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Open Access Research article

Low-frequency intermediate penetrance variants in the ROCK1 gene predispose to Tetralogy of Fallot

Julian Palomino Doza1*, Ana Topf1, Jamie Bentham2, Shoumo Bhattacharya2, Catherine Cosgrove3, J David Brook3, Javier Granados-Riveron3, Frances A Bu’Lock4, John O’Sullivan5, A Graham Stuart6, Jonathan Parsons7, Caroline Relton1, Judith Goodship1, Deborah J Henderson1 and Bernard Keavney1

Author Affiliations

1 Institute of Genetic Medicine, Newcastle University, Newcastle, UK

2 Department of Cardiovascular Medicine, Oxford University, Oxford, UK

3 Institute of Genetics, Nottingham University, Nottingham, UK

4 University Hospitals of Leicester NHS Trust, Leicester, UK

5 Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK

6 Bristol Royal Hospital for Children, Bristol, UK

7 Leeds Teaching Hospitals NHS Trust, Leeds, UK

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BMC Genetics 2013, 14:57  doi:10.1186/1471-2156-14-57

Published: 19 June 2013

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.

Keywords:
Congenital heart disease; Tetralogy of fallot; Genetics; Planar cell polarity pathway