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 E. Tansey; Roy H. Perlis; Joanna Hauser; Neven Henigsberg; Wolfgang Maier; Ole N Mors; Anna Placentino; Marcella Rietschel; Daniel Souery; Gerome D. Breen; Charles J. C. Curtis; L Sang-Hyuk; Stephen Newhouse; Hamel Patel; Michel Guipponi; Nader Ali Perroud; Guido Bondolfi; Michael C. O’Donovan; Glyn Lewis; Joanna M. Biernacka; Richard M. Weinshilboum; ANNE E. FARMER; Katherine Jean Aitchison; Ian Craig; Peter McGuffin; Rudolf Uher; Cathryn M. Lewis

doi:10.1038/tpj.2017.44

GenomicsThe Pharmacogenomics JournalNov 21, 2017

Peer-reviewed journal article

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

Chiara Fabbri iD, Katherine E. Tansey iD, Roy H. Perlis iD, Joanna Hauser iD, Neven Henigsberg iD, Wolfgang Maier iD, Ole N Mors iD, Anna Placentino, Marcella Rietschel iD, Daniel Souery iD, Gerome D. Breen iD, Charles J. C. Curtis iD, L Sang-Hyuk, Stephen Newhouse iD, Hamel Patel iD, Michel Guipponi iD, Nader Ali Perroud iD, Guido Bondolfi iD, Michael C. O’Donovan iD, Glyn Lewis iD, Joanna M. Biernacka iD, Richard M. Weinshilboum iD, ANNE E. FARMER, Katherine Jean Aitchison iD, Ian Craig iD, , Cathryn M. Lewis iD

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.\n\nA 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. NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) served for replication.\n\n7,062,950 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.\n\nITGA9 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, no convincing replication was achieved. Further studies may help in clarifying their role.

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