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.
