A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk.
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.
Emison
Eileen Sproat
ES
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
McCallion
Andrew S
AS
Kashuk
Carl S
CS
Bush
Richard T
RT
Grice
Elizabeth
E
Lin
Shin
S
Portnoy
Matthew E
ME
Cutler
David J
DJ
Green
Eric D
ED
Chakravarti
Aravinda
A
D000818:Animals; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D023281:Genomics; D006239:Haplotypes; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012727:Sex Characteristics
D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C494999:Ret protein, mouse