title: Low-frequency intermediate penetrance variants in the ROCK1 gene predispose to Tetralogy of Fallot.
abstract: BACKGROUND
  Epidemiological studies indicate a substantial excess familial recurrence of non-syndromic Tetralogy of Fallot (TOF), implicating genetic factors that remain largely unknown. The Rho induced kinase 1 gene (ROCK1) is a key component of the planar cell polarity signalling pathway, which plays an important role in normal cardiac development. The aim of this study was to investigate the role of genetic variation in ROCK1 on the risk of TOF.
  
  
  RESULTS
  ROCK1 was sequenced in a discovery cohort of 93 non-syndromic TOF probands to identify rare variants. TagSNPs were selected to capture commoner variation in ROCK1. Novel variants and TagSNPs were genotyped in a discovery cohort of 458 TOF cases and 1331 healthy controls, and positive findings were replicated in a further 209 TOF cases and 1290 healthy controls. Association between genotypes and TOF was assessed using LAMP.A rare SNP (c.807C > T; rs56085230) discovered by sequencing was associated with TOF risk (p = 0.006) in the discovery cohort. The variant was also significantly associated with the risk of TOF in the replication cohort (p = 0.018). In the combined cohorts the odds ratio for TOF was 2.61 (95% CI 1.58-4.30); p < 0.0001. The minor allele frequency of rs56085230 in the cases was 0.02, and in the controls it was 0.007. The variant accounted for 1% of the population attributable risk (PAR) of TOF. We also found significant association with TOF for an uncommon TagSNP in ROCK1, rs288979 (OR 1.64 [95% CI 1.15-2.30]; p = 1.5x10⁻⁵). The minor allele frequency of rs288979 in the controls was 0.043, and the variant accounted for 11% of the PAR of TOF. These association signals were independent of each other, providing additional internal validation of our result.
  
  
  CONCLUSIONS
  Low frequency intermediate penetrance (LFIP) variants in the ROCK1 gene predispose to the risk of TOF.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle, UK. julianpalomino@gmail.com
authors.forename: Julian
authors.initials: J
authors.lastname: Palomino Doza
authors.forename: Ana
authors.initials: A
authors.lastname: Topf
authors.forename: Jamie
authors.initials: J
authors.lastname: Bentham
authors.forename: Shoumo
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Catherine
authors.initials: C
authors.lastname: Cosgrove
authors.forename: J David
authors.initials: JD
authors.lastname: Brook
authors.forename: Javier
authors.initials: J
authors.lastname: Granados-Riveron
authors.forename: Frances A
authors.initials: FA
authors.lastname: Bu'Lock
authors.forename: John
authors.initials: J
authors.lastname: O'Sullivan
authors.forename: A Graham
authors.initials: AG
authors.lastname: Stuart
authors.forename: Jonathan
authors.initials: J
authors.lastname: Parsons
authors.forename: Caroline
authors.initials: C
authors.lastname: Relton
authors.forename: Judith
authors.initials: J
authors.lastname: Goodship
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Henderson
authors.forename: Bernard
authors.initials: B
authors.lastname: Keavney
mesh_terms: D016022:Case-Control Studies; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D013771:Tetralogy of Fallot / Q000235:genetics*; D054460:rho-Associated Kinases / Q000235:genetics*
chemical_list: C515851:ROCK1 protein, human; D054460:rho-Associated Kinases