Received on October 21, 2008
Accepted on January 30, 2009

Molecular Diagnostics and Genetics

Interindividual and Interethnic Variation in Genome-Wide Gene Expression: Insights into the Biological Variation of Gene Expression and Clinical Implications

¹ Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
² Departments of Chemical Pathology, and Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
³ Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
⁴ Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China, and Laboratory for Genetics of Disease Susceptibility, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China

^* To whom correspondence should be addressed. E-mail: nelsontang{at}cuhk.edu.hk.

BACKGROUND: Analysis of gene expression in peripheral blood samples is increasingly being applied in biomarker studies of disease diagnosis and prognosis. Although knowledge of interindividual and interethnic variation in gene expression is required to set ethnicity-specific reference intervals and to select reference genes and preferred markers from a list of candidate genes, few studies have attempted to characterize such biological variation on a genome-wide scale.

METHODS: The genome-wide expression profiles of 11 355 transcripts expressed among 210 multiethnic individuals of the HapMap project were obtained and analyzed; 4 replicates were included for each sample. The total biological CV in gene expression (CV_b) was partitioned into interindividual (CV_g), inter–ethnic group (CV_e), and residual components by random-effects mixed models.

RESULTS: CV_g was the major component of CV_b, and the differences among transcripts were large (up to 38%). Distinct groups of genes were characterized by CV values and expression levels. Of the genes with lowest biological variation (CV_b < 1.5%), 35 genes were highly expressed, whereas 32 had intermediate or low expression. Although CV_g was almost always greater than CV_e, we identified 10 genes in which ethnic variation predominated (range, 8%–18%). On the other hand, 17 annotated genes were highly variable with CV_g values ranging between 15% and 38%.

CONCLUSIONS: Genome-wide analysis of gene expression variation demonstrated biological differences among transcripts. Transcripts with the least biological variation are better candidates for reference genes, whereas those with low interindividual variation may be good disease markers. The presence of interethnic variation suggests that ethnicity-specific reference intervals may be necessary.