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Analysis of pharmacogenomic variants associated with population differentiation.

Yeon B, Ahn E, Kim KI, Kim IW, Oh JM, Park T - PLoS ONE (2015)

Bottom Line: Among the 17 genes related to cell communication identified in the HD gene group, five genes (STX4, PPARD, DCK, GRIK4, and DRD3) contained single nucleotide polymorphisms with Fst values greater than 0.5.In the analysis using DR genes as the background, the HD gene group contained six significant terms.Our analysis suggests that the HD gene group from PharmGKB is associated with cell communication and drug binding.

View Article: PubMed Central - PubMed

Affiliation: Interdisciplinary Program in Bioinformatics, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, Korea.

ABSTRACT
In the present study, we systematically investigated population differentiation of drug-related (DR) genes in order to identify common genetic features underlying population-specific responses to drugs. To do so, we used the International HapMap project release 27 Data and Pharmacogenomics Knowledge Base (PharmGKB) database. First, we compared four measures for assessing population differentiation: the chi-square test, the analysis of variance (ANOVA) F-test, Fst, and Nearest Shrunken Centroid Method (NSCM). Fst showed high sensitivity with stable specificity among varying sample sizes; thus, we selected Fst for determining population differentiation. Second, we divided DR genes from PharmGKB into two groups based on the degree of population differentiation as assessed by Fst: genes with a high level of differentiation (HD gene group) and genes with a low level of differentiation (LD gene group). Last, we conducted a gene ontology (GO) analysis and pathway analysis. Using all genes in the human genome as the background, the GO analysis and pathway analysis of the HD genes identified terms related to cell communication. "Cell communication" and "cell-cell signaling" had the lowest Benjamini-Hochberg's q-values (0.0002 and 0.0006, respectively), and "drug binding" was highly enriched (16.51) despite its relatively high q-value (0.0142). Among the 17 genes related to cell communication identified in the HD gene group, five genes (STX4, PPARD, DCK, GRIK4, and DRD3) contained single nucleotide polymorphisms with Fst values greater than 0.5. Specifically, the Fst values for rs10871454, rs6922548, rs3775289, rs1954787, and rs167771 were 0.682, 0.620, 0.573, 0.531, and 0.510, respectively. In the analysis using DR genes as the background, the HD gene group contained six significant terms. Five were related to reproduction, and one was "Wnt signaling pathway," which has been implicated in cancer. Our analysis suggests that the HD gene group from PharmGKB is associated with cell communication and drug binding.

No MeSH data available.


Related in: MedlinePlus

Specificities (%) of each measure from simulation data under H0:d = 0 due to an increase in sample size (Scenario I).The chi-square test and ANOVA F-test are similar, and Fst and SSd from NSCM are nearly identical. Blue line: chi-square test; red line: Fst; black dotted line: ANOVA F-test; green dotted line: SSd from NSCM.
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pone.0119994.g003: Specificities (%) of each measure from simulation data under H0:d = 0 due to an increase in sample size (Scenario I).The chi-square test and ANOVA F-test are similar, and Fst and SSd from NSCM are nearly identical. Blue line: chi-square test; red line: Fst; black dotted line: ANOVA F-test; green dotted line: SSd from NSCM.

Mentions: The chi-square test and ANOVA F-test depended on total sample sizes, as indicated by the specificities calculated under the hypothesis (d = 0) for Scenario I (Fig. 3). When the total sample sizes were small, the chi-square test and ANOVA F-test showed high specificities; however, the specificities fell to 92% as the sample size increased. This reflects a general characteristic of test statistics, where the test statistic tends to reject the hypothesis more when the sample size increases. For Scenario II, all four measures yielded high specificities that were close to one.


Analysis of pharmacogenomic variants associated with population differentiation.

Yeon B, Ahn E, Kim KI, Kim IW, Oh JM, Park T - PLoS ONE (2015)

Specificities (%) of each measure from simulation data under H0:d = 0 due to an increase in sample size (Scenario I).The chi-square test and ANOVA F-test are similar, and Fst and SSd from NSCM are nearly identical. Blue line: chi-square test; red line: Fst; black dotted line: ANOVA F-test; green dotted line: SSd from NSCM.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4373713&req=5

pone.0119994.g003: Specificities (%) of each measure from simulation data under H0:d = 0 due to an increase in sample size (Scenario I).The chi-square test and ANOVA F-test are similar, and Fst and SSd from NSCM are nearly identical. Blue line: chi-square test; red line: Fst; black dotted line: ANOVA F-test; green dotted line: SSd from NSCM.
Mentions: The chi-square test and ANOVA F-test depended on total sample sizes, as indicated by the specificities calculated under the hypothesis (d = 0) for Scenario I (Fig. 3). When the total sample sizes were small, the chi-square test and ANOVA F-test showed high specificities; however, the specificities fell to 92% as the sample size increased. This reflects a general characteristic of test statistics, where the test statistic tends to reject the hypothesis more when the sample size increases. For Scenario II, all four measures yielded high specificities that were close to one.

Bottom Line: Among the 17 genes related to cell communication identified in the HD gene group, five genes (STX4, PPARD, DCK, GRIK4, and DRD3) contained single nucleotide polymorphisms with Fst values greater than 0.5.In the analysis using DR genes as the background, the HD gene group contained six significant terms.Our analysis suggests that the HD gene group from PharmGKB is associated with cell communication and drug binding.

View Article: PubMed Central - PubMed

Affiliation: Interdisciplinary Program in Bioinformatics, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, Korea.

ABSTRACT
In the present study, we systematically investigated population differentiation of drug-related (DR) genes in order to identify common genetic features underlying population-specific responses to drugs. To do so, we used the International HapMap project release 27 Data and Pharmacogenomics Knowledge Base (PharmGKB) database. First, we compared four measures for assessing population differentiation: the chi-square test, the analysis of variance (ANOVA) F-test, Fst, and Nearest Shrunken Centroid Method (NSCM). Fst showed high sensitivity with stable specificity among varying sample sizes; thus, we selected Fst for determining population differentiation. Second, we divided DR genes from PharmGKB into two groups based on the degree of population differentiation as assessed by Fst: genes with a high level of differentiation (HD gene group) and genes with a low level of differentiation (LD gene group). Last, we conducted a gene ontology (GO) analysis and pathway analysis. Using all genes in the human genome as the background, the GO analysis and pathway analysis of the HD genes identified terms related to cell communication. "Cell communication" and "cell-cell signaling" had the lowest Benjamini-Hochberg's q-values (0.0002 and 0.0006, respectively), and "drug binding" was highly enriched (16.51) despite its relatively high q-value (0.0142). Among the 17 genes related to cell communication identified in the HD gene group, five genes (STX4, PPARD, DCK, GRIK4, and DRD3) contained single nucleotide polymorphisms with Fst values greater than 0.5. Specifically, the Fst values for rs10871454, rs6922548, rs3775289, rs1954787, and rs167771 were 0.682, 0.620, 0.573, 0.531, and 0.510, respectively. In the analysis using DR genes as the background, the HD gene group contained six significant terms. Five were related to reproduction, and one was "Wnt signaling pathway," which has been implicated in cancer. Our analysis suggests that the HD gene group from PharmGKB is associated with cell communication and drug binding.

No MeSH data available.


Related in: MedlinePlus