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Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes

Nature Genetics volume 39, pages 1208–1216 (2007)Cite this article

Abstract

Quantitative differences in gene expression are thought to contribute to phenotypic differences between individuals. We generated genome-wide transcriptional profiles of lymphocyte samples from 1,240 participants in the San Antonio Family Heart Study. The expression levels of 85% of the 19,648 detected autosomal transcripts were significantly heritable. Linkage analysis uncovered >1,000 cis-regulated transcripts at a false discovery rate of 5% and showed that the expression quantitative trait loci with the most significant linkage evidence are often located at the structural locus of a given transcript. To highlight the usefulness of this much-enlarged map of cis-regulated transcripts for the discovery of genes that influence complex traits in humans, as an example we selected high-density lipoprotein cholesterol concentration as a phenotype of clinical importance, and identified the cis-regulated vanin 1 (VNN1) gene as harboring sequence variants that influence high-density lipoprotein cholesterol concentrations.

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Figure 1
Figure 2: Identification of VNN1 (vanin 1) as an HDL-C (high-density lipoprotein cholesterol) candidate gene and association analysis of VNN1 promoter variants and VNN1 transcript abundance.
Figure 3: EMSA (electrophoretic mobility shift assay) analysis of the VNN1 (vanin 1) −137 polymorphism and surrounding sequences.

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Acknowledgements

We are grateful to the participants in the San Antonio Family Heart Study. Data collection was supported by a grant from the US National Institute for Heart, Lungs and Blood (HL045222). A donation from the Azar and Shepperd families paid for the transcriptional profiling. Additional funds for transcriptional profiling, sequencing, genotyping and statistical analysis were provided by ChemGenex Pharmaceuticals. The SOLAR statistical genetics computer package is supported by a grant from the US National Institute of Mental Health (MH059490). The supercomputing facilities used for this work at the AT&T Genetics Computing Center were supported in part by a gift from the SBC Foundation. The laboratory work was carried out in facilities that were constructed with support from the US National Center for Research Resources (RR013556).

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Authors and Affiliations

  1. Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, 78245, Texas, USA

    Harald H H Göring, Joanne E Curran, Matthew P Johnson, Thomas D Dyer, Jac Charlesworth, Shelley A Cole, David L Rainwater, Anthony G Comuzzie, Michael C Mahaney, Laura Almasy, Jean W MacCluer, Eric K Moses & John Blangero

  2. International Diabetes Institute, Caulfield, 3162, Victoria, Australia

    Jeremy B M Jowett

  3. ChemGenex Pharmaceuticals, Geelong, 3216, Victoria, Australia

    Jeremy B M Jowett, Gregory R Collier & John Blangero

  4. School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Crawley, 6009, Western Australia, Australia

    Lawrence J Abraham

  5. TOPS Center for Obesity and Metabolic Research, Medical College of Wisconsin, Milwaukee, 53226, Wisconsin, USA

    Ahmed H Kissebah

  6. Metabolic Research Unit, School of Health Sciences, Deakin University, Waurn Ponds, 3216, Victoria, Australia

    Gregory R Collier

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Contributions

J.B., E.K.M. and G.R.C. initiated the study. H.H.H.G. and J.B. performed or supervised all aspects of the statistical analysis and were aided by T.D.D. and J.C. E.K.M., J.E.C. and L.J.A. were responsible for all molecular analyses, including transcriptional profiles, resequencing, SNP typing and functional analysis, with aid from M.P.J. J.B., J.W.M., M.C.M., A.G.C., and L.A. were responsible for the Mexican American family samples. S.A.C. and J.B. were responsible for the 10-cM STR typing. D.L.R. was responsible for the HDL-C measurement. J.B.M.J. and J.C. performed bioinformatic analyses. A.H.K. and G.R.C. provided additional biological interpretation.

Corresponding author

Correspondence to Harald H H Göring.

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Competing interests

Funds for resequencing, genotyping, transcriptional profiling, and statistical analyses were provided in part by ChemGenex Pharmaceuticals. G.R.C. has personal financial interests in ChemGenex. G.R.C. is also the Chief Executive Officer and Managing Director of ChemGenex. J.B. is a member of the Scientific Advisory Board of ChemGenex. J.B. also serves as Senior Director of Human Genomics.

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Supplementary Tables 1–3,5 and Supplementary Figure 1 (PDF 290 kb)

Supplementary Table 4

Heritability estimates, cis lod scores and maximum trans lod scores for all transcripts (XLS 1684 kb)

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Göring, H., Curran, J., Johnson, M. et al. Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes. Nat Genet 39, 1208–1216 (2007). https://doi.org/10.1038/ng2119

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