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. 2013 Apr 1;22(7):1473-81.
doi: 10.1093/hmg/dds552. Epub 2013 Jan 7.

Genome-wide association study identifies loci on 12q24 and 13q32 associated with tetralogy of Fallot

Heather J Cordell  1 , Ana Töpf, Chrysovalanto Mamasoula, Alex V Postma, Jamie Bentham, Diana Zelenika, Simon Heath, Gillian Blue, Catherine Cosgrove, Javier Granados Riveron, Rebecca Darlay, Rachel Soemedi, Ian J Wilson, Kristin L Ayers, Thahira J Rahman, Darroch Hall, Barbara J M Mulder, Aelko H Zwinderman, Klaartje van Engelen, J David Brook, Kerry Setchfield, Frances A Bu'Lock, Chris Thornborough, John O'Sullivan, A Graham Stuart, Jonathan Parsons, Shoumo Bhattacharya, David Winlaw, Seema Mital, Marc Gewillig, Jeroen Breckpot, Koen Devriendt, Antoon F M Moorman, Anita Rauch, G Mark Lathrop, Bernard D Keavney, Judith A Goodship
Affiliations

Genome-wide association study identifies loci on 12q24 and 13q32 associated with tetralogy of Fallot

Heather J Cordell et al. Hum Mol Genet. .

Abstract

We conducted a genome-wide association study to search for risk alleles associated with Tetralogy of Fallot (TOF), using a northern European discovery set of 835 cases and 5159 controls. A region on chromosome 12q24 was associated (P = 1.4 × 10(-7)) and replicated convincingly (P = 3.9 × 10(-5)) in 798 cases and 2931 controls [per allele odds ratio (OR) = 1.27 in replication cohort, P = 7.7 × 10(-11) in combined populations]. Single nucleotide polymorphisms in the glypican 5 gene on chromosome 13q32 were also associated (P = 1.7 × 10(-7)) and replicated convincingly (P = 1.2 × 10(-5)) in 789 cases and 2927 controls (per allele OR = 1.31 in replication cohort, P = 3.03 × 10(-11) in combined populations). Four additional regions on chromosomes 10, 15 and 16 showed suggestive association accompanied by nominal replication. This study, the first genome-wide association study of a congenital heart malformation phenotype, provides evidence that common genetic variation influences the risk of TOF.

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Figures

Figure 1.
Figure 1.
Manhattan plots of the genome-wide association results. The top panel (PLINK results) shows the –log10 P-values from the Cochran–Armitage trend test (for autosomal SNPs) or logistic regression allowing for gender as a covariate (for X-chromosomal SNPs). The bottom panel (EMIM results) shows the −log10 P-values from the child trend test (autosomal SNPs only). Dashed lines are shown at significance thresholds for suggestive (P = 1 × 10−5) and significant (P = 5 × 10−8) association, respectively.
Figure 2.
Figure 2.
LocusZoom plots for the replicating loci on chromosomes 12 (PLINK results) and 13 (EMIM results). The colour coding indicates the degree of LD of each SNP with the named index SNP (shown as a purple diamond), as estimated from the HapMap CEU population.
See this image and copyright information in PMC

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