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  • Review Article
  • Published:

Mapping complex disease traits with global gene expression

Nature Reviews Genetics volume 10, pages 184–194 (2009)Cite this article

Key Points

  • Genome-wide association (GWA) studies have identified many new loci associated with human disease, but the association signals have yet to be translated into a proper understanding of which gene or genetic elements are mediating disease susceptibility at particular loci.

  • The functional effects of DNA polymorphism on multifactorial disease are infrequently mediated through mutations that alter protein function, and variation in gene expression is likely to be a more important mechanism underlying susceptibility to complex disease.

  • Transcript abundances of genes are directly modified by polymorphism in regulatory elements and transcript abundances can be considered as quantitative traits that can be mapped with considerable power. These have been named expression QTLs (eQTLs).

  • This Review explores the value of systematic identification of eQTLs as one means of characterizing the function of loci underlying complex disease traits.

  • The combination of whole-genome genetic association studies and measurement of global gene expression allows the systematic identification of eQTLs.

  • The resulting comprehensive eQTL maps provide an important source of reference for categorizing both cis and trans effects on disease-associated SNPs on gene expression.

  • In addition to providing information about the biological control of gene expression, such data aid in interpreting the results of GWA studies. The availability of systematically generated eQTL information provides immediate insight into a probable biological basis for the disease associations, and can help to identify networks of genes involved in disease pathogenesis.

  • First, we briefly introduce the principles and current methods of eQTL mapping and describe the basis of eQTLs. We then explore the relevance of these results to disease gene identification.

  • The limits of current eQTL mapping data are discussed, as is the expected impact of new technologies, international efforts to extend results to new samples and tissues and how cell lines might be tested with stimuli relevant to disease.

Abstract

Variation in gene expression is an important mechanism underlying susceptibility to complex disease. The simultaneous genome-wide assay of gene expression and genetic variation allows the mapping of the genetic factors that underpin individual differences in quantitative levels of expression (expression QTLs; eQTLs). The availability of systematically generated eQTL information could provide immediate insight into a biological basis for disease associations identified through genome-wide association (GWA) studies, and can help to identify networks of genes involved in disease pathogenesis. Although there are limitations to current eQTL maps, understanding of disease will be enhanced with novel technologies and international efforts that extend to a wide range of new samples and tissues.

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Figure 1: eQTL mapping.

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Acknowledgements

The work was supported by the Wellcome Trust and the EC funded GABRIEL project, the French Ministry of Research and Higher Education and by grants from the National Institutes of Health.

Author information

Authors and Affiliations

  1. National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK

    William Cookson & Miriam Moffatt

  2. Department of Biostatistics, Center for Statistical Genetics, SPH II, Ann Arbor, 48109-2029, Michigan, USA

    Liming Liang & Gonçalo Abecasis

  3. CEA / Centre National de Genotypage, Evry, 91057, France

    Mark Lathrop

Authors
  1. William Cookson
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  2. Liming Liang
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  3. Gonçalo Abecasis
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  4. Miriam Moffatt
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Correspondence to William Cookson, Liming Liang, Gonçalo Abecasis, Miriam Moffatt or Mark Lathrop.

Related links

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FURTHER INFORMATION

Liming Liang's homepage

Abecasis laboratory homepage (contains programs for genome-scale data analysis)

Catalog of Published Genome-Wide Association Studies

Database of Genomic Variants

dbSNP

D-HaploDB

Genotype-Tissue Expression (GTEx)

H-InvDB

mRNA by SNP Browser v 1.0.1

UniGene

VarySysDB

WaferGen

Glossary

Genome-wide association study

(GWA study). An examination of common genetic variation across the genome designed to identify associations with traits such as common diseases. Typically, several hundred thousand SNPs are interrogated using microarray or bead chip technologies.

Epigenetic

A mitotically stable change in gene expression that depends not on a change in DNA sequence, but on covalent modifications of DNA or chromatin proteins such as histones.

Heritability

(H2). The heritability of an individual trait is estimated by the ratio of genetic variance to total trait variance, so that 0 indicates no genetic effects on trait variance and 1 indicates that all variance is under genetic control.

Major histocompatibility complex

(MHC). A complex locus on chromosome 6p that comprises numerous genes, including the human leukocyte antigen genes, which are involved in the immune response.

Gene Ontology

(GO). A widely used classification system of gene functions and other gene attributes that uses a standardized vocabulary. The system uses a hierarchical organization of concepts (an ontology) with three organizing principles: molecular functions (the tasks done by individual gene products), biological processes (for example, mitosis) and cellular components (examples include the nucleus and the telomere).

Human leukocyte antigen

(HLA). A glycoprotein, encoded at the major histocompatibility complex locus, that is found on the surface of antigen-presenting cells and that present antigen for recognition by helper T cells.

Serial analysis of gene expression

(SAGE). A method for quantitative and simultaneous analysis of a large number of transcripts. Short sequence tags are isolated, concentrated and cloned; their sequencing reveals a gene expression pattern that is characteristic of the tissue or cell type from which the tags were isolated.

Additive genetic effects

A mechanism of quantitative inheritance such that the combined effects of genetic alleles at two or more gene loci are equal to the sum of their individual effects.

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Cookson, W., Liang, L., Abecasis, G. et al. Mapping complex disease traits with global gene expression. Nat Rev Genet 10, 184–194 (2009). https://doi.org/10.1038/nrg2537

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