Pharmacogenomics of selective serotonin reuptake inhibitor treatment for major depressive disorder: genome-wide associations and functional genomics.
A genome-wide association (GWA) study of treatment outcomes (response and remission) of selective serotonin reuptake inhibitors (SSRIs) was conducted using 529 subjects with major depressive disorder. While no SNP associations reached the genome-wide level of significance, 14 SNPs of interest were identified for functional analysis. The rs11144870 SNP in the riboflavin kinase (RFK) gene on chromosome 9 was associated with 8-week treatment response (odds ratio (OR)=0.42, P=1.04 × 10⁻⁶). The rs915120 SNP in the G protein-coupled receptor kinase 5 (GRK5) gene on chromosome 10 was associated with 8-week remission (OR=0.50, P=1.15 × 10⁻⁵). Both SNPs were shown to influence transcription by a reporter gene assay and to alter nuclear protein binding using an electrophoretic mobility shift assay. This report represents an example of joining functional genomics with traditional GWA study results derived from a GWA analysis of SSRI treatment outcomes. The goal of this analytical strategy is to provide insights into the potential relevance of biologically plausible observed associations.
Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
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Y
Ji
J M
JM
Biernacka
S
S
Hebbring
Y
Y
Chai
G D
GD
Jenkins
A
A
Batzler
K A
KA
Snyder
M S
MS
Drews
Z
Z
Desta
D
D
Flockhart
T
T
Mushiroda
M
M
Kubo
Y
Y
Nakamura
N
N
Kamatani
D
D
Schaid
R M
RM
Weinshilboum
D A
DA
Mrazek
D000328:Adult; D002879:Chromosomes, Human, Pair 10; D002899:Chromosomes, Human, Pair 9; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D023281:Genomics / Q000379:methods; D006801:Humans; D008297:Male; D010597:Pharmacogenetics / Q000379:methods; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012701:Serotonin / Q000235:genetics / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D014158:Transcription, Genetic; D016896:Treatment Outcome
D054774:G-Protein-Coupled Receptor Kinase 5; D017853:Phosphotransferases (Alcohol Group Acceptor); D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C022532:riboflavin kinase; C517898:GRK5 protein, human