title: Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment.
abstract: Single-nucleotide polymorphisms (SNPs) in the FKBP5, GRIK4, and HTR2A genes have been shown to be associated with response to citalopram treatment in the STAR(*)D sample, but only associations with FKBP5 have so far been tested in the Munich Antidepressant Response Signature (MARS) project. Response and remission of depressive symptoms after 5 weeks of antidepressant treatment were tested against 82 GRIK4 and 37 HTR2A SNPs. Association analysis was conducted in about 300 depressed patients from the MARS project, 10% of whom had bipolar disorder. The most predictive SNPs from these two genes and rs1360780 in FKBP5 were then genotyped in a total of 387 German depressed in-patients to analyze potential additive and interactive effects of these variants. We could not replicate previous findings of the Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) study in our sample. Although not statistically significant, the effect for the best GRIK4 SNP of STAR(*)D (rs1954787, p=0.076, p(corrected)=0.98) seemed to be in the same direction. On the other hand, the nominally significant association with the top HTR2A SNPs of STAR(*)D (rs7997012, allelic, p=0.043, p(corrected)=0.62) was with the opposite risk allele. The GRIK4 SNP (rs12800734, genotypic, p=0.0019, p(corrected)=0.12) and the HTR2A SNP (rs17288723, genotypic, p=0.0011, p(corrected)=0.02), which showed the strongest association with remission in our sample, had not been reported previously. Associations across all genetic markers within the GRIK4 (genotypic, p=0.022) or HTR2A (genotypic, p=0.012) locus using the Fisher's product method (FPM) were also significant. In all 374 patients, the best predictive model included a main effect for GRIK4 rs12800734 and two significant interactions between GRIK4 rs12800734 and FKBP5 rs1360780, and GRIK4 rs12800734 and HTR2A rs17288723. This three SNP model explained 13.1% of the variance for remission after 5 weeks (p=0.00051 for the model). Analyzing a sub-sample of 194 patients, plasma ACTH (p=0.002) and cortisol (p=0.021) responses of rs12800734 GG (GRIK4) carriers, who also showed favorable treatment response, were significantly lower in the second combined dexamethasone (dex)/corticotrophin-releasing hormone (CRH) test before discharge compared with the other two genotype groups. Despite large differences in ethnicity and design compared with the STAR(*)D study, our results from the MARS study further support both independent and interactive involvement of GRIK4, HTR2A and FKBP5 in antidepressant treatment response.
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany. horstmann@mpipsykl.mpg.de
authors.forename: Sonja
authors.initials: S
authors.lastname: Horstmann
authors.forename: Susanne
authors.initials: S
authors.lastname: Lucae
authors.forename: Andreas
authors.initials: A
authors.lastname: Menke
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Hennings
authors.forename: Marcus
authors.initials: M
authors.lastname: Ising
authors.forename: Darina
authors.initials: D
authors.lastname: Roeske
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D003866:Depressive Disorder / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011237:Predictive Value of Tests; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics*; D018092:Kainic Acid Receptors / Q000235:genetics*; D012074:Remission Induction; D022021:Tacrolimus Binding Proteins / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult; D000099159:Tacrolimus Binding Protein 5
chemical_list: D000928:Antidepressive Agents; D005819:Genetic Markers; D044402:Receptor, Serotonin, 5-HT2A; D018092:Kainic Acid Receptors; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C514872:GRIK4 protein, human