Abstract
BackgroundEpidemiological 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.ResultsROCK1 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.ConclusionsLow frequency intermediate penetrance (LFIP) variants in the ROCK1 gene predispose to the risk of TOF.
Highlights
Epidemiological studies indicate a substantial excess familial recurrence of non-syndromic Tetralogy of Fallot (TOF), implicating genetic factors that remain largely unknown
We explored the involvement of both low frequency and common genetic variation in Rho induced kinase 1 gene (ROCK1) on the risk of TOF in a case/control study
Novel low frequency variants Three variants undescribed at the time of the sequencing study were found in screening of the first 26 exons of ROCK1 in 93 TOF probands
Summary
Epidemiological studies indicate a substantial excess familial recurrence of non-syndromic Tetralogy of Fallot (TOF), implicating genetic factors that remain largely unknown. Recurrence risk studies in the remaining ~80% of “sporadic” cases indicate a significant familial predisposition, implicating genetic factors [2,3]. Very rare or private variants in candidate genes such as Nkx2.5 and Tbx have been shown in previous studies to account for small proportions of the population attributable risk of TOF [4,5]. Association between rare copy number variants [6,7] and between commoner genetic variation and TOF has been demonstrated [8] but the associations discovered so far account for only a small proportion of the estimated heritability of the condition
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