Human Molecular Genetics Advance Access originally published online on October 26, 2005
Human Molecular Genetics 2005 14(23):3741-3749; doi:10.1093/hmg/ddi404
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Gene expression variation and expression quantitative trait mapping of human chromosome 21 genes
1Department of Genetic Medicine and Development, Geneva University Medical School, 1 Rue Michel Servet, CH-1211 Geneva, Switzerland, 2Population and comparative genomics group, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK, 3Vital-IT Centre, Swiss Institute of Bioinformatics, Lausanne, Switzerland, 4Ludwig Institute for Cancer Research, Office of Information Technology, Ch. des Boveresses 155 Epalinges, Switzerland and 5School of Medicine, University of Massachusetts, 55 Lake Avenue North, Worcester, MA, USA
* To whom correspondence should be addressed. Tel: +41 223795708; Fax: +41 223795706; Email: stylianos.antonarakis{at}medecine.unige.ch
Received August 9, 2005; Accepted October 19, 2005
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, which has been associated with many Down syndrome (DS) 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 genomewide linkage analysis led to the identification of significant eQTLs for nine 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.
These authors equally contributed to this study.
Present address: EPAM, Norwegian Institute of Public Health, Oslo, Norway.
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