New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR∗D studies: Rare variant analysis and high-density imputation

C. Fabbri; K. E. Tansey; R. H. Perlis; J. Hauser; N. Henigsberg; W. Maier; O. Mors; A. Placentino; M. Rietschel; D. Souery; G. Breen; C. Curtis; L. Sang-Hyuk; S. Newhouse; H. Patel; M. Guipponi; N. Perroud; G. Bondolfi; M. O'Donovan; G. Lewis; J. M. Biernacka; R. M. Weinshilboum; A. Farmer; K. J. Aitchison; I. Craig; P. McGuffin; R. Uher; C. M. Lewis

doi:10.1038/tpj.2017.44

New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR∗D studies: Rare variant analysis and high-density imputation

C. Fabbri, K. E. Tansey, R. H. Perlis, J. Hauser, N. Henigsberg, W. Maier, O. Mors, A. Placentino, M. Rietschel, D. Souery, G. Breen, C. Curtis, L. Sang-Hyuk, S. Newhouse, H. Patel, M. Guipponi, N. Perroud, G. Bondolfi, M. O'Donovan, G. LewisJ. M. Biernacka, R. M. Weinshilboum, A. Farmer, K. J. Aitchison, I. Craig, P. McGuffin, R. Uher, C. M. Lewis

Medicine

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Resumen

Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STARD) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. Significant findings were investigated in NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication. A total of 7062 950 SNPs were analyzed in GENDEP (n = 738) and STARD (n = 1409). rs116692768 (P = 1.80e ? 08, ITGA9 (integrin ?9)) and rs76191705 (P = 2.59e ? 08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At the gene level, no consistent effect was found. At the pathway level, the Gene Ontology (GO) terms GO: 0005694 (chromosome) and GO: 0044427 (chromosomal part) were associated with improvement (corrected P = 0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (P = 0.047), whereas rs76191705 was not. The two SNPs did not replicate in NEWMEDS. ITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, replication was partial. Further studies may help in clarifying their role.

Idioma original	English
Páginas (desde-hasta)	413-421
Número de páginas	9
Publicación	Pharmacogenomics Journal
Volumen	18
N.º	3
DOI	https://doi.org/10.1038/tpj.2017.44
Estado	Published - may. 22 2018

Nota bibliográfica

Funding Information:
NH participated in clinical trials sponsored by pharmaceutical companies including GlaxoSmithKline and Lundbeck. DS is serving in national advisory boards or consulting for Janssen, TEVA, GlaxoSmithKline. His center is receiving unrestricted financial support from Lundbeck and Fondation René de Spoellberghe. WM, KJA, AEF and PMcG have received consultancy fees and honoraria for participating in expert panels from pharmaceutical companies including Lundbeck and GlaxoSmithKline and Roche Diagnostics. RHP reported serving on scientific advisory boards or consulting for Genomind LLC, Healthrageous, Pfizer, Perfect Health, Proteus Biomedical, PsyBrain and RID Ventures LLC and reported receiving royalties through Massachusetts General Hospital from Concordant Rater Systems (now Bracket/ Medco). NP received honoraria for participating in expert panels from pharmaceutical companies including Lundbeck. GB is a member of a national advisory board for Bristol-Myer Squibb and Pfizer and has received research funding from GlaxoSmithKline, Wyeth-Lederle, Bristol-Myers-Squibb and Sanofi Aventis. The department of MO’D received £2000 in lieu of an honorarium to MO’D from Lilly as a result of his participation in sponsored symposia in 2012. Those symposia were unrelated to the contents of this manuscript. The other authors declare no conflict of interest.

Funding Information:
The PGRN-AMPS data set used for the analyses described in this manuscript was obtained from dbGaP (study accession phs000670.v1.p1). PGRN-AMPS was supported, in part, by NIH grants RO1 GM28157, U19 GM61388 (The Pharmacoge-nomics Research Network), U01 HG005137, R01 CA138461, P20 1P20AA017830-01 (The Mayo Clinic Center for Individualized Treatment of Alcohol Dependence) and a PhRMA Foundation Center of Excellence in Clinical Pharmacology Award. RU is supported by the Canada Research Chairs Program.

Funding Information:
This paper represents independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. The GENDEP project was supported by a European Commission Framework 6 grant (contract reference: LSHB-CT-2003-503428). The Medical Research Council, United Kingdom, and GlaxoSmithKline (G0701420) provided support for genotyping.

