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 ¼ 0.076, p corrected ¼ 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 ¼ 0.043, p corrected ¼ 0.62) was with the opposite risk allele. The GRIK4 SNP (rs12800734, genotypic, p ¼ 0.0019, p corrected ¼ 0.12) and the HTR2A SNP (rs17288723, genotypic, p ¼ 0.0011, p corrected ¼ 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 ¼ 0.022) or HTR2A (genotypic, p ¼ 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 ¼ 0.00051 for the model). Analyzing a sub-sample of 194 patients, plasma ACTH (p ¼ 0.002) and cortisol (p ¼ 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.

Pharmacogenomics in the treatment of mood disorders: Strategies and Opportunities for personalized psychiatry

“…SSRIs) treatment response accounts for genetic factors, progress in uncovering the particular genetic polymorphisms has been slow [112]. As described in Table 1, candidate gene studies have pointed to a number of genes and SNPs that may influence antidepressant treatment outcomes [6, 7, 8-10, 26, 27, 54], including polymorphisms within the COMT [8,30], HTR2A [54,86,121], HTR1A [26], CNR1 [26], SLC6A4 [9], NPY [6], MAOA [27,30], IL1B [7,30], GRIK4 [64], BDNF [30,86], GNB3 [30], FKBP5 [86], CYP2D6 [31,121], CYP2C19 [31,121], and ABCB1 [12,86] genes (Table 1). For example, a negative influence of a higher activity COMT 158 val/val genotype on antidepressant treatment response was shown [].…”

Pharmacogenetics of antidepressant response

“…This first report was replicated in 2 subsequent studies; 261,431 however, a more recent study showed controversial results. 432 Furthermore, genes encoding for GRIK2, GRIA1, GRIA3 and GRIN3A receptors have been recently investigated in relation with response to sexual side effects from antidepressant treatment. 431,433,434 However, the study of the relation between genetic variants in the glutamate system and antidepressant response is a promising topic in pharmacogenetics.…”

Single-Nucleotide Polymorphism of the FKBP5 Gene and Childhood Maltreatment as Predictors of Structural Changes in Brain Areas Involved in Emotional Processing in Depression

“…Furthermore, a study has also found an independent and interactive involvement of FKBP5 (as well as GRIK4 and HTR2A) in antidepressant treatment response (Horstmann et al, 2010), emphasizing the potential importance for treatment in the study of this gene.…”