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A genome-wide linkage study of GAW15 gene expression data.

Kan D, Cooper R, Zhu X - BMC Proc (2007)

Bottom Line: Heritability was estimated for the expression levels of each individual phenotype.Heritability exceeded 0.21 for 50% of the expressed phenotypes.We did not identify any hot spots of transcriptional regulation when assuming LOD score > 5.3 for significant linkage evidence.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Preventive Medicine and Epidemiology, Loyola University Medical Center, Maywood, Illinois 60153, USA. dkan@lumc.edu

ABSTRACT

Background: Recently, gene expression levels have been shown to demonstrate familial aggregation, suggesting a direct role of heritable DNA variation. We studied the gene expression levels in lymphoblastoid cells of the Centre d'Etude du Polymorphisme Humain Utah families made available to Genetic Analysis Workshop 15 (GAW15), using genome-wide linkage analyses.

Methods: Heritability was estimated for the expression levels of each individual phenotype. Genome wide linkage analysis was then performed using the 2819 SNPs for the expression levels of all the genes.

Results: Heritability exceeded 0.21 for 50% of the expressed phenotypes. Genome-wide linkage analysis demonstrated that 19 of them reached significance after correcting for multiple comparisons, only 4 of which were reported previously. We did not identify any hot spots of transcriptional regulation when assuming LOD score > 5.3 for significant linkage evidence.

Conclusion: Our analysis suggests that inconsistent results in comparison to the previous report may be due to the different approaches, phenotype transformation, and different pedigree data used in the analyses.

No MeSH data available.


Related in: MedlinePlus

LOD scores vs. heritability.
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Figure 2: LOD scores vs. heritability.

Mentions: We next performed multipoint linkage analysis using the variance-components approach implemented in Merlin. We observed 197 genome scans with LOD scores > 3.3 among the 3354 genome scans. In this report we used the criterion of a LOD score = 3.3 to correspond to a false-positive rate of ~0.05 for a genome-wide linkage analysis of one trait [7], however we acknowledge that a better approach might be through simulations. We expected 168 genome scans to have LOD score over 3.3 by chance among the 3354 scans, i.e., relatively fewer than we observed. We identified 19 expression phenotypes that reached genome-wide significance after correction for 3354 tests (LOD > 5.3) according to Morley et al. [2] and these genes are listed in Table 1. However, only 4 of them overlapped with the set of phenotypes with the strongest evidence of linkage found by Morley et al. [2], who used SIBPAL in their analysis. Given the potential concern that the inconsistencies were due to the different analysis methods, genetic maps, or phenotype transformation, we reanalyzed these 19 gene expression phenotypes using SIBPAL. Ten of the 19 gene expression phenotypes had p-values less than 10-10, suggesting these two approaches did contribute the difference of the results. Because SIBPAL is robust to the trait normality assumption [8] and the results of Morley et al. used the log transformation of the phenotypes, we also performed linkage analysis for the log transformation of the 19 gene expression phenotypes using the two methods. The LOD score of UGT2B17 dropped substantial using Merlin and a similar change was also observed using SIBPAL. The expression of UGT2B17 had a bimodal distribution before the log transformation and was skewed after the log transformation, which may explain the difference. We also observed substantial differences of linkage evidence for expression of PYGB and TMED10 when analyzed by Merlin and SIBPAL. However, we did not observe any substantial departure from a normal distribution for these two expression phenotypes either before or after the log transformation, suggesting SIBPAL may be less powerful than the variance-components method when a trait is normally distributed. The range of heritability for these expression phenotypes is between 0.22 and 0.87. The correlation between the maximum LOD score and heritability is 0.64 (Fig. 2). The correlation remains large (0.54) when we limited to the LOD scores with heritability less than 0.1.


A genome-wide linkage study of GAW15 gene expression data.

Kan D, Cooper R, Zhu X - BMC Proc (2007)

LOD scores vs. heritability.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2367464&req=5

Figure 2: LOD scores vs. heritability.
Mentions: We next performed multipoint linkage analysis using the variance-components approach implemented in Merlin. We observed 197 genome scans with LOD scores > 3.3 among the 3354 genome scans. In this report we used the criterion of a LOD score = 3.3 to correspond to a false-positive rate of ~0.05 for a genome-wide linkage analysis of one trait [7], however we acknowledge that a better approach might be through simulations. We expected 168 genome scans to have LOD score over 3.3 by chance among the 3354 scans, i.e., relatively fewer than we observed. We identified 19 expression phenotypes that reached genome-wide significance after correction for 3354 tests (LOD > 5.3) according to Morley et al. [2] and these genes are listed in Table 1. However, only 4 of them overlapped with the set of phenotypes with the strongest evidence of linkage found by Morley et al. [2], who used SIBPAL in their analysis. Given the potential concern that the inconsistencies were due to the different analysis methods, genetic maps, or phenotype transformation, we reanalyzed these 19 gene expression phenotypes using SIBPAL. Ten of the 19 gene expression phenotypes had p-values less than 10-10, suggesting these two approaches did contribute the difference of the results. Because SIBPAL is robust to the trait normality assumption [8] and the results of Morley et al. used the log transformation of the phenotypes, we also performed linkage analysis for the log transformation of the 19 gene expression phenotypes using the two methods. The LOD score of UGT2B17 dropped substantial using Merlin and a similar change was also observed using SIBPAL. The expression of UGT2B17 had a bimodal distribution before the log transformation and was skewed after the log transformation, which may explain the difference. We also observed substantial differences of linkage evidence for expression of PYGB and TMED10 when analyzed by Merlin and SIBPAL. However, we did not observe any substantial departure from a normal distribution for these two expression phenotypes either before or after the log transformation, suggesting SIBPAL may be less powerful than the variance-components method when a trait is normally distributed. The range of heritability for these expression phenotypes is between 0.22 and 0.87. The correlation between the maximum LOD score and heritability is 0.64 (Fig. 2). The correlation remains large (0.54) when we limited to the LOD scores with heritability less than 0.1.

Bottom Line: Heritability was estimated for the expression levels of each individual phenotype.Heritability exceeded 0.21 for 50% of the expressed phenotypes.We did not identify any hot spots of transcriptional regulation when assuming LOD score > 5.3 for significant linkage evidence.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Preventive Medicine and Epidemiology, Loyola University Medical Center, Maywood, Illinois 60153, USA. dkan@lumc.edu

ABSTRACT

Background: Recently, gene expression levels have been shown to demonstrate familial aggregation, suggesting a direct role of heritable DNA variation. We studied the gene expression levels in lymphoblastoid cells of the Centre d'Etude du Polymorphisme Humain Utah families made available to Genetic Analysis Workshop 15 (GAW15), using genome-wide linkage analyses.

Methods: Heritability was estimated for the expression levels of each individual phenotype. Genome wide linkage analysis was then performed using the 2819 SNPs for the expression levels of all the genes.

Results: Heritability exceeded 0.21 for 50% of the expressed phenotypes. Genome-wide linkage analysis demonstrated that 19 of them reached significance after correcting for multiple comparisons, only 4 of which were reported previously. We did not identify any hot spots of transcriptional regulation when assuming LOD score > 5.3 for significant linkage evidence.

Conclusion: Our analysis suggests that inconsistent results in comparison to the previous report may be due to the different approaches, phenotype transformation, and different pedigree data used in the analyses.

No MeSH data available.


Related in: MedlinePlus