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Figure 11.4 Genome-wide association for gene expression phenotypes. Genome-wide association chromosomal plot for LRAP and AA827892 together with higher resolution plots showing superimposed association (bars) and linkage analysis (dashed lines) with target genes indicated by arrow heads. Reprinted by permission from Macmillan Publishers Ltd: Nature (Cheung et at 2005), copyright 2005.

available for interrogation, which remained modest for each population, namely 60 cell lines established from unrelated individuals of European descent (CEU), 60 of African (YRI) ancestry, 45 of Chinese (CHB) ancestry, and 45 of Japanese (JPT) ancestry, giving a total of 210 lymphoblastoid cell lines analysed in this study (Stranger et al. 2007b).

For the association study, 2.2 million common SNPs with a minor allele frequency greater than 5% were used to determine eQTLs for 13 643 genes in lymphoblastoid cell lines for each of the four populations (Stranger et al. 2007b). Reassuringly, for the 60 CEU individuals there was a significant correlation with the results of their earlier study of a limited number of genes with different RNA samples (Stranger et al. 2005). In the current genome-wide analysis, 299 genes in the CEU panel of lymphoblastoid cell lines showed significant local, likely c/s-acting associations where only 14 would be expected by chance; the definition of c/s-acting used here was based on SNP markers lying within 1 Mb of the centre of the transcriptional unit whose expression levels were analysed (Stranger et al. 2007b). Across all the populations, a total of 1348 genes showed significant local eQTLs of which 37% were found in at least two populations (Stranger et al. 2007b). In almost all cases of shared associations between populations, the direction of allelic difference in expression was the same. Local eQTLs were found to predominantly occur very close to the transcriptional start site and more often than expected within evolutionarily conserved sequences (Stranger et al. 2007b).

Population differences in gene expression have been characterized by other investigators using HapMap (Frazer et al. 2007) and other sources of lymphoblastoid cell li nes (Hinds et al. 2005). Spielman and colleagues found that for 4197 genes analysed and expressed in these lines, 25% were significantly different between lines of European ancestry compared to those of Asian descent (Spielman et al. 2007). Underlying allele frequency differences between the populations accounted for many of these differences in expression when a small number of the expression phenotypes were characterized more fully. For example, a high producer allele for a SNP of POMZP3 was much more frequent in Europeans than East Asians, accounting for the observed population differences in expression (Fig. 11.5) (Spielman et al. 2007). As a further example, the UGT2B17 gene showed significant differences in gene expression between European ancestry and East Asian populations consistent with previous data showing population-specific copy number variation for this gene (Wilson et al. 2004; McCarroll et al. 2006; Xue et al. 2008). UGT2B17 at chromosome 4q13 encodes an enzyme involved in steroid metabolism and is subject to a 117 kb deletion

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