A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk

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. Hirschsprung disease is a rare congenital bowel disorder in which the ganglion cells that control the bowel''s rhythmic contractions are missing. The disease runs in families and affects boys more often than girls, but it has a complex inheritance pattern. Now by merging data from comparative genomics and haploid mapping it has been possible to localize a common non-coding mutation in the gene for the receptor tyrosine kinase RET. This allele is relatively common in the general population and causes Hirschsprung disease only in the presence of additional mutations. The techniques used in this study should lend themselves to unravelling the nature of other complex diseases.