Funding Information:
We thank the NIMH for having had the possibility of analyzing their data on the STAR-D sample. We also thank the authors of previous publications in this data set, and foremost, we thank the patients and their families who accepted to be enrolled in the study. Data and biomaterials were obtained from the limited access datasets distributed from the NIH-supported ‘Sequenced Treatment Alternatives to Relieve Depression’ (STAR*D). The study was supported by NIMH Contract No. N01MH90003 to the University of Texas Southwestern Medical Center. The ClinicalTrials.gov identifier is NCT00021528.

Funding Information:
The NEWMEDS study was funded by the Innovative Medicine Initiative Joint Undertaking (IMI-JU) under grant agreement no. 115008 of which resources are composed of European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA) in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013). EFPIA members Pfizer, GlaxoSmithKline and F Hoffmann La-Roche have contributed work and samples to the project presented here.

Publisher Copyright:
© 2018 Macmillan Publishers Limited, part of Springer Nature.

ASJC Scopus Subject Areas

Molecular Medicine
Genetics
Pharmacology

PubMed: MeSH publication types

Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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10.1038/tpj.2017.44

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Fabbri, C., Tansey, K. E., Perlis, R. H., Hauser, J., Henigsberg, N., Maier, W., Mors, O., Placentino, A., Rietschel, M., Souery, D., Breen, G., Curtis, C., Sang-Hyuk, L., Newhouse, S., Patel, H., Guipponi, M., Perroud, N., Bondolfi, G., O'Donovan, M., ... Lewis, C. M. (2018). New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR∗D studies: Rare variant analysis and high-density imputation. Pharmacogenomics Journal, 18(3), 413-421. https://doi.org/10.1038/tpj.2017.44

Fabbri, C, Tansey, KE, Perlis, RH, Hauser, J, Henigsberg, N, Maier, W, Mors, O, Placentino, A, Rietschel, M, Souery, D, Breen, G, Curtis, C, Sang-Hyuk, L, Newhouse, S, Patel, H, Guipponi, M, Perroud, N, Bondolfi, G, O'Donovan, M, Lewis, G, Biernacka, JM, Weinshilboum, RM, Farmer, A, Aitchison, KJ, Craig, I, McGuffin, P, Uher, R & Lewis, CM 2018, 'New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR∗D studies: Rare variant analysis and high-density imputation', Pharmacogenomics Journal, vol. 18, n.º 3, pp. 413-421. https://doi.org/10.1038/tpj.2017.44

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title = "New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR∗D studies: Rare variant analysis and high-density imputation",

abstract = "Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STARD) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. Significant findings were investigated in NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication. A total of 7062 950 SNPs were analyzed in GENDEP (n = 738) and STARD (n = 1409). rs116692768 (P = 1.80e ? 08, ITGA9 (integrin ?9)) and rs76191705 (P = 2.59e ? 08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At the gene level, no consistent effect was found. At the pathway level, the Gene Ontology (GO) terms GO: 0005694 (chromosome) and GO: 0044427 (chromosomal part) were associated with improvement (corrected P = 0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (P = 0.047), whereas rs76191705 was not. The two SNPs did not replicate in NEWMEDS. ITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, replication was partial. Further studies may help in clarifying their role.",

author = "C. Fabbri and Tansey, {K. E.} and Perlis, {R. H.} and J. Hauser and N. Henigsberg and W. Maier and O. Mors and A. Placentino and M. Rietschel and D. Souery and G. Breen and C. Curtis and L. Sang-Hyuk and S. Newhouse and H. Patel and M. Guipponi and N. Perroud and G. Bondolfi and M. O'Donovan and G. Lewis and Biernacka, {J. M.} and Weinshilboum, {R. M.} and A. Farmer and Aitchison, {K. J.} and I. Craig and P. McGuffin and R. Uher and Lewis, {C. M.}",

