1. McKusick – Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
2. Genome Technology Branch and
3. NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
4. These authors contributed equally to this work

Correspondence to: Aravinda Chakravarti¹ Correspondence and requests for materials should be addressed to A.C. (Email: aravinda@jhmi.edu).
GenBank accession numbers for genomic sequences reported in this paper are as follows: AC125509 and AC125512 (baboon), AC124166 (cat), AC138567 (chicken), RP43-171H18 (chimpanzee), AC124163 and AC124164 (cow), AC123973 (dog), AC124911 and AC125500 (fugu), AC122156 and AC124165 (pig), AC114881 (rat), AC135546 (tetra) and AC124155 (zebrafish).

Abstract

The identification of common variants that contribute to the genesis of human inherited disorders remains a significant challenge. Hirschsprung disease (HSCR) is a multifactorial, non-mendelian disorder in which rare high-penetrance coding sequence mutations in the receptor tyrosine kinase RET contribute to risk in combination with mutations at other genes. We have used family-based association studies to identify a disease interval, and integrated this with comparative and functional genomic analysis to prioritize conserved and functional elements within which mutations can be sought. We now show that a common non-coding RET variant within a conserved enhancer-like sequence in intron 1 is significantly associated with HSCR susceptibility and makes a 20-fold greater contribution to risk than rare alleles do. This mutation reduces in vitro enhancer activity markedly, has low penetrance, has different genetic effects in males and females, and explains several features of the complex inheritance pattern of HSCR. Thus, common low-penetrance variants, identified by association studies, can underlie both common and rare diseases.

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