OBJECTIVES: FKBP51 (51 kDa immunophilin) acts as a modulator of the glucocorticoid receptor and a negative regulator of the Akt pathway. Genetic variation in FKBP5 plays a role in antidepressant response. The aim of this study was to comprehensively assess the role of genetic variation in FKBP5, identified by both Sanger and Next Generation DNA resequencing, as well as genome-wide single nucleotide polymorphisms (SNPs) associated with FKBP5 expression in the response to the selective serotonin reuptake inhibitor (SSRI) treatment of major depressive disorder. METHODS: We identified 657 SNPs in FKBP5 by Next Generation sequencing of 96 DNA samples from white patients, and 149 SNPs were selected for the genotyping together with 235 SNPs that were trans-associated with variation in FKBP5 expression in lymphoblastoid cells. A total of 529 DNA samples from the Mayo Clinic PGRN-SSRI Pharmacogenomic trial for which genome-wide SNPs had already been obtained were genotyped for these 384 SNPs, and associations with treatment outcomes were determined. The most significant SNPs were genotyped using 96 DNA samples from white non-Hispanic patients of the NIMH-supported Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study to attempt replication, followed by functional genomic studies. RESULTS: Genotype-phenotype association analysis indicated that rs352428 was associated with both 8-week treatment response in the Mayo study (odds ratio=0.49; P=0.003) and 6-week response in the STAR*D replication study (odds ratio=0.74; P=0.05). The electrophoresis mobility shift assay and the reporter gene assay confirmed the possible role of this SNP in transcription regulation. CONCLUSION: This comprehensive FKBP5 sequence study provides insight into the role of common genetic polymorphisms that might influence SSRI treatment outcomes in major depressive disorder patients.
OBJECTIVES: FKBP51 (51 kDa immunophilin) acts as a modulator of the glucocorticoid receptor and a negative regulator of the Akt pathway. Genetic variation in FKBP5 plays a role in antidepressant response. The aim of this study was to comprehensively assess the role of genetic variation in FKBP5, identified by both Sanger and Next Generation DNA resequencing, as well as genome-wide single nucleotide polymorphisms (SNPs) associated with FKBP5 expression in the response to the selective serotonin reuptake inhibitor (SSRI) treatment of major depressive disorder. METHODS: We identified 657 SNPs in FKBP5 by Next Generation sequencing of 96 DNA samples from white patients, and 149 SNPs were selected for the genotyping together with 235 SNPs that were trans-associated with variation in FKBP5 expression in lymphoblastoid cells. A total of 529 DNA samples from the Mayo Clinic PGRN-SSRI Pharmacogenomic trial for which genome-wide SNPs had already been obtained were genotyped for these 384 SNPs, and associations with treatment outcomes were determined. The most significant SNPs were genotyped using 96 DNA samples from white non-Hispanic patients of the NIMH-supported Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study to attempt replication, followed by functional genomic studies. RESULTS: Genotype-phenotype association analysis indicated that rs352428 was associated with both 8-week treatment response in the Mayo study (odds ratio=0.49; P=0.003) and 6-week response in the STAR*D replication study (odds ratio=0.74; P=0.05). The electrophoresis mobility shift assay and the reporter gene assay confirmed the possible role of this SNP in transcription regulation. CONCLUSION: This comprehensive FKBP5 sequence study provides insight into the role of common genetic polymorphisms that might influence SSRI treatment outcomes in major depressive disorderpatients.
Authors: Daniel L Riggs; Patricia J Roberts; Samantha C Chirillo; Joyce Cheung-Flynn; Viravan Prapapanich; Thomas Ratajczak; Richard Gaber; Didier Picard; David F Smith Journal: EMBO J Date: 2003-03-03 Impact factor: 11.598
Authors: J L Blouin; B A Dombroski; S K Nath; V K Lasseter; P S Wolyniec; G Nestadt; M Thornquist; G Ullrich; J McGrath; L Kasch; M Lamacz; M G Thomas; C Gehrig; U Radhakrishna; S E Snyder; K G Balk; K Neufeld; K L Swartz; N DeMarchi; G N Papadimitriou; D G Dikeos; C N Stefanis; A Chakravarti; B Childs; D E Housman; H H Kazazian; S Antonarakis; A E Pulver Journal: Nat Genet Date: 1998-09 Impact factor: 38.330
Authors: Elisabeth B Binder; Daria Salyakina; Peter Lichtner; Gabriele M Wochnik; Marcus Ising; Benno Pütz; Sergi Papiol; Shaun Seaman; Susanne Lucae; Martin A Kohli; Thomas Nickel; Heike E Künzel; Brigitte Fuchs; Matthias Majer; Andrea Pfennig; Nikola Kern; Jürgen Brunner; Sieglinde Modell; Thomas Baghai; Tobias Deiml; Peter Zill; Brigitta Bondy; Rainer Rupprecht; Thomas Messer; Oliver Köhnlein; Heike Dabitz; Tanja Brückl; Nina Müller; Hildegard Pfister; Roselind Lieb; Jakob C Mueller; Elin Lõhmussaar; Tim M Strom; Thomas Bettecken; Thomas Meitinger; Manfred Uhr; Theo Rein; Florian Holsboer; Bertram Muller-Myhsok Journal: Nat Genet Date: 2004-11-21 Impact factor: 38.330
Authors: Ronald C Kessler; Patricia Berglund; Olga Demler; Robert Jin; Doreen Koretz; Kathleen R Merikangas; A John Rush; Ellen E Walters; Philip S Wang Journal: JAMA Date: 2003-06-18 Impact factor: 56.272
Authors: A John Rush; Maurizio Fava; Stephen R Wisniewski; Philip W Lavori; Madhukar H Trivedi; Harold A Sackeim; Michael E Thase; Andrew A Nierenberg; Frederic M Quitkin; T Michael Kashner; David J Kupfer; Jerrold F Rosenbaum; Jonathan Alpert; Jonathan W Stewart; Patrick J McGrath; Melanie M Biggs; Kathy Shores-Wilson; Barry D Lebowitz; Louise Ritz; George Niederehe Journal: Control Clin Trials Date: 2004-02