A genome-wide association study of antidepressant response in Koreans.
We conducted a three-stage genome-wide association study (GWAS) of response to antidepressant drugs in an ethnically homogeneous sample of Korean patients in untreated episodes of nonpsychotic unipolar depression, mostly of mature onset. Strict quality control was maintained in case selection, diagnosis, verification of adherence and outcome assessments. Analyzed cases completed 6 weeks of treatment with adequate plasma drug concentrations. The overall successful completion rate was 85.5%. Four candidate single-nucleotide polymorphisms (SNPs) on three chromosomes were identified by genome-wide search in the discovery sample of 481 patients who received one of four allowed selective serotonin reuptake inhibitor (SSRI) antidepressant drugs (Stage 1). In a focused replication study of 230 SSRI-treated patients, two of these four SNP candidates were confirmed (Stage 2). Analysis of the Stage 1 and Stage 2 samples combined (n = 711) revealed GWAS significance (P = 1.60 × 10(-8)) for these two SNP candidates, which were in perfect linkage disequilibrium. These two significant SNPs were confirmed also in a focused cross-replication study of 159 patients treated with the non-SSRI antidepressant drug mirtazapine (Stage 3). Analysis of the Stage 1, Stage 2 and Stage 3 samples combined (n = 870) also revealed GWAS significance for these two SNPs, which was sustained after controlling for gender, age, number of previous episodes, age at onset and baseline severity (P = 3.57 × 10(-8)). For each SNP, the response rate decreased (odds ratio=0.31, 95% confidence interval: 0.20-0.47) as a function of the number of minor alleles (non-response alleles). The two SNPs significantly associated with antidepressant response are rs7785360 and rs12698828 of the AUTS2 gene, located on chromosome 7 in 7q11.22. This gene has multiple known linkages to human psychological functions and neurobehavioral disorders. Rigorous replication efforts in other ethnic populations are recommended.
Department of Psychiatry, Samsung Medical Center, Seoul, Korea.|Sungkyunkwan University School of Medicine, Seoul, Korea.
W
W
Myung
Center for Clinical Research, Samsung Biomedical Research Institute, Seoul, Korea.
J
J
Kim
Sungkyunkwan University School of Medicine, Seoul, Korea.|Center for Clinical Research, Samsung Biomedical Research Institute, Seoul, Korea.
S-W
SW
Lim
Center for Clinical Research, Samsung Biomedical Research Institute, Seoul, Korea.
S
S
Shim
Center for Clinical Research, Samsung Biomedical Research Institute, Seoul, Korea.
H-H
HH
Won
Biostatistics Team, Samsung Biomedical Research Institute, Seoul, Korea.
Seonwoo
S
Kim
Department of Psychiatry, Samsung Medical Center, Seoul, Korea.|Sungkyunkwan University School of Medicine, Seoul, Korea.
Sangha
S
Kim
Department of Psychiatry, College of Medicine, Korea University, Seoul, Korea.
M-S
MS
Lee
Soonchunhyang Medical Institute, College of Medicine, Soonchunhyang University, Asan, Korea.
H S
HS
Chang
Sungkyunkwan University School of Medicine, Seoul, Korea.|Department of Laboratory Medicine and Genetics, Samsung Medical Center, Seoul, Korea.
J-W
JW
Kim
Pacific Behavioral Research Foundation, Carmel, CA, USA.
B J
BJ
Carroll
Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea|Sungkyunkwan University School of Medicine, Seoul, Korea.
D K
DK
Kim
D000328:Adult; D000368:Aged; D000928:Antidepressive Agents / Q000494:pharmacology*; D003866:Depressive Disorder / Q000188:drug therapy* / Q000235:genetics* / Q000523:psychology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data*; D006801:Humans; D007723:Korea; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D000928:Antidepressive Agents; D017367:Selective Serotonin Reuptake Inhibitors