note = "Funding Information: NH participated in clinical trials sponsored by pharmaceutical companies including GlaxoSmithKline and Lundbeck. DS is serving in national advisory boards or consulting for Janssen, TEVA, GlaxoSmithKline. His center is receiving unrestricted financial support from Lundbeck and Fondation Ren{\'e} de Spoellberghe. WM, KJA, AEF and PMcG have received consultancy fees and honoraria for participating in expert panels from pharmaceutical companies including Lundbeck and GlaxoSmithKline and Roche Diagnostics. RHP reported serving on scientific advisory boards or consulting for Genomind LLC, Healthrageous, Pfizer, Perfect Health, Proteus Biomedical, PsyBrain and RID Ventures LLC and reported receiving royalties through Massachusetts General Hospital from Concordant Rater Systems (now Bracket/ Medco). NP received honoraria for participating in expert panels from pharmaceutical companies including Lundbeck. GB is a member of a national advisory board for Bristol-Myer Squibb and Pfizer and has received research funding from GlaxoSmithKline, Wyeth-Lederle, Bristol-Myers-Squibb and Sanofi Aventis. The department of MO{\textquoteright}D received £2000 in lieu of an honorarium to MO{\textquoteright}D from Lilly as a result of his participation in sponsored symposia in 2012. Those symposia were unrelated to the contents of this manuscript. The other authors declare no conflict of interest. Funding Information: The PGRN-AMPS data set used for the analyses described in this manuscript was obtained from dbGaP (study accession phs000670.v1.p1). PGRN-AMPS was supported, in part, by NIH grants RO1 GM28157, U19 GM61388 (The Pharmacoge-nomics Research Network), U01 HG005137, R01 CA138461, P20 1P20AA017830-01 (The Mayo Clinic Center for Individualized Treatment of Alcohol Dependence) and a PhRMA Foundation Center of Excellence in Clinical Pharmacology Award. RU is supported by the Canada Research Chairs Program. Funding Information: This paper represents independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. The GENDEP project was supported by a European Commission Framework 6 grant (contract reference: LSHB-CT-2003-503428). The Medical Research Council, United Kingdom, and GlaxoSmithKline (G0701420) provided support for genotyping. Funding Information: We thank the NIMH for having had the possibility of analyzing their data on the STAR-D sample. We also thank the authors of previous publications in this data set, and foremost, we thank the patients and their families who accepted to be enrolled in the study. Data and biomaterials were obtained from the limited access datasets distributed from the NIH-supported {\textquoteleft}Sequenced Treatment Alternatives to Relieve Depression{\textquoteright} (STAR*D). The study was supported by NIMH Contract No. N01MH90003 to the University of Texas Southwestern Medical Center. The ClinicalTrials.gov identifier is NCT00021528. Funding Information: The NEWMEDS study was funded by the Innovative Medicine Initiative Joint Undertaking (IMI-JU) under grant agreement no. 115008 of which resources are composed of European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA) in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013). EFPIA members Pfizer, GlaxoSmithKline and F Hoffmann La-Roche have contributed work and samples to the project presented here. Publisher Copyright: {\textcopyright} 2018 Macmillan Publishers Limited, part of Springer Nature.",

year = "2018",

month = may,

day = "22",

doi = "10.1038/tpj.2017.44",

language = "English",

volume = "18",

pages = "413--421",

journal = "Pharmacogenomics Journal",

issn = "1470-269X",

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TY - JOUR

T1 - New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR∗D studies

T2 - Rare variant analysis and high-density imputation

AU - Fabbri, C.

AU - Tansey, K. E.

AU - Perlis, R. H.

AU - Hauser, J.

AU - Henigsberg, N.

AU - Maier, W.

AU - Mors, O.

AU - Placentino, A.

AU - Rietschel, M.

AU - Souery, D.

AU - Breen, G.

AU - Curtis, C.

AU - Sang-Hyuk, L.

AU - Newhouse, S.

AU - Patel, H.

AU - Guipponi, M.

AU - Perroud, N.

AU - Bondolfi, G.

AU - O'Donovan, M.

AU - Lewis, G.

AU - Biernacka, J. M.

AU - Weinshilboum, R. M.

AU - Farmer, A.

AU - Aitchison, K. J.

AU - Craig, I.

AU - McGuffin, P.

AU - Uher, R.

AU - Lewis, C. M.

