Mapping with Expression DOI: 10.1038/Nrg2214 in Recent Years, Several Studies Have of a Novel Candidate Gene, Vanin 1 270 Participants in the Hapmap

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H U m an genetics Mapping with expression DOI: 10.1038/nrg2214 In recent years, several studies have of a novel candidate gene, vanin 1 270 participants in the HapMap. made inroads into the genetic control (VNN1) for heart disease. Their results show not only a large of gene expression, showing that Although the study by Göring number of cis associations of gene transcript abundance for individual et al. examines a large number of expression with particular SNPs, genes can be treated as heritable individuals, the use of a relatively but also confirm previous findings quantitative traits. Although this small set of microsatellite markers on significant differences between work promises to improve our limits the mapping resolution populations. Finally, the density of understanding of gene regulation, the of the individual eQTLs. By con- genotyped SNPs allowed the authors published work has been limited by trast, the two other new studies to map many of the associations to relatively small sample sizes, incom- use genome-wide SNP association. regions very close to the transcrip- plete coverage of the genome, and the In the study by William Cookson tional start sites of genes, in regions use of transformed cells. Three new and colleagues, transcript levels of highly conserved sequence. papers address these shortcomings from more than 20,000 genes in All told, these studies provide the in a complementary fashion, and lymphoblastoid cell lines were most comprehensive view yet of provide a more complete picture of associated with more than 400,000 the abundant cis-regulatory varia- so-called ‘expression QTLs’ (eQTLs). SNPs that had been genotyped in tion in the human genome. In Although the use of cell lines has 400 children as part of a study of concert with genome-wide associa- obvious advantages, it is also possible asthma. In addition to generating tion studies of disease, they should that transcription in such cells does a rich resource of SNPs associated provide powerful aids to under- not represent the natural state of with transcript abundance, available standing how disease susceptibility gene expression. Harald Göring and at the downloadable mRNA by SNP varies among individuals. colleagues addressed this potential Browser, this effort also shows how Alan Packer, Senior Editor, problem by carrying out genome- such a resource can be leveraged Nature Genetics wide transcriptional profiling of to pinpoint variants that might be ORIGINAL RESEARCH PAPERS freshly isolated lymphocytes from involved in asthma as well as other Göring, H. H. et al. Discovery of expression QTLs more than 1,200 participants in the diseases. For example, a 206-kb using large-scale transcriptional profiling in San Antonio Family Heart Study susceptibility locus for asthma was human lymphocytes. Nature Genet. 16 September 2007 (doi:10.1038/ng2119) | Dixon, A. L. et al. (previous eQTL studies had typically found to harbour highly associated A genome-wide association study of global gene been done in 100–200 individuals). SNPs that were also associated with expression. Nature Genet. 16 September 2007 They confirmed the broad, if mod- expression levels of ORM1-like 3 (doi:10.1038/ng2109) | Stranger, B. E. et al. Population genomics of human gene expression. est, heritability of most transcript (ORMDL3; see Further Reading), Nature Genet. 16 September 2007 (doi: 10.1038/ levels, and proceeded to carry out suggesting that cis-regulatory vari- ng2142) FURTHER READING Moffatt, M. F. et al. linkage analysis of all transcripts ation in this gene is associated with Genetic variants regulating ORMDL3 expression with 432 highly polymorphic risk of asthma. contribute to the risk of childhood asthma. microsatellite markers. More than Finally, Emmanouil Dermitzakis Nature 448, 470–473 (2007) WEB SITES 1,300 cis-regulated transcripts and colleagues carried out a San Antonio Family Heart Study: http://www. were identified, with the strength genome-wide association study of sfbr.org/pages/genetics_projects.php?p=24 of cis-regulation correlating with gene expression using 2.2 million GENEVAR project: http://www.sanger.ac.uk/humgen/genevar transcript heritability. Correlations SNPs derived from phase II of the mRNA by SNP Browser: between cis-regulated transcripts and International HapMap Project, and http://www.sph.umich.edu/csg/liang/asthma/ International HapMap Project: high-density lipoprotein (HDL) cho- transcriptional profiles of lympho http://www.hapmap.org/ lesterol levels led to the identification blastoid cell lines derived from all