title: Population variation in total genetic risk of Hirschsprung disease from common RET, SEMA3 and NRG1 susceptibility polymorphisms.
abstract: The risk of Hirschsprung disease (HSCR) is ∼15/100 000 live births per newborn but has been reported to show significant inter-individual variation from the effects of seven common susceptibility alleles at the RET, SEMA3 and NRG1 loci. We show, by analyses of these variants in 997 samples from 376 HSCR families of European ancestry, that significant genetic risk can only be detected at RET (rs2435357 and rs2506030) and at SEMA3 (rs11766001), but not at NRG1. RET rs2435357 also showed significant frequency differences by gender, segment length of aganglionosis and familiality. Further, in combination, disease risk varied >30-fold between individuals with none and up to 6 susceptibility alleles. Thus, these polymorphisms can be used to stratify the newborn population into distinct phenotypic classes with defined risks to understand HSCR etiology.
authors: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Ashish
authors: A
authors: Kapoor
authors: Department of Medical Genetics, Capital Institute of Pediatrics, Beijing 100020, China and.
authors: Qian
authors: Q
authors: Jiang
authors: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Sumantra
authors: S
authors: Chatterjee
authors: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA, Indian Statistical Institute, Kolkata, West Bengal 700108, India.
authors: Prakash
authors: P
authors: Chakraborty
authors: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Maria X
authors: MX
authors: Sosa
authors: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Courtney
authors: C
authors: Berrios
authors: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA, aravinda@jhmi.edu.
authors: Aravinda
authors: A
authors: Chakravarti
mesh_terms: D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D020890:Neuregulin-1 / Q000235:genetics*; D011110:Polymorphism, Genetic; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D012307:Risk Factors; D040121:Semaphorin-3A / Q000235:genetics*; D012737:Sex Factors; D044465:White People / Q000235:genetics
chemical_list: C094131:NRG1 protein, human; D020890:Neuregulin-1; C108639:SEMA3A protein, human; D040121:Semaphorin-3A; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human