Figure presents the distribution of heritability of 3354 expression phenotypes. The range of heritability is from 0 to 0.87 with an average of 0.22, suggesting a modest amount of genetic contribution to the expression level. The heritability distribution did not show clustering in chromosome regions, suggesting the inheritable expression phenotypes are randomly distributed across the genome.
The heritability distribution of 3354 gene expression phenotypes.
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 . 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
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. ). The correlation remains large (0.54) when we limited to the LOD scores with heritability less than 0.1.
19 gene expression phenotypes with genome-wide significant linkage evidence after correcting for multiple tests
We next examined how many genes fall in the 1-LOD drop linkage region of its corresponding expression phenotype. The average width of the 1-LOD drop linkage region was 8.8 cM. Among the 197 regions with LOD scores > 3.3, only five genes fell in the 1-LOD drop region of the corresponding gene expression phenotype, indicating that the majority of the expression phenotypes are regulated by other genes. Morley et al. identified several master regulators of expression phenotypes through use of linkage evidence. We performed similar analyses by dividing the autosomal genome into 331 windows of 8.8-cM intervals and counted the number of linkage peaks falling in each window among the 197 linkage peaks. We identified five windows with over five hits and these windows are presented in Table . We calculated the probability of observing five or more hits per window using the same method described in Morley et al., and the probability is less than 0.00038. When the critical LOD score was increased to 4.0, we observed 81 linkage peaks and two windows with over four hits. The probability of four or more hits per window is less than 0.00012, assuming 81 linkage peaks randomly distributed. This suggested the possible existence of master regulators of transcription. We observed three hits in the hot spot region on chromosome 20 reported by Morley et al. when using the LOD > 3.3. However, the hot spot on chromosome 14 observed by Morley et al. [2
] was not represented in our analysis. We did not observe any hot spots when the critical LOD score was increased to 5.3.
Hotspots of transcriptional regulation