Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort.
OBJECTIVE
An initial pharmacogenetic study of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical trial reported an association between genetic variation in the HTR2A gene and outcome of citalopram treatment. By design, the study analyzed only those markers that showed reproducible association in the first wave of genotypes (comprising 1,297 patients) in the complete cohort of patients. The purpose of the present study was to utilize a second wave of genotype results, for a more powerful analysis, in the complete cohort of patients with available deoxyribonucleic acid (DNA) samples.


METHODS
The authors tested the association between treatment response and 768 markers that were genotyped in the full set of 1,816 eligible patients from the STAR*D cohort. In order to control for multiple testing, the subjects were divided into two study groups: discovery and replication.


RESULTS
In addition to the previously identified marker in the HTR2A gene, a new marker (rs1954787) in the GRIK4 gene, which codes for the kainic acid-type glutamate receptor KA1, was observed. The effect size of the GRIK4 marker alone was modest, but homozygote carriers of the treatment-response-associated marker alleles of both the GRIK4 and HTR2A genes were 23% less likely to experience nonresponse to treatment relative to participants who did not carry any of these marker alleles.


CONCLUSIONS
The findings demonstrate that genetic variation in a kainic acid-type glutamate receptor is reproducibly associated with response to the antidepressant citalopram. This finding suggests that the glutamate system plays an important role in modulating response to selective serotonin reuptake inhibitors (SSRIs).
Paddock
Silvia
S
Genetic Basis of Mood and Anxiety Disorders, Mood and Anxiety Program, NIMH, NIH, Department of Health and Human Services, Bethesda, MD, USA. silvia.paddock@ki.se
Laje
Gonzalo
G
Charney
Dennis
D
Rush
A John
AJ
Wilson
Alexander F
AF
Sorant
Alexa J M
AJ
Lipsky
Robert
R
Wisniewski
Stephen R
SR
Manji
Husseini
H
McMahon
Francis J
FJ
D000328:Adult; D001741:Black or African American / Q000235:genetics; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001483:Base Sequence; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D015283:Citalopram / Q000494:pharmacology / Q000627:therapeutic use; D015331:Cohort Studies; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D040641:Quantitative Trait Loci / Q000235:genetics; D012372:ROC Curve; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects; D018092:Kainic Acid Receptors / Q000187:drug effects / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D044465:White People / Q000235:genetics
D000928:Antidepressive Agents; D015283:Citalopram; D005819:Genetic Markers; D044402:Receptor, Serotonin, 5-HT2A; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D017367:Selective Serotonin Reuptake Inhibitors; C514872:GRIK4 protein, human