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Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease

Nature Genetics volume 32, pages 237–244 (2002)Cite this article

Abstract

Genetic studies of Hirschsprung disease, a common congenital malformation, have identified eight genes with mutations that can be associated with this condition. Mutations at individual loci are, however, neither necessary nor sufficient to cause clinical disease. We conducted a genome-wide association study in 43 Mennonite family trios using 2,083 microsatellites and single-nucleotide polymorphisms and a new multipoint linkage disequilibrium method that searches for association arising from common ancestry. We identified susceptibility loci at 10q11, 13q22 and 16q23; the gene at 13q22 is EDNRB, encoding a G protein–coupled receptor (GPCR) and the gene at 10q11 is RET, encoding a receptor tyrosine kinase (RTK). Statistically significant joint transmission of RET and EDNRB alleles in affected individuals and non-complementation of aganglionosis in mouse intercrosses between Ret null and the Ednrb hypomorphic piebald allele are suggestive of epistasis between EDNRB and RET. Thus, genetic interaction between mutations in RET and EDNRB is an underlying mechanism for this complex disorder.

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Figure 1: Genomic structure and linkage disequilibrium at RET.
Figure 2: Acetylcholinesterase staining of whole-mount mouse intestinal tract.

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Acknowledgements

We thank previous and current members of the Chakravarti lab for their contributions to this study, helpful discussions and comments on this manuscript; J. Scott for invaluable help in family recruitment; and A. Lynn for map construction. This study was begun at the Department of Genetics of Case Western Reserve University and is a portion of the Ph.D. dissertation of M.M.C.

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Authors and Affiliations

  1. McKusick–Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Jefferson St. Bldg., 2-109, Baltimore, 21287, Maryland, USA

    Minerva M. Carrasquillo, Andrew S. McCallion, Carl S. Kashuk & Aravinda Chakravarti

  2. Clinic for Special Children, Strasburg, Pennsylvania, USA

    Erik G. Puffenberger

  3. Affymetrix, Inc., Santa Clara, California, USA

    Nassim Nouri

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  1. Minerva M. Carrasquillo
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  2. Andrew S. McCallion
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  3. Erik G. Puffenberger
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Correspondence to Aravinda Chakravarti.

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A.C. is a paid member of the Scientific Advisory Board of Affymetrix. The terms of this arrangement are being managed by Johns Hopkins University in accordance with its conflict of interest policies.

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Carrasquillo, M., McCallion, A., Puffenberger, E. et al. Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease. Nat Genet 32, 237–244 (2002). https://doi.org/10.1038/ng998

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