Limits...
Possible associations of NTRK2 polymorphisms with antidepressant treatment outcome: findings from an extended tag SNP approach.

Hennings JM, Kohli MA, Czamara D, Giese M, Eckert A, Wolf C, Heck A, Domschke K, Arolt V, Baune BT, Horstmann S, Brückl T, Klengel T, Menke A, Müller-Myhsok B, Ising M, Uhr M, Lucae S - PLoS ONE (2013)

Bottom Line: Three NTRK2 SNPs (rs10868223, rs1659412 and rs11140778) also showed associations in at least one replication sample and in the combined sample with the same direction of effects (Pcorr  = .018, Pcorr  = .015 and Pcorr  = .004, respectively).We observed an across-gene BDNF-NTRK2 SNP interaction for rs4923468 and rs1387926.These new variants need further validation in future association studies.

View Article: PubMed Central - PubMed

Affiliation: Max-Planck-Institute of Psychiatry, Munich, Germany. hennings@mpipsykl.mpg.de

ABSTRACT

Background: Data from clinical studies and results from animal models suggest an involvement of the neurotrophin system in the pathology of depression and antidepressant treatment response. Genetic variations within the genes coding for the brain-derived neurotrophic factor (BDNF) and its key receptor Trkb (NTRK2) may therefore influence the response to antidepressant treatment.

Methods: We performed a single and multi-marker association study with antidepressant treatment outcome in 398 depressed Caucasian inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Two Caucasian replication samples (N = 249 and N = 247) were investigated, resulting in a total number of 894 patients. 18 tagging SNPs in the BDNF gene region and 64 tagging SNPs in the NTRK2 gene region were genotyped in the discovery sample; 16 nominally associated SNPs were tested in two replication samples.

Results: In the discovery analysis, 7 BDNF SNPs and 9 NTRK2 SNPs were nominally associated with treatment response. Three NTRK2 SNPs (rs10868223, rs1659412 and rs11140778) also showed associations in at least one replication sample and in the combined sample with the same direction of effects (Pcorr  = .018, Pcorr  = .015 and Pcorr  = .004, respectively). We observed an across-gene BDNF-NTRK2 SNP interaction for rs4923468 and rs1387926. No robust interaction of associated SNPs was found in an analysis of BDNF serum protein levels as a predictor for treatment outcome in a subset of 93 patients.

Conclusions/limitations: Although not all associations in the discovery analysis could be unambiguously replicated, the findings of the present study identified single nucleotide variations in the BDNF and NTRK2 genes that might be involved in antidepressant treatment outcome and that have not been previously reported in this context. These new variants need further validation in future association studies.

Show MeSH

Related in: MedlinePlus

Development of HAM-D values during antidepressive treatment depending on the rs10868223 (A), rs1659412 (B) and rs11140778 (C) genotype (combined sample).Repeated measurements (Greenhouse-Geisser, age and sex as covariates) revealed significant interaction effects for rs10868223 (P = .007) and rs1659412 (P = .012), but not for rs11140778 (P = .645). Stars indicate significant between-subjects differences at different time points (*, p<.05; **, p<.01; GLM with age and sex as covariates). Error bars are standard errors of the means.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3672143&req=5

pone-0064947-g001: Development of HAM-D values during antidepressive treatment depending on the rs10868223 (A), rs1659412 (B) and rs11140778 (C) genotype (combined sample).Repeated measurements (Greenhouse-Geisser, age and sex as covariates) revealed significant interaction effects for rs10868223 (P = .007) and rs1659412 (P = .012), but not for rs11140778 (P = .645). Stars indicate significant between-subjects differences at different time points (*, p<.05; **, p<.01; GLM with age and sex as covariates). Error bars are standard errors of the means.

Mentions: Treatment outcome was tested in replication samples under the allelic model, which showed the strongest associations in the discovery sample. Of the 16 nominally associated SNPs in the discovery sample, we found one BDNF SNP (rs11602246; P = .01) and one NTRK2 SNP (rs10868223; P = .009) to be nominally associated with outcome in the MARS replication sample (N = 249). In the Muenster replication sample, the three NTRK2 SNPs rs1659412, rs1662695 and rs11140778 showed nominal associations (P = .01; P = .03; P = .003, respectively). In the combined analysis of all patients across the three samples we found the SNPs rs2049046 (BDNF; Pcorr = .021), rs10868223 (NTRK2; Pcorr = .018), rs1659412 (NTRK2; Pcorr = .015) and rs11140778 (NTRK2; Pcorr = .004) to be significantly associated with response after correction for multiple testing (Table 3, Figure 1). According to our definition of a positive replication, we could replicate the three NTRK2 SNPs (rs10868223, rs1659412 and rs11140778) as they showed associations in at least one replication sample and had a lower P value in the combined analysis compared to any single sample of the study, withstanding correction for multiple testing. For these three markers, we calculated the Armitage test of trends as a measure of the effect size separately in the three different samples and for both phenotypes (Figure 2). Under the definition for a replication, the most significantly associated BDNF marker in the discovery sample, rs2049046 could not be replicated, although the association in the combined analysis still withstood correction for multiple testing (Pcorr = .02).


