Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility

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Abstract

A genome-wide association scan in individuals with Crohn's disease by the Wellcome Trust Case Control Consortium detected strong association at four novel loci. We tested 37 SNPs from these and other loci for association in an independent case-control sample. We obtained replication for the autophagy-inducing IRGM gene on chromosome 5q33.1 (replication P = 6.6 × 10−4, combined P = 2.1 × 10−10) and for nine other loci, including NKX2-3, PTPN2 and gene deserts on chromosomes 1q and 5p13.

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Figure 1: Associated region at IRGM.

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Acknowledgements

We acknowledge use of DNA from the 1958 British Birth Cohort collection (R. Jones, S. Ring, W. McArdle and M. Pembrey), funded by the UK MRC (grant G0000934) and The Wellcome Trust (grant 068545/Z/02). We also acknowledge the National Association for Colitis and Crohn's disease and the Wellcome Trust for supporting the case DNA collections and UCB Pharma for supporting this study with an unrestricted educational grant. We thank D. Kelberman, all subjects who contributed samples and consultants and nursing staff across the UK who helped with recruitment of study subjects.

Author information

M.P., J.S., J.C.M., D.P.J. and C.G.M. are principal investigators for the five participating centers; E.R.N., C.B. and P.D. did DNA extraction, normalization and quality control; W.M. and D.S. supplied control DNA samples; M.T., F.R.C., H.D., C.W.L., S.A.K., C.E.T., T.A., C.M.O., A.F. and J.S. recruited study subjects and extracted phenotype data; N.J.P., R.G.R., R.B., D.A.B. undertook genotyping and sequence analysis and G.B. performed expression analysis; J.C.B., C.A.A., S.A.F., C.M.L. and L.C. undertook the statistical analysis; WTCCC provided initial data for Crohn's disease and other case-control panels and M.P., J.C.B. and C.G.M. wrote the manuscript. Members of the WTCCC are listed in the Supplementary Note online.

Correspondence to Miles Parkes.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Details of Crohn's disease cases. (PDF 18 kb)

Supplementary Table 2

SNPs with converging allele frequencies. (PDF 35 kb)

Supplementary Table 3

SNP genotype call rates. (PDF 28 kb)

Supplementary Table 4

SNP genotype counts. (PDF 33 kb)

Supplementary Table 5

IRGM resequencing primers. (PDF 14 kb)

Supplementary Table 6

Association with Crohn's disease subphenotypes. (PDF 24 kb)

Supplementary Methods (PDF 18 kb)

Supplementary Note (PDF 58 kb)

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