N1 - Funding Information: NH participated in clinical trials sponsored by pharmaceutical companies including GlaxoSmithKline and Lundbeck. DS is serving in national advisory boards or consulting for Janssen, TEVA, GlaxoSmithKline. His center is receiving unrestricted financial support from Lundbeck and Fondation René de Spoellberghe. WM, KJA, AEF and PMcG have received consultancy fees and honoraria for participating in expert panels from pharmaceutical companies including Lundbeck and GlaxoSmithKline and Roche Diagnostics. RHP reported serving on scientific advisory boards or consulting for Genomind LLC, Healthrageous, Pfizer, Perfect Health, Proteus Biomedical, PsyBrain and RID Ventures LLC and reported receiving royalties through Massachusetts General Hospital from Concordant Rater Systems (now Bracket/ Medco). NP received honoraria for participating in expert panels from pharmaceutical companies including Lundbeck. GB is a member of a national advisory board for Bristol-Myer Squibb and Pfizer and has received research funding from GlaxoSmithKline, Wyeth-Lederle, Bristol-Myers-Squibb and Sanofi Aventis. The department of MO’D received £2000 in lieu of an honorarium to MO’D from Lilly as a result of his participation in sponsored symposia in 2012. Those symposia were unrelated to the contents of this manuscript. The other authors declare no conflict of interest. Funding Information: The PGRN-AMPS data set used for the analyses described in this manuscript was obtained from dbGaP (study accession phs000670.v1.p1). PGRN-AMPS was supported, in part, by NIH grants RO1 GM28157, U19 GM61388 (The Pharmacoge-nomics Research Network), U01 HG005137, R01 CA138461, P20 1P20AA017830-01 (The Mayo Clinic Center for Individualized Treatment of Alcohol Dependence) and a PhRMA Foundation Center of Excellence in Clinical Pharmacology Award. RU is supported by the Canada Research Chairs Program. Funding Information: This paper represents independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. The GENDEP project was supported by a European Commission Framework 6 grant (contract reference: LSHB-CT-2003-503428). The Medical Research Council, United Kingdom, and GlaxoSmithKline (G0701420) provided support for genotyping. Funding Information: We thank the NIMH for having had the possibility of analyzing their data on the STAR-D sample. We also thank the authors of previous publications in this data set, and foremost, we thank the patients and their families who accepted to be enrolled in the study. Data and biomaterials were obtained from the limited access datasets distributed from the NIH-supported ‘Sequenced Treatment Alternatives to Relieve Depression’ (STAR*D). The study was supported by NIMH Contract No. N01MH90003 to the University of Texas Southwestern Medical Center. The ClinicalTrials.gov identifier is NCT00021528. Funding Information: The NEWMEDS study was funded by the Innovative Medicine Initiative Joint Undertaking (IMI-JU) under grant agreement no. 115008 of which resources are composed of European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA) in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013). EFPIA members Pfizer, GlaxoSmithKline and F Hoffmann La-Roche have contributed work and samples to the project presented here. Publisher Copyright: © 2018 Macmillan Publishers Limited, part of Springer Nature.

PY - 2018/5/22

Y1 - 2018/5/22

N2 - Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STARD) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. Significant findings were investigated in NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication. A total of 7062 950 SNPs were analyzed in GENDEP (n = 738) and STARD (n = 1409). rs116692768 (P = 1.80e ? 08, ITGA9 (integrin ?9)) and rs76191705 (P = 2.59e ? 08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At the gene level, no consistent effect was found. At the pathway level, the Gene Ontology (GO) terms GO: 0005694 (chromosome) and GO: 0044427 (chromosomal part) were associated with improvement (corrected P = 0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (P = 0.047), whereas rs76191705 was not. The two SNPs did not replicate in NEWMEDS. ITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, replication was partial. Further studies may help in clarifying their role.

AB - Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STARD) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. Significant findings were investigated in NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication. A total of 7062 950 SNPs were analyzed in GENDEP (n = 738) and STARD (n = 1409). rs116692768 (P = 1.80e ? 08, ITGA9 (integrin ?9)) and rs76191705 (P = 2.59e ? 08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At the gene level, no consistent effect was found. At the pathway level, the Gene Ontology (GO) terms GO: 0005694 (chromosome) and GO: 0044427 (chromosomal part) were associated with improvement (corrected P = 0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (P = 0.047), whereas rs76191705 was not. The two SNPs did not replicate in NEWMEDS. ITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, replication was partial. Further studies may help in clarifying their role.

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New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR∗D studies: Rare variant analysis and high-density imputation

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