title: Hypospadias and genes related to genital tubercle and early urethral development.
abstract: OBJECTIVE
  We determined whether variants in genes associated with genital tubercle (the anlage for the penis) and early urethral development were associated with hypospadias in humans.
  
  
  METHODS
  We examined 293 relatively common tag single nucleotide polymorphisms in BMP4, BMP7, FGF8, FGF10, FGFR2, HOXA13, HOXD13, HOXA4, HOXB6, SRY, WT1, WTAP, SHH, GLI1, GLI2 and GLI3. The analysis included 624 cases (81 mild, 319 moderate, 209 severe, 15 undetermined severity) and 844 population based nonmalformed male controls born in California from 1990 to 2003.
  
  
  RESULTS
  There were 28 single nucleotide polymorphisms for which any of the comparisons (ie overall or for a specific severity) had a p value of less than 0.01. The homozygous variant genotypes for 4 single nucleotide polymorphisms in BMP7 were associated with at least a twofold increased risk of hypospadias regardless of severity. Five single nucleotide polymorphisms for FGF10 were associated with threefold to fourfold increased risks, regardless of severity. For 4 of them the results were restricted to whites. For GLI1, GLI2 and GLI3 there were 12 associated single nucleotide polymorphisms but results were inconsistent by severity and race/ethnicity. For SHH 1 single nucleotide polymorphism was associated with a 2.4-fold increased risk of moderate hypospadias. For WT1 6 single nucleotide polymorphisms were associated with approximately a twofold increased risk, primarily for severe hypospadias.
  
  
  CONCLUSIONS
  This study provides evidence that single nucleotide polymorphisms in several genes that contribute to genital tubercle and early urethral development are associated with hypospadias risk.
authors.affiliation: Department of Pediatrics, Division of Neonatology, Stanford University School of Medicine, Stanford, California. Electronic address: scarmichael@stanford.edu.
authors.forename: Suzan L
authors.initials: SL
authors.lastname: Carmichael
authors.forename: Chen
authors.initials: C
authors.lastname: Ma
authors.forename: Shweta
authors.initials: S
authors.lastname: Choudhry
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lammer
authors.forename: John S
authors.initials: JS
authors.lastname: Witte
authors.forename: Gary M
authors.initials: GM
authors.lastname: Shaw
mesh_terms: D016022:Case-Control Studies; D006801:Humans; D007021:Hypospadias / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D010413:Penis / Q000254:growth & development*; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D014521:Urethra / Q000254:growth & development*
keywords: BPA; British Pediatric Association; MAF; SNP; genes; hypospadias; minor allele frequency; penis; single nucleotide polymorphism; urethra