Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases1,2,3. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10−68; rs9388451, P = 5.1 × 10−17) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10−14). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10−81). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction4,5,6,7 can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development8. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.
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We thank L. Beekman, C. de Gier-de Vries, B. de Jonge and the Genomic Platform of Nantes (Biogenouest Genomics) for technical support. We are also grateful to the French Clinical Network against Inherited Cardiac Arrhythmias, which includes the University Hospitals of Nantes, Bordeaux, Rennes, Tours, Brest, Strasbourg, La Réunion, Angers and Montpellier. This study was funded by research grants from the Leducq Foundation (CVD-05; Alliance Against Sudden Cardiac Death), the Ministry of Education, Culture, Sports, Science and Technology of Japan (grant-in-aid for the Project in Sado for Total Health, PROST), the Ministry of Health, Labour and Welfare of Japan (research grant for cardiovascular diseases, H24-033),the French Ministry of Health (PHRC AOR04070, P040411 and PHRCI DGS2001/0248), INSERM (ATIP-Avenir program to R.R.) and the French Regional Council of Pays-de-la-Loire. This research was also supported by the Netherlands Heart Institute (grant 061.02 to C.A.R. and C.R.B.) and the Division for Earth and Life Sciences (ALW; project 836.09.003 to C.A.R.) with financial aid from the Netherlands Organization for Scientific Research (NWO). C.R.B. acknowledges support from the Netherlands Heart Foundation (NHS 2007B202 and 2009B066). J.B. was supported by a research grant from the European Society of Cardiology and the Netherlands Heart Institute (ICIN) and by the French-Dutch Academy through the Van Gogh program. E.S.-B. was supported by the Interdisziplinären Zentrums für Klinische Forschung (IZKF) of the University of Münster and the Collaborative Research Center SFB656. M.G. acknowledges support from the German Research Foundation (DFG-SFB 688 and TP A16). This manuscript is dedicated to the memory of Denis Escande, who founded the Leducq Foundation Network Alliance Against Sudden Cardiac Death.
The authors declare no competing financial interests.
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Bezzina, C., Barc, J., Mizusawa, Y. et al. Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Nat Genet 45, 1044–1049 (2013). https://doi.org/10.1038/ng.2712
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