New insights on the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation

Chiara Fabbri; Katherine Tansey; Roy Perlis; Joanna Hauser; Neven Henigsberg; Wolfgang Maier; Ole Mors; Anna Placentino; Marcella Rietschel; Daniel Souery; Gerome Breen; Charles Curtis; Lee Sang-Hyuk; Stephen Newhouse; Hamel Patel; Michel Guipponi; Nader Perroud; Guido Bondolfi; Michael O'Donovan; Glyn Lewis; Joanna Biernacka; Richard Weinshilboum; Anne Farmer; Katherine Aitchison; Ian Craig; Peter McGuffin; Rudolf Uher; Cathryn Lewis

New insights on the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation

Chiara Fabbri, Katherine Tansey, Roy Perlis, Joanna Hauser, Neven Henigsberg, Wolfgang Maier, Ole Mors, Anna Placentino, Marcella Rietschel, Daniel Souery, Gerome Breen, Charles Curtis, Lee Sang-Hyuk, Stephen Newhouse, Hamel Patel, Michel Guipponi, Nader Perroud, Guido Bondolfi, Michael O'Donovan, Glyn LewisJoanna Biernacka, Richard Weinshilboum, Anne Farmer, Katherine Aitchison, Ian Craig, Peter McGuffin, Rudolf Uher, Cathryn Lewis

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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 (STAR*D) studies was performed at SNP, gene and pathway level. Coverage of genetic variants was increased compared to 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.
7,062,950 SNPs were analysed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (p=1.80e-08, ITGA9 (integrin alpha 9)) and rs76191705 (p=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At gene level, no consistent effect was found. At pathway level, the Gene Ontology 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), while 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.

Original language	English
Pages (from-to)	413-421
Journal	The pharmacogenomics journal
Volume	18
Early online date	21 Nov 2017
Publication status	Published - 22 May 2018

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Fabbri, C., Tansey, K., Perlis, R., 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. (2018). New insights on the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation. The pharmacogenomics journal, 18, 413-421.

@article{07e86c7e570f415999610fd6161fe7ca,

title = "New insights on 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 (STAR*D) studies was performed at SNP, gene and pathway level. Coverage of genetic variants was increased compared to 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 NetworkAntidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication.7,062,950 SNPs were analysed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (p=1.80e-08, ITGA9 (integrin alpha 9)) and rs76191705 (p=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At gene level, no consistent effect was found. At pathway level, the Gene Ontology 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), while 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 = "Chiara Fabbri and Katherine Tansey and Roy Perlis and Joanna Hauser and Neven Henigsberg and Wolfgang Maier and Ole Mors and Anna Placentino and Marcella Rietschel and Daniel Souery and Gerome Breen and Charles Curtis and Lee Sang-Hyuk and Stephen Newhouse and Hamel Patel and Michel Guipponi and Nader Perroud and Guido Bondolfi and Michael O'Donovan and Glyn Lewis and Joanna Biernacka and Richard Weinshilboum and Anne Farmer and Katherine Aitchison and Ian Craig and Peter McGuffin and Rudolf Uher and Cathryn Lewis",

year = "2018",

month = may,

day = "22",

language = "English",

volume = "18",

pages = "413--421",

journal = "The pharmacogenomics journal",

issn = "1470-269X",

publisher = "Springer Nature [academic journals on nature.com]",

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Fabbri, C, Tansey, K, Perlis, R, 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, J, Weinshilboum, R, Farmer, A, Aitchison, K, Craig, I , McGuffin, P, Uher, R & Lewis, C 2018, 'New insights on the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation', The pharmacogenomics journal, vol. 18, pp. 413-421.

TY - JOUR

T1 - New insights on the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies

T2 - rare variant analysis and high-density imputation

AU - Fabbri, Chiara

AU - Tansey, Katherine

AU - Perlis, Roy

AU - Hauser, Joanna

AU - Henigsberg, Neven

AU - Maier, Wolfgang

AU - Mors, Ole

AU - Placentino, Anna

AU - Rietschel, Marcella

AU - Souery, Daniel

AU - Breen, Gerome

AU - Curtis, Charles

AU - Sang-Hyuk, Lee

AU - Newhouse, Stephen

AU - Patel, Hamel

AU - Guipponi, Michel

AU - Perroud, Nader

AU - Bondolfi, Guido

AU - O'Donovan, Michael

AU - Lewis, Glyn

AU - Biernacka, Joanna

AU - Weinshilboum, Richard

AU - Farmer, Anne

AU - Aitchison, Katherine

AU - Craig, Ian

AU - McGuffin, Peter

AU - Uher, Rudolf

AU - Lewis, Cathryn

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 (STAR*D) studies was performed at SNP, gene and pathway level. Coverage of genetic variants was increased compared to 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 NetworkAntidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication.7,062,950 SNPs were analysed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (p=1.80e-08, ITGA9 (integrin alpha 9)) and rs76191705 (p=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At gene level, no consistent effect was found. At pathway level, the Gene Ontology 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), while 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 (STAR*D) studies was performed at SNP, gene and pathway level. Coverage of genetic variants was increased compared to 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 NetworkAntidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication.7,062,950 SNPs were analysed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (p=1.80e-08, ITGA9 (integrin alpha 9)) and rs76191705 (p=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At gene level, no consistent effect was found. At pathway level, the Gene Ontology 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), while 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.

M3 - Article

SN - 1470-269X

VL - 18

SP - 413

EP - 421

JO - The pharmacogenomics journal

JF - The pharmacogenomics journal

ER -

New insights on the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation

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