Possible associations of NTRK2 polymorphisms with antidepressant treatment outcome: findings from an extended tag SNP approach.

Hennings JM, Kohli MA, Czamara D, Giese M, Eckert A, Wolf C, Heck A, Domschke K, Arolt V, Baune BT, Horstmann S, Brückl T, Klengel T, Menke A, Müller-Myhsok B, Ising M, Uhr M, Lucae S - PLoS ONE (2013)

Development of HAM-D values during antidepressive treatment depending on the rs10868223 (A), rs1659412 (B) and rs11140778 (C) genotype (combined sample).Repeated measurements (Greenhouse-Geisser, age and sex as covariates) revealed significant interaction effects for rs10868223 (P = .007) and rs1659412 (P = .012), but not for rs11140778 (P = .645). Stars indicate significant between-subjects differences at different time points (*, p<.05; **, p<.01; GLM with age and sex as covariates). Error bars are standard errors of the means.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3672143&req=5

pone-0064947-g001: Development of HAM-D values during antidepressive treatment depending on the rs10868223 (A), rs1659412 (B) and rs11140778 (C) genotype (combined sample).Repeated measurements (Greenhouse-Geisser, age and sex as covariates) revealed significant interaction effects for rs10868223 (P = .007) and rs1659412 (P = .012), but not for rs11140778 (P = .645). Stars indicate significant between-subjects differences at different time points (*, p<.05; **, p<.01; GLM with age and sex as covariates). Error bars are standard errors of the means.
Mentions: Treatment outcome was tested in replication samples under the allelic model, which showed the strongest associations in the discovery sample. Of the 16 nominally associated SNPs in the discovery sample, we found one BDNF SNP (rs11602246; P = .01) and one NTRK2 SNP (rs10868223; P = .009) to be nominally associated with outcome in the MARS replication sample (N = 249). In the Muenster replication sample, the three NTRK2 SNPs rs1659412, rs1662695 and rs11140778 showed nominal associations (P = .01; P = .03; P = .003, respectively). In the combined analysis of all patients across the three samples we found the SNPs rs2049046 (BDNF; Pcorr = .021), rs10868223 (NTRK2; Pcorr = .018), rs1659412 (NTRK2; Pcorr = .015) and rs11140778 (NTRK2; Pcorr = .004) to be significantly associated with response after correction for multiple testing (Table 3, Figure 1). According to our definition of a positive replication, we could replicate the three NTRK2 SNPs (rs10868223, rs1659412 and rs11140778) as they showed associations in at least one replication sample and had a lower P value in the combined analysis compared to any single sample of the study, withstanding correction for multiple testing. For these three markers, we calculated the Armitage test of trends as a measure of the effect size separately in the three different samples and for both phenotypes (Figure 2). Under the definition for a replication, the most significantly associated BDNF marker in the discovery sample, rs2049046 could not be replicated, although the association in the combined analysis still withstood correction for multiple testing (Pcorr = .02).

Bottom Line: Three NTRK2 SNPs (rs10868223, rs1659412 and rs11140778) also showed associations in at least one replication sample and in the combined sample with the same direction of effects (Pcorr  = .018, Pcorr  = .015 and Pcorr  = .004, respectively).We observed an across-gene BDNF-NTRK2 SNP interaction for rs4923468 and rs1387926.These new variants need further validation in future association studies.

View Article: PubMed Central - PubMed

Affiliation: Max-Planck-Institute of Psychiatry, Munich, Germany. hennings@mpipsykl.mpg.de

ABSTRACT

Background: Data from clinical studies and results from animal models suggest an involvement of the neurotrophin system in the pathology of depression and antidepressant treatment response. Genetic variations within the genes coding for the brain-derived neurotrophic factor (BDNF) and its key receptor Trkb (NTRK2) may therefore influence the response to antidepressant treatment.

Methods: We performed a single and multi-marker association study with antidepressant treatment outcome in 398 depressed Caucasian inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Two Caucasian replication samples (N = 249 and N = 247) were investigated, resulting in a total number of 894 patients. 18 tagging SNPs in the BDNF gene region and 64 tagging SNPs in the NTRK2 gene region were genotyped in the discovery sample; 16 nominally associated SNPs were tested in two replication samples.

Results: In the discovery analysis, 7 BDNF SNPs and 9 NTRK2 SNPs were nominally associated with treatment response. Three NTRK2 SNPs (rs10868223, rs1659412 and rs11140778) also showed associations in at least one replication sample and in the combined sample with the same direction of effects (Pcorr  = .018, Pcorr  = .015 and Pcorr  = .004, respectively). We observed an across-gene BDNF-NTRK2 SNP interaction for rs4923468 and rs1387926. No robust interaction of associated SNPs was found in an analysis of BDNF serum protein levels as a predictor for treatment outcome in a subset of 93 patients.

Conclusions/limitations: Although not all associations in the discovery analysis could be unambiguously replicated, the findings of the present study identified single nucleotide variations in the BDNF and NTRK2 genes that might be involved in antidepressant treatment outcome and that have not been previously reported in this context. These new variants need further validation in future association studies.

Show MeSH
Related in: MedlinePlus