpretation or writing the report.",

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month = feb,

doi = "10.1038/tpj.2010.70",

language = "English",

volume = "12",

pages = "68--77",

journal = "Pharmacogenomics Journal",

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T1 - Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project

AU - Perroud, N.

AU - Uher, R.

AU - Ng, M. Y.M.

AU - Guipponi, M.

AU - Hauser, J.

AU - Henigsberg, N.

AU - Maier, W.

AU - Mors, O.

AU - Gennarelli, M.

AU - Rietschel, M.

AU - Souery, D.

AU - Dernovsek, M. Z.

AU - Stamp, A. S.

AU - Lathrop, M.

AU - Farmer, A.

AU - Breen, G.

AU - Aitchison, K. J.

AU - Lewis, C. M.

AU - Craig, I. W.

AU - McGuffin, P.

N1 - Funding Information: We acknowledge the contribution of Maja Bajs, Mara Barreto, Cristian Bonvicini, Desmond Campbell, Elzbieta Cegielska, Monika Dmitrzak-Weglarz, Amanda Elkin, Caterina Giovannini, Joanna M Gray, Cerisse Gunasinghe, Bhanu Gupta, Sudhir Kumar, Susanne Höfels, Petra Kalember, Pawe" Kapelski, Zrnka Kovacic, Dejan Kozel, Anna Leszczynska-Rodziewicz, Sylvie Linotte, Andrej Marusic, Julien Mendlewicz, Metka Paragi, Laura Pedrini, Jorge Perez, Ute Pfeiffer, Aleksandra Rajewska-Rager, Luciana Rillosi, Christine Schmäl, Anna Schuhmacher, Maria Skibiñska, Rebecca Smith, Farzana Hoda, Jana Strohmaier, Jerneja Sveticic, Aleksandra Szczepankiewicz, Alenka Tancic, Sandra Weber, Thomas Schulze, Piotr Czerski and Richard J Williamson. The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref: LSHB-CT-2003-503428. Lundbeck provided both nortriptyline and escitalopram free of charge for the GENDEP study. GlaxoSmithKline, the Medical Research Council and the Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King’s College London and South London and Maudsley NHS Foundation Trust (funded by the National Institute for Health Research, Department of Health, UK) contributed by funding add-on projects in the London center. The genotyping was funded by joint grant from the Medical Research Council, UK and GlaxoSmithKline (G0701420). The fund providers had no role in the design and conduct of the study, in data collection, analysis, interpretation or writing the report.

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N2 - Suicidal thoughts during antidepressant treatment have been the focus of several candidate gene association studies. The aim of the present genome-wide association study was to identify additional genetic variants involved in increasing suicidal ideation during escitalopram and nortriptyline treatment. A total of 706 adult participants of European ancestry, treated for major depression with escitalopram or nortriptyline over 12 weeks in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study were genotyped with Illumina Human 610-Quad Beadchips (Illumina, San Diego, CA, USA). A total of 244 subjects experienced an increase in suicidal ideation during follow-up. The genetic marker most significantly associated with increasing suicidality (8.28 × 10 7) was a single-nucleotide polymorphism (SNP; rs11143230) located 30 kb downstream of a gene encoding guanine deaminase (GDA) on chromosome 9q21.13. Two suggestive drug-specific associations within KCNIP4 (Kv channel-interacting protein 4; chromosome 4p15.31) and near ELP3 (elongation protein 3 homolog; chromosome 8p21.1) were found in subjects treated with escitalopram. Suggestive drug by gene interactions for two SNPs near structural variants on chromosome 4q12, one SNP in the apolipoprotein O (APOO) gene on chromosome Xp22.11 and one on chromosome 11q24.3 were found. The most significant association within a set of 33 candidate genes was in the neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene. Finally, we also found trend for an association within genes previously associated with psychiatric phenotypes indirectly linked to suicidal behavior, that is, GRIP1, NXPH1 and ANK3. The results suggest novel pathways involved in increasing suicidal ideation during antidepressant treatment and should help to target treatment to reduce the risk of this dramatic adverse event. Limited power precludes definitive conclusions and replication in larger sample is warranted.

AB - Suicidal thoughts during antidepressant treatment have been the focus of several candidate gene association studies. The aim of the present genome-wide association study was to identify additional genetic variants involved in increasing suicidal ideation during escitalopram and nortriptyline treatment. A total of 706 adult participants of European ancestry, treated for major depression with escitalopram or nortriptyline over 12 weeks in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study were genotyped with Illumina Human 610-Quad Beadchips (Illumina, San Diego, CA, USA). A total of 244 subjects experienced an increase in suicidal ideation during follow-up. The genetic marker most significantly associated with increasing suicidality (8.28 × 10 7) was a single-nucleotide polymorphism (SNP; rs11143230) located 30 kb downstream of a gene encoding guanine deaminase (GDA) on chromosome 9q21.13. Two suggestive drug-specific associations within KCNIP4 (Kv channel-interacting protein 4; chromosome 4p15.31) and near ELP3 (elongation protein 3 homolog; chromosome 8p21.1) were found in subjects treated with escitalopram. Suggestive drug by gene interactions for two SNPs near structural variants on chromosome 4q12, one SNP in the apolipoprotein O (APOO) gene on chromosome Xp22.11 and one on chromosome 11q24.3 were found. The most significant association within a set of 33 candidate genes was in the neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene. Finally, we also found trend for an association within genes previously associated with psychiatric phenotypes indirectly linked to suicidal behavior, that is, GRIP1, NXPH1 and ANK3. The results suggest novel pathways involved in increasing suicidal ideation during antidepressant treatment and should help to target treatment to reduce the risk of this dramatic adverse event. Limited power precludes definitive conclusions and replication in larger sample is warranted.

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Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

UN SDGs

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