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Genome-wide genetic association of complex traits in heterogeneous stock mice

Abstract

Difficulties in fine-mapping quantitative trait loci (QTLs) are a major impediment to progress in the molecular dissection of complex traits in mice. Here we show that genome-wide high-resolution mapping of multiple phenotypes can be achieved using a stock of genetically heterogeneous mice. We developed a conservative and robust bootstrap analysis to map 843 QTLs with an average 95% confidence interval of 2.8 Mb. The QTLs contribute to variation in 97 traits, including models of human disease (asthma, type 2 diabetes mellitus, obesity and anxiety) as well as immunological, biochemical and hematological phenotypes. The genetic architecture of almost all phenotypes was complex, with many loci each contributing a small proportion to the total variance. Our data set, freely available at http://gscan.well.ox.ac.uk, provides an entry point to the functional characterization of genes involved in many complex traits.

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Change history

  • 04 August 2006

    In the supplementary information initially published online to accompany this article, Supplementary Table 1 contained numerous errors. The original file has been replaced with a corrected version of the table. The error has been corrected online.

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Acknowledgements

This work was supported by grants from The Wellcome Trust and the European Union (contract LHSG-CT-2003-503265). D.G. holds a Wellcome senior fellowship in basic biomedical science (057733). We are grateful to R. Hitzemann for providing heterogeneous stock mice, to M. Daly and R. Williams for help with SNP selection and to S. McCormick and A. Morris for comments on the manuscript.

Author information

The heterogeneous stock study was designed by J.F., R.M., W.O.C., L.C.S., D.G. and J.N.P.R. Phenotype and genotype assessments were performed by S.B., P.K., J.F. and L.C.S. W.V., M.S.T., J.F. and R.M. were responsible for the analysis. All authors contributed to the writing of the paper.

Competing interests

The authors declare no competing financial interests.

Correspondence to Richard Mott or Jonathan Flint.

Supplementary information

  1. Supplementary Figure 1

    Distribution of the number of genes contained within 50% confidence intervals of 843 QTLs. (PDF 113 kb)

  2. Supplementary Table 1

    QTLs with bootstrap posterior probabilities (BPP) values > 0.25 (XLS 356 kb)

  3. Supplementary Table 2

    Sex-specific QTLs (found by a genome scan for sex by genotype interaction) that exceed logP 5. (XLS 39 kb)

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Further reading

Figure 1: Fine-mapping of three phenotypes on chromosome 14.
Figure 2: QTL apparent effect sizes and total additive genetic variance.
Figure 3: Test for the presence of a diallelic QTL on chromosome 12.
Figure 4: Large-effect QTLs that suggest a small number of candidates for molecular cloning.