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发布于:2018-2-9 22:53:12  访问:1 次 回复:0 篇
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PLX-4720 Was Simply Too Easy Previously, But Now Its Virtually Impossible
SNP rs679620 is a nonsynonymous variant in the MMP3 gene that results in a change from Lysine to Glutamic acid at amino acid position 45 in the MMP3 protein and has been implicated in several human disease processes [Niu and buy PLX-4720 Qi, 2012]. The association analysis of SNPs surrounding rs679620 with MMP3 protein levels in CSF (Fig.?1) illustrated that SNPs in LD with the functional SNP showed both mean and variance heterogeneity. Mean heterogeneity fades as LD (|r|) with the functional SNP decreases. However, variance heterogeneity begins to rise and peak in a short interval where LD (|r|) is less than 0.5 (r2 < 0.25) with the functional SNP (Fig.?1A). To determine if detected variance heterogeneity is due to LD with a true functional variant with mean heterogeneity, instead of true functional variance heterogeneity, we would expect a strong signal of mean heterogeneity among SNPs in LD with the detected SNP with variance heterogeneity (Fig.?1B). Using the real MMP3 genetic data, we also performed association analysis with a simulated Entinostat quantitative trait on a common variant (Supplementary Fig. 2), and a simulated quantitative trait on an uncommon variant (Supplementary Fig. 3), separately. Consistent mean and variance heterogeneity patterns due to LD (|r|) were observed from simulation studies. In addition to LD measurement |r|, we also explored the relationship between variance heterogeneity and LD measurement D�� Docetaxel (Supplementary Figs. 2 and 3). We found a distinct relationship between variance heterogeneity and D��, compared with the relationship between variance heterogeneity and |r|. If a functional variant is common with only a mean effect, it is likely that any relatively uncommon variant in high D�� with it will show a variance heterogeneity peak but it will occur for relatively low |r| values (roughly according to our limited data and simulations 0.5 > |r| > 0.1, which translates to 0.25 > r2 > 0.01). For the opposite situation, if we have a relatively uncommon functional variant with only a mean effect, it is likely that any common functional variant in high D�� with it will show variance heterogeneity at about the same distance (|r| < 0.5 and r2 < 0.25) as the prior case. In addition to the simulation and real-data analysis results, we also analytically demonstrated why variance heterogeneity can arise due to LD with a functional locus with only mean effect (see supplementary text). We have demonstrated how our method has utility for finding loci that affect trait means, variances, or both without a great sacrifice in power. This provides a nice way to identify classes of loci that may ordinarily be missed by most traditional single-locus tests without sacrificing power to detect traditional loci that only affect means. In addition, as other papers have noted, loci that affect variances (vQTL) automatically become a priori hypotheses for G �� G interactions.
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