Association of the glutamate transporter gene SLC1A1 with atypical antipsychotics-induced obsessive-compulsive symptoms.
BACKGROUND
Several studies have indicated that atypical antipsychotics (AAP) induce obsessive-compulsive (OC) symptoms. Research exploring the mechanism of this phenomenon, however, has been extremely limited. Considering the indirect evidence of genetic control and difficulties in developing animal models and performing gene expression studies, genetic association studies could be an important approach to understanding the molecular mechanism of AAP-induced OC symptoms. The glutamate transporter gene SLC1A1, which was recently reported to be associated with obsessive-compulsive disorder (OCD), is a promising candidate gene for susceptibility to AAP-induced OC symptoms.


OBJECTIVE
To determine whether polymorphisms in SLC1A1 are associated with AAP-induced OC symptoms in patients with schizophrenia.


METHODS
A pharmacogenetic case-control association study.


METHODS
Outpatient schizophrenia clinics.


METHODS
Clinically stable patients with schizophrenia who were receiving AAP treatment (n = 94; OC group). The OC group consisted of 40 patients with AAP-induced OC symptoms, and the non-OC group consisted of 54 patients who had received AAP for more than 24 months without developing OC symptoms.


METHODS
Allele, genotype, and haplotype frequencies. The association was tested with a logistic regression model using age, sex, and medication type as covariates.


RESULTS
Trends of association were observed in rs2228622 and rs3780412 (nominal P = .01; adjusted permutation P = .07) for the dominant model that was the inheritance model that best fit our data. In the haplotype -based analysis, the A/C/G haplotype at rs2228622-rs3780413-rs3780412 showed a significant association with AAP-induced OC symptoms; this association withstood multiple test correction (nominal P = .01; adjusted permutation P = .04; odds ratio, 3.955; 95% confidence interval, 1.366-11.452, for dominant model).


CONCLUSIONS
These results suggest that sequence variations in SLC1A1 are associated with susceptibility to AAP-induced OC symptoms. This is the first published pharmacogenetic study on this phenomenon and provides preliminary evidence of the involvement of glutamatergic neurotransmission in the pathogenesis of AAP-induced OC symptoms.
Kwon
Jun Soo
JS
Department of Neuropsychiatry, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.
Joo
Yeon Ho
YH
Nam
Hee Jung
HJ
Lim
Meerae
M
Cho
Eun-Young
EY
Jung
Myung Hun
MH
Choi
Jung-Seok
JS
Kim
Byungsu
B
Kang
Do-Hyung
DH
Oh
Sohee
S
Park
Taesung
T
Hong
Kyung Sue
KS
D027322:Amino Acid Transport System X-AG / Q000235:genetics; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016022:Case-Control Studies; D050580:Excitatory Amino Acid Transporter 3 / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D009771:Obsessive-Compulsive Disorder / Q000139:chemically induced* / Q000235:genetics; D011110:Polymorphism, Genetic; D012559:Schizophrenia / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D043922:Toxicogenetics
D027322:Amino Acid Transport System X-AG; D014150:Antipsychotic Agents; D050580:Excitatory Amino Acid Transporter 3