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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

Boxplots representing four measures of simulation data with an increase in d.A. Variation of distributions due to increase in sample sizes (Case I). B. Variation of distributions due to bias of sample sizes (Case II). For both cases, the x-axis denotes the distance d, and the y-axis and denotes the following measures: -log10Pvalue for chi-square test and ANOVA F-test; Weir and Cockerham’s Fst estimates for Fst;  for NSCM.
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pone.0119994.g002: Boxplots representing four measures of simulation data with an increase in d.A. Variation of distributions due to increase in sample sizes (Case I). B. Variation of distributions due to bias of sample sizes (Case II). For both cases, the x-axis denotes the distance d, and the y-axis and denotes the following measures: -log10Pvalue for chi-square test and ANOVA F-test; Weir and Cockerham’s Fst estimates for Fst; for NSCM.

Mentions: From these conditions, we generated 200 sets of genotype frequency data from three binomial distributions under Hardy-Weinberg Equilibrium (HWE): binomial distribution, binomial distribution (ni, 2piqi) and binomial distribution. We then calculated the four PD measures. Fig. 2 shows the box plots representing the distributions of the measures from two scenarios. As d increased, the box sizes of the chi-square test, ANOVA F-test, and NSCM increased, while those of Fst did not. All measures increased as d increased. As the total sample size increased, the p-values from the chi-square test and ANOVA F-test decreased, while those from Fst and SSd from NSCM did not change significantly (Fig. 2A).


Analysis of pharmacogenomic variants associated with population differentiation.

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

Boxplots representing four measures of simulation data with an increase in d.A. Variation of distributions due to increase in sample sizes (Case I). B. Variation of distributions due to bias of sample sizes (Case II). For both cases, the x-axis denotes the distance d, and the y-axis and denotes the following measures: -log10Pvalue for chi-square test and ANOVA F-test; Weir and Cockerham’s Fst estimates for Fst;  for NSCM.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0119994.g002: Boxplots representing four measures of simulation data with an increase in d.A. Variation of distributions due to increase in sample sizes (Case I). B. Variation of distributions due to bias of sample sizes (Case II). For both cases, the x-axis denotes the distance d, and the y-axis and denotes the following measures: -log10Pvalue for chi-square test and ANOVA F-test; Weir and Cockerham’s Fst estimates for Fst; for NSCM.
Mentions: From these conditions, we generated 200 sets of genotype frequency data from three binomial distributions under Hardy-Weinberg Equilibrium (HWE): binomial distribution, binomial distribution (ni, 2piqi) and binomial distribution. We then calculated the four PD measures. Fig. 2 shows the box plots representing the distributions of the measures from two scenarios. As d increased, the box sizes of the chi-square test, ANOVA F-test, and NSCM increased, while those of Fst did not. All measures increased as d increased. As the total sample size increased, the p-values from the chi-square test and ANOVA F-test decreased, while those from Fst and SSd from NSCM did not change significantly (Fig. 2A).

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