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Sex, age and generation effects on genome-wide linkage analysis of gene expression in transformed lymphoblasts.

Rangrej J, Beyene J, Hu P, Paterson AD - BMC Proc (2007)

Bottom Line: When generation was included in the model with age, all but 6 of the GEE age effects were no longer significant.However, there were minimal changes in the linkage results.The effect of age on linkage analyses was apparent for the expression of many genes, which appear to be mostly due to differences between the generations.

View Article: PubMed Central - HTML - PubMed

Affiliation: Programs in Genetics and Genome Biology, The Hospital for Sick Children, 101 College Street, TMDT East Tower, Toronto, Ontario M5G 1X8 Canada. jrangrej@sickkids.ca

ABSTRACT

Background: Many traits differ by age and sex in humans, but genetic analysis of gene expression has typically not included them in the analysis.

Methods: We used Genetic Analysis Workshop 15 Problem 1 data to determine whether gene expression in lymphoblasts showed differences by age and/or sex using generalized estimating equations (GEE). We performed quantitative trait linkage analysis of these genes including age and sex as covariates to determine whether the linkage results changed when they were included as covariates. Because the families included in the study all contain three generations, we also determined what effect inclusion of generation in the model had on the age effects.

Results: When controlling the false-discovery rate at 1%, using GEE we identified 30 transcripts that showed significant differences in expression by sex, while 1950 transcripts showed differences in expression associated with age. When subjected to linkage analysis, there were 37 linkages that disappeared, while 17 appeared when sex was included as a covariate. All these genes were, as expected, on the sex chromosomes. In contrast, when age was included in the linkage analysis, 462 linkage signals were no longer significant, while 223 became significant. When generation was included in the model with age, all but 6 of the GEE age effects were no longer significant. However, there were minimal changes in the linkage results.

Conclusion: The effect of age on linkage analyses was apparent for the expression of many genes, which appear to be mostly due to differences between the generations.

No MeSH data available.


Distribution of LOD scores when covariates are included in linkage analysis. Sex (A) or age (B) were included as covariates and are plotted on vertical axis, compared to no covariates on the horizontal axis. C, On the vertical axis age and generation were included as covariates, compared to age as a covariate on the horizontal axis. The solid line indicates symmetry, the dashed lines are at ±3 LOD scores from symmetry.
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Figure 2: Distribution of LOD scores when covariates are included in linkage analysis. Sex (A) or age (B) were included as covariates and are plotted on vertical axis, compared to no covariates on the horizontal axis. C, On the vertical axis age and generation were included as covariates, compared to age as a covariate on the horizontal axis. The solid line indicates symmetry, the dashed lines are at ±3 LOD scores from symmetry.

Mentions: Figure 2 shows the LOD scores with and without sex and age, respectively. Note the greater change in LOD scores when age (Fig. 2B) was included as a covariate than when sex (Fig. 2A) was included. Specifically, 37 linkage signals disappear and 17 appear when sex was included. As expected, all of those traits with linkage results that changed when sex was included map to the sex chromosomes, and the loci showing changes in linkage were on the autosomes (Table 2). Of particular interest were the four genes that are on the X chromosome and for which linkage signals appear on the autosomes when sex is included. This suggests that autosomal loci influence the expression of some genes that escape X-inactivation. For the age analysis, 462 significant linkage results disappeared while 223 appeared when age was included in the analysis. Table 3 provides a list of the 10 top SNPs and traits that show evidence for linkage when age is either included or excluded as a covariate. When linkage analysis was performed with both age and generation as covariates, the change in the linkage results (Fig. 2C) was not as marked as when only age was included as a covariate (Fig. 2B). According to our criteria, only four linkage results disappeared when generation was added to age, and none appeared.


Sex, age and generation effects on genome-wide linkage analysis of gene expression in transformed lymphoblasts.

Rangrej J, Beyene J, Hu P, Paterson AD - BMC Proc (2007)

Distribution of LOD scores when covariates are included in linkage analysis. Sex (A) or age (B) were included as covariates and are plotted on vertical axis, compared to no covariates on the horizontal axis. C, On the vertical axis age and generation were included as covariates, compared to age as a covariate on the horizontal axis. The solid line indicates symmetry, the dashed lines are at ±3 LOD scores from symmetry.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2367486&req=5

Figure 2: Distribution of LOD scores when covariates are included in linkage analysis. Sex (A) or age (B) were included as covariates and are plotted on vertical axis, compared to no covariates on the horizontal axis. C, On the vertical axis age and generation were included as covariates, compared to age as a covariate on the horizontal axis. The solid line indicates symmetry, the dashed lines are at ±3 LOD scores from symmetry.
Mentions: Figure 2 shows the LOD scores with and without sex and age, respectively. Note the greater change in LOD scores when age (Fig. 2B) was included as a covariate than when sex (Fig. 2A) was included. Specifically, 37 linkage signals disappear and 17 appear when sex was included. As expected, all of those traits with linkage results that changed when sex was included map to the sex chromosomes, and the loci showing changes in linkage were on the autosomes (Table 2). Of particular interest were the four genes that are on the X chromosome and for which linkage signals appear on the autosomes when sex is included. This suggests that autosomal loci influence the expression of some genes that escape X-inactivation. For the age analysis, 462 significant linkage results disappeared while 223 appeared when age was included in the analysis. Table 3 provides a list of the 10 top SNPs and traits that show evidence for linkage when age is either included or excluded as a covariate. When linkage analysis was performed with both age and generation as covariates, the change in the linkage results (Fig. 2C) was not as marked as when only age was included as a covariate (Fig. 2B). According to our criteria, only four linkage results disappeared when generation was added to age, and none appeared.

Bottom Line: When generation was included in the model with age, all but 6 of the GEE age effects were no longer significant.However, there were minimal changes in the linkage results.The effect of age on linkage analyses was apparent for the expression of many genes, which appear to be mostly due to differences between the generations.

View Article: PubMed Central - HTML - PubMed

Affiliation: Programs in Genetics and Genome Biology, The Hospital for Sick Children, 101 College Street, TMDT East Tower, Toronto, Ontario M5G 1X8 Canada. jrangrej@sickkids.ca

ABSTRACT

Background: Many traits differ by age and sex in humans, but genetic analysis of gene expression has typically not included them in the analysis.

Methods: We used Genetic Analysis Workshop 15 Problem 1 data to determine whether gene expression in lymphoblasts showed differences by age and/or sex using generalized estimating equations (GEE). We performed quantitative trait linkage analysis of these genes including age and sex as covariates to determine whether the linkage results changed when they were included as covariates. Because the families included in the study all contain three generations, we also determined what effect inclusion of generation in the model had on the age effects.

Results: When controlling the false-discovery rate at 1%, using GEE we identified 30 transcripts that showed significant differences in expression by sex, while 1950 transcripts showed differences in expression associated with age. When subjected to linkage analysis, there were 37 linkages that disappeared, while 17 appeared when sex was included as a covariate. All these genes were, as expected, on the sex chromosomes. In contrast, when age was included in the linkage analysis, 462 linkage signals were no longer significant, while 223 became significant. When generation was included in the model with age, all but 6 of the GEE age effects were no longer significant. However, there were minimal changes in the linkage results.

Conclusion: The effect of age on linkage analyses was apparent for the expression of many genes, which appear to be mostly due to differences between the generations.

No MeSH data available.