title: Influence of polymorphisms in genes SLC1A1, GRIN2B, and GRIK2 on clozapine-induced obsessive-compulsive symptoms.
abstract: BACKGROUND
  Clinical observations indicate that atypical antipsychotics, especially clozapine, induce obsessive-compulsive (OC) symptoms in schizophrenia patients. Recent data from neuroimaging and clinical trials suggest a role for altered glutamate neurotransmission in the etiology of OC disorder (OCD), and SLC1A1, GRIN2B, and GRIK2 have all been reported to regulate glutamate transmission and affect OCD pathophysiology.
  
  
  OBJECTIVE
  This study aimed to determine whether SLC1A1, GRIN2B, and GRIK2 are associated with clozapine-induced OC symptoms.
  
  
  METHODS
  A total of 250 clinically stable schizophrenia patients receiving clozapine treatment were recruited. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was used to evaluate the severity of OC symptoms. Based on their Y-BOCS scores, 250 patients were divided into the OC and non-OC groups (patients with or without OC symptoms, respectively). Additionally, three reported OCD susceptibility polymorphisms, SLC1A1 (rs2228622), GRIN2B (rs890), and GRIK2 (rs1556995), were genotyped.
  
  
  RESULTS
  Trends of association with OC symptoms were observed in rs2228622A and rs890T alleles. SLC1A1 and GRIN2B interaction was found in the significant two-locus gene-gene interaction model (p = 0.0021), using the multifactor dimensionality reduction method. Further analysis showed a significant interaction between SLC1A1 and GRIN2B on the Y-BOCS score (F 6, 137 = 7.650, p < 0.001), and individuals with AA/TT genotypes had a significantly higher mean Y-BOCS score than those with other genotypes, except AG/TT.
  
  
  CONCLUSIONS
  These results suggest that SLC1A1, GRIN2B, and interactions between the two may potentially confer a susceptibility to OC symptoms in schizophrenia patients receiving clozapine.
authors: Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, People's Republic of China.
authors: Jun
authors: J
authors: Cai
authors: Wen
authors: W
authors: Zhang
authors: Zhenghui
authors: Z
authors: Yi
authors: Weihong
authors: W
authors: Lu
authors: Zhiguo
authors: Z
authors: Wu
authors: Jun
authors: J
authors: Chen
authors: Shunying
authors: S
authors: Yu
authors: Yiru
authors: Y
authors: Fang
authors: Chen
authors: C
authors: Zhang
mesh_terms: D000328:Adult; D000483:Alleles; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D003024:Clozapine / Q000009:adverse effects* / Q000627:therapeutic use; D003430:Cross-Sectional Studies; D050580:Excitatory Amino Acid Transporter 3 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009771:Obsessive-Compulsive Disorder / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology; D011110:Polymorphism, Genetic; D011569:Psychiatric Status Rating Scales; D018092:Kainic Acid Receptors / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics; D012720:Severity of Illness Index; D000097806:GluK2 Kainate Receptor
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine; D050580:Excitatory Amino Acid Transporter 3; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D000097806:GluK2 Kainate Receptor; C121001:NR2B NMDA receptor; C493400:SLC1A1 protein, human
references: Schizophr Res. 2005 Jun 15;75(2-3):349-62
references: 15885526
references: J Mol Neurosci. 2011 Mar;43(3):406-11
references: 20938755
references: Am J Psychiatry. 2006 Apr;163(4):600-10
references: 16585434
references: Psychopharmacology (Berl). 2004 Aug;174(4):530-8
references: 15083261
references: Twin Res Hum Genet. 2005 Oct;8(5):450-8
references: 16212834
references: J Neural Transm (Vienna). 1997;104(6-7):761-6
references: 9444574
references: Arch Gen Psychiatry. 2006 Jul;63(7):778-85
references: 16818867
references: Psychiatry Clin Neurosci. 2005 Jun;59(3):291-5
references: 15896222
references: J Am Acad Child Adolesc Psychiatry. 2000 Sep;39(9):1096-103
references: 10986805
references: J Psychiatry Neurosci. 2001 Jan;26(1):55-9
references: 11212595
references: N Engl J Med. 2005 Sep 22;353(12):1209-23
references: 16172203
references: Arch Gen Psychiatry. 2006 Jul;63(7):769-76
references: 16818866
references: Pharmacol Biochem Behav. 2012 Feb;100(4):726-35
references: 22024159
references: Prog Neuropsychopharmacol Biol Psychiatry. 2010 Apr 16;34(3):506-9
references: 20144677
references: Arch Gen Psychiatry. 2009 Nov;66(11):1233-41
references: 19884611
references: J Clin Psychiatry. 1999 Jun;60(6):364-5
references: 10401913
references: Compr Psychiatry. 2009 Sep-Oct;50(5):437-42
references: 19683614
references: Curr Top Med Chem. 2012;12(4):238-53
references: 22204483
references: Arch Gen Psychiatry. 1989 Nov;46(11):1006-11
references: 2684084
references: Neuropsychopharmacology. 2005 Sep;30(9):1735-40
references: 15841109
references: Mol Psychiatry. 2002;7(3):302-10
references: 11920157
references: Cell Res. 2005 Feb;15(2):97-8
references: 15740637
references: Am J Med Genet B Neuropsychiatr Genet. 2011 Dec;156B(8):949-59
references: 21990008
references: Curr Neuropharmacol. 2012 Mar;10(1):88-95
references: 22942882
references: CNS Neurosci Ther. 2011 Jun;17(3):141-7
references: 20370803
references: Psychiatry Clin Neurosci. 2005 Apr;59(2):219-22
references: 15823172
references: Prog Neuropsychopharmacol Biol Psychiatry. 2006 Aug 30;30(6):1051-7
references: 16687198
references: Psychol Med. 2011 Nov;41(11):2361-73
references: 21466748
references: Am J Med Genet C Semin Med Genet. 2008 May 15;148C(2):133-9
references: 18412099
references: Annu Rev Neurosci. 1994;17:31-108
references: 8210177
references: Am J Med Genet B Neuropsychiatr Genet. 2007 Dec 5;144B(8):1027-33
references: 17894418
references: Bioinformatics. 2003 Feb 12;19(3):376-82
references: 12584123
references: Brain Imaging Behav. 2009 Mar 1;3(1):64-76
references: 21031159
references: Cochrane Database Syst Rev. 2010 Nov 10;(11):CD006633
references: 21069690
references: Am J Psychiatry. 1986 Apr;143(4):437-41
references: 3953886
references: Am J Med Genet B Neuropsychiatr Genet. 2011 Jun;156B(4):472-7
references: 21445956
references: Neuroreport. 2004 Mar 22;15(4):699-702
references: 15094479
references: Nat Med. 2000 Jun;6(6):637-41
references: 10835679