Computational protocol: Possible Associations of NTRK2 Polymorphisms with Antidepressant Treatment Outcome: Findings from an Extended Tag SNP Approach

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Protocol publication

[…] Genetic association analysis with binary response variables (response at week 5 and remission at discharge) was performed by Χ2 statistics using the WG-Permer software (http://www.mpipsykl.mpg.de/wg-permer) with allelic and genotypic models. For all association tests, the level of significance was set to.05, and P values were corrected for multiple comparisons using a resampling method as proposed by Westfall and Young applying 105 permutations over all performed tests (i.e., for 82 SNPs analyzed in the discovery sample and for 16 SNPs analyzed in the replication or in the combined sample). Empirical P values were obtained using the Monte Carlo method implemented in the WG-Permer software to approximate the exact P value with the given standard distribution without relying on asymptotic distributional theory .In case of a significant association, the Armitage’s test for trends was calculated using the software provided by the Institute for Human Genetics, Munich (http://ihg2.helmholtz-muenchen.de) and confidence intervals were calculated using a log-normal distribution. Forest plots were drawn using the rmeta software package for R-2.5.0 (http://cran.r-project.org). In the replication study, we used Fisher products corresponding to the geometric mean of the P values of the two response variables (i.e. response after 5 weeks and remission at discharge) to account for possible sample heterogeneity. We defined successful replication as a nominal association in one of the replication samples and same direction of the effect.Group differences in demographic and baseline clinical data were compared using Pearson χ2 test in case of qualitative data and with t-tests for independent samples in case of quantitative data. Average change during treatment outcome was evaluated with t-tests for paired samples. Additionally, an analysis of covariance was applied to evaluate the effects of treatment outcome (response, remission) on BDNF serum protein concentration with age, sex, and baseline BDNF as covariates. A logistic regression analysis was applied for evaluating SNP×protein interactions as a predictor for response or remission, respectively) using age and sex as covariates. All statistical analyses were conducted with SPSS for Windows (version 18.0, SPSS, Chicago, USA). [...] The phenotype showing the strongest effect in the single-marker association analysis was further investigated in a haplotype analysis using the Haploview 4.1 software . In order to detect informative associations complementary to our tagging SNP approach, haplotype analysis was performed using a D’-based linkage disequilibrium (LD) map based on haplotype blocks defined according to Gabriel et al. (). Analysis was performed in the discovery sample providing sufficient marker coverage. We used 105 random permutations implemented in Haploview to control for false-positive findings. Rare haplotypes (frequencies <.01) were excluded from the analysis. We report P values for at least nominally significant haplotypes. [...] We used the Haploview 4.1 software to map the r2-based LD pattern from the CEU population (release 21). Haplotype blocks were defined according to the method of Gabriel et al. . Using the SNP Annotation and Proxy Search (SNAP) program provided by the BROAD Institute (http://www.broadinstitute.org/mpg/snap), we further tested, whether the four SNPs that withstood correction for multiple testing in our combined analysis (rs2049046, rs10868223, rs1659412, rs11140778) were in gene-wise LD (within the BDNF and NTRK2 gene, respectively) with at least nominally associated SNPs reported in previous studies –, –. We used the 1000 Genomes Project Data set implemented in SNAP to retrieve LD informations of recently identified SNPs (e.g. rs61888800). We found only the BDNF SNP rs2030324, previously reported by Licinio , to be in high LD (r2 = .90) with rs2049046 of the present study. Neither for any other BDNF (rs7124442, rs61888800, rs908867) nor NTRK2 SNP (rs1187362, rs1187327, rs2289656, rs2378672, rs7020204, rs2013566, rs11140793) annotated in the data set, we could identify proxies with an r2≥.80. […]

Pipeline specifications

Software tools rmeta, SPSS, Haploview, SNAP
Applications Miscellaneous, GWAS
Organisms Homo sapiens
Chemicals Nucleotides