Human Molecular Genetics Advance Access published online on October 26, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi404
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1 Department of Genetic Medicine and Development, Geneva University Medical School, 1 Rue Michel Servet, Geneva, Switzerland
* To whom correspondence should be addressed. Inter-individual differences in gene expression are likely to account for an important fraction of phenotypic differences, including susceptibility to common disorders. Recent studies have shown extensive variation in gene expression levels in humans and other organisms, and that a fraction of this variation is under genetic control. We investigated the patterns of gene expression variation in a 25 Mb region of human chromosome 21 that has been associated with many Down syndrome phenotypes. Taqman real-time PCR was used to measure expression variation of 41 genes in lymphoblastoid cells of 40 unrelated individuals. For 25 genes found to be differentially expressed, additional analysis was performed in 10 CEPH families to determine heritabilities and map loci harboring regulatory variation. Seventy-six percent of the differentially expressed genes had significant heritabilities, and genome-wide linkage analysis led to the identification of significant eQTLs for 9 genes. Most eQTLs were in trans, with the best result (p = 7.46x10-8) obtained for TMEM1 on chromosome 12q24.33. A cis eQTL identified for CCT8 was validated by performing an association study in 60 individuals from the HapMap project. SNP rs965951 located within CCT8 was found to be significantly associated with its expression levels (p = 2.5x10-5) confirming cis regulatory variation. The results of our study provide a representative view of expression variation of chromosome 21 genes, identify loci involved in their regulation, and suggest that genes for which expression differences are significantly larger than 1.5-fold in control samples, are unlikely to be involved in DS-phenotypes present in all affected individuals.
Revised October 13, 2005
Accepted October 19, 2005
Article
Gene Expression Variation and Expression Quantitative Trait (eQTL) Mapping of Human Chromosome 21 Genes
2 Population and comparative genomics group, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK
3 School of Medicine, University of Massachusetts, 55 Lake Avenue North, Worcester, Massachusetts
4 Vital-IT Centre, Swiss Institute of Bioinformatics, Lausanne, Switzerland
5 Vital-IT Centre, Swiss Institute of Bioinformatics, Lausanne, Switzerland; Ludwig Institute for Cancer Research, Office of Information Technology, Ch. des Boveresses 155 Epalinges, Switzerland
6 Department of Genetic Medecine and Development, Geneva University Medical School, 1 Rue Michel Servet, CH-1211, Geneva, Switzerland
Stylianos E. Antonarakis, E-mail: Stylianos.Antonarakis{at}medecine.unige.ch
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