FKBP5 genetic variation: Association with selective serotonin reuptake inhibitor treatment outcomes in major depressive disorder

Katarzyna A. Ellsworth, Irene Moon, Bruce W. Eckloff, Brooke L. Fridley, Gregory D. Jenkins, Anthony Batzler, Joanna M Biernacka, Ryan Abo, Abra Brisbin, Yuan Ji, Scott Hebbring, Eric D Wieben, David A. Mrazek, Richard M Weinshilboum, Liewei M Wang

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)156-166
Number of pages11
JournalPharmacogenetics and Genomics
Volume23
Issue number3
DOIs
StatePublished - Mar 2013

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Major Depressive Disorder
Serotonin Uptake Inhibitors
Single Nucleotide Polymorphism
DNA
Odds Ratio
Immunophilins
Genome
Depression
National Institute of Mental Health (U.S.)
Pharmacogenetics
Glucocorticoid Receptors
Genetic Association Studies
Electrophoretic Mobility Shift Assay
Genetic Polymorphisms
Therapeutics
DNA Sequence Analysis
Reporter Genes
Antidepressive Agents
Electrophoresis

Keywords

  • FKBP5
  • genotypephenotype association
  • major depressive disorder
  • Next Generation DNA resequencing
  • selective serotonin reuptake inhibitor
  • single nucleotide polymorphism

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

FKBP5 genetic variation : Association with selective serotonin reuptake inhibitor treatment outcomes in major depressive disorder. / Ellsworth, Katarzyna A.; Moon, Irene; Eckloff, Bruce W.; Fridley, Brooke L.; Jenkins, Gregory D.; Batzler, Anthony; Biernacka, Joanna M; Abo, Ryan; Brisbin, Abra; Ji, Yuan; Hebbring, Scott; Wieben, Eric D; Mrazek, David A.; Weinshilboum, Richard M; Wang, Liewei M.

In: Pharmacogenetics and Genomics, Vol. 23, No. 3, 03.2013, p. 156-166.

Research output: Contribution to journalArticle

Ellsworth, Katarzyna A. ; Moon, Irene ; Eckloff, Bruce W. ; Fridley, Brooke L. ; Jenkins, Gregory D. ; Batzler, Anthony ; Biernacka, Joanna M ; Abo, Ryan ; Brisbin, Abra ; Ji, Yuan ; Hebbring, Scott ; Wieben, Eric D ; Mrazek, David A. ; Weinshilboum, Richard M ; Wang, Liewei M. / FKBP5 genetic variation : Association with selective serotonin reuptake inhibitor treatment outcomes in major depressive disorder. In: Pharmacogenetics and Genomics. 2013 ; Vol. 23, No. 3. pp. 156-166.
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AU - Eckloff, Bruce W.

AU - Fridley, Brooke L.

AU - Jenkins, Gregory D.

AU - Batzler, Anthony

AU - Biernacka, Joanna M

AU - Abo, Ryan

AU - Brisbin, Abra

AU - Ji, Yuan

AU - Hebbring, Scott

AU - Wieben, Eric D

AU - Mrazek, David A.

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