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Variants conferring risk of atrial fibrillation on chromosome 4q25


Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria1. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality2. Recent studies have provided evidence of a genetic contribution to AF3,4,5. Mutations in potassium-channel genes have been associated with familial AF6,7,8,9,10 but account for only a small fraction of all cases of AF11,12. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left–right asymmetry of the heart13,14,15.

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Figure 1: Diagram of the haplotype structure at the associated region.
Figure 2: Overview of a 200-kb genomic neighbourhood of rs2200733 and rs10033464.

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We thank the patients and their family members whose contribution made this work possible; the nurses at Noatun (deCODE’s sample recruitment center), personnel at the deCODE core facilities, and M. Shea for the ongoing enrolment of patients at Massachusetts General Hospital; and A. Plourde and S. Makino for technical assistance.

Author Contributions D.F.G., D.O.A., A.H., S.G., P.T.E., J.R. U.T. and K.S. wrote the first draft of the paper. D.O.A., H.H., R.S., J.T.S. and G.T. collected and diagnosed the Icelandic AF samples. Ko.K. and J.H. collected and diagnosed the Swedish samples. K.L.F., S.M.G., M.S., P.K., C.A.M., E.E.S., J.R. and P.T.E. collected and diagnosed the US samples. M.C.Y.N., L.B., W.Y.S., K.S.W., J.C.N.C. and R.C.W.M collected and diagnosed the Hong Kong samples. A.H., S.G., A.S., A.J., A.B., T.B., V.M.B., G.A.H. and E.P. performed genotyping and experimental work. D.F.G., G.T., A.P., P.S., A.H. and A.K. analyzed the data. D.F.G., D.O.A., A.H., S.G., Kr.K., J.R., J.H., R.C.W.M., P.T.E, G.T, J.R.G., A.K., U.T. and K.S. planned, supervised and coordinated the work. All authors contributed to the final version of the paper.

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Correspondence to Daniel F. Gudbjartsson or Kari Stefansson.

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Some of the authors own stock and/or stock options in deCODE genetics, Inc.

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This file contains Supplementary Methods, Supplementary Tables 1-9, Supplementary Figures 1-4 and additional references. (PDF 612 kb)

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Gudbjartsson, D., Arnar, D., Helgadottir, A. et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 448, 353–357 (2007).

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