A genomewide association study of citalopram response in major depressive disorder.
BACKGROUND
Antidepressant response is likely influenced by genetic constitution, but the actual genes involved have yet to be determined. We have carried out a genomewide association study to determine whether common DNA variation influences antidepressant response.


METHODS
Our sample is derived from Level 1 participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, all treated with citalopram. Association for the response phenotype included 883 responders and 608 nonresponders. For the remission phenotype, 743 subjects that achieved remission were compared with 608 nonresponders. We used a subset of single nucleotide polymorphisms (SNPs; n = 430,198) from the Affymetrix 500K and 5.0 Human SNP Arrays, and association analysis was carried out after correcting for population stratification.


RESULTS
We identified three SNPs associated with response with p values less than 1 x 10(-5) near the UBE3C gene (rs6966038, p = 4.65 x 10(-7)), another 100 kb away from BMP7 (rs6127921, p = 3.45 x 10(-6)), and a third that is intronic in the RORA gene (rs809736, p = 8.19 x 10(-6)). These same SNPs were also associated with remission. Thirty-nine additional SNPs are of interest with p values < or = .0001 for the response and remission phenotypes.


CONCLUSIONS
Although the findings reported here do not meet a genomewide threshold for significance, the regions identified from this study provide targets for independent replication and novel pathways to investigate mechanisms of antidepressant response. This study was not placebo controlled, making it possible that we are also observing associations to nonspecific aspects of drug treatment of depression.
Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143-0984, USA.
Holly A
HA
Garriock
Jeffrey B
JB
Kraft
Stanley I
SI
Shyn
Eric J
EJ
Peters
Jennifer S
JS
Yokoyama
Gregory D
GD
Jenkins
Megan S
MS
Reinalda
Susan L
SL
Slager
Patrick J
PJ
McGrath
Steven P
SP
Hamilton
D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use*; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics; D015283:Citalopram / Q000627:therapeutic use*; D016000:Cluster Analysis; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics; D016017:Odds Ratio; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011569:Psychiatric Status Rating Scales; D012737:Sex Factors; D013223:Statistics as Topic; D016896:Treatment Outcome; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics
D018687:Antidepressive Agents, Second-Generation; C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539738:RORA protein, human; D015283:Citalopram; C471607:UBE2N protein, human; D044763:Ubiquitin-Conjugating Enzymes