Common variants in KCNN3 are associated with lone atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 × 10−12), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40–1.64; P = 1.83 × 10−21). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

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Figure 1: Manhattan plot of meta-analysis results for genome-wide association to lone AF.
Figure 2: Regional plot for locus on chromosome 1 associated with lone atrial fibrillation.

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Acknowledgements

Acknowledgements are contained in the Supplementary Note.

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Authors

Contributions

Study concept and design: P.T.E., K.L.L., N.L.G., A.P., M.K.C., A.A., J.C.M.W., D.E.A., E.J.B., S.R.H. and S.K.

Acquisition of data: P.T.E., K.L.L., N.L.G., A.P., A.A., M.K.C., M.F.S., P.I.W.d.B., M.M., S.A.L., E.F., D.D., N.L.S., J.D.S., R.B.S., E.Z.S., K.M.R., D.R.V.W., B.-M.B, C.v.N., K.W., G.B.E., J.I.R., S.L.H., G.S., A.V.S., L.J.L., T.B.H., S.M., M.N., D.J.M., S.P., T.E., S.M., C.N.-C., M.L., S.M., K.W., T.J.W., W.H.L.K., E.B., V.G., B.M.P., J.C.M.W., J.B., D.E.A., E.J.B., S.R.H. and S.K.

Analysis and interpretations of data: K.L.L., N.L.G., A.P., M.M., J.B., D.E.A. and K.W.

Drafting of the manuscript: P.T.E., K.L.L., E.J.B., S.R.H. and S.K.

Critical revision of the manuscript for important intellectual content: K.L.L., N.L.G., A.P., A.A., M.K.C., M.F.S., P.I.W.d.B., M.M., S.A.L., E.F., D.D., N.L.S., J.D.S., R.B.S., E.Z.S., K.M.R., D.R.V.W., B.-M.B., C.v.N., K.W., G.B.E., S.L.H., G.S., A.V.S., L.J.L., T.B.H., S.M., M.M.N., D.J.M., S.P., T.E., A.K., S.M., C.N.-C., M.L., S.M.,T.J.W., W.H.L.K., R.S.V., M.N., C.A.M., B.H.C.S., A.H., A.G.U., D.L., E.B., A.M., E.J.T., A.C., V.G., B.M.P., D.M.R., T.M., H.-E.W., J.C.M.W., J.B., D.E.A., E.J.B. and S.R.H.

Statistical analysis: K.L.L., N.L.G., A.P., M.M., J.B., D.E.A. and K.W.

Obtained funding: P.T.E., A.P., A.A., M.K.C., M.F.S., P.I.W.d.B., M.M., S.A.L., E.F., N.L.S., J.D.S., K.M.R., D.R.V.W., J.I.R., S.L.H., S.M., B.H.Ch.S., A.H., A.G.U., D.L., E.B., A.M., E.J.T., A.C., V.G., B.M.P., D.M.R., T.M., J.C.M.W., J.B., D.E.A., E.J.B., S.R.H. and S.K.

Study supervision: P.T.E., K.L.L., N.L.G., A.P., A.A., M.K.C., M.F.S., J.C.M.W., J.B., D.E.A., E.J.B., S.R.H. and S.K.

P.T.E., K.L.L., N.L.G., A.P., A.A., M.K.C., M.F.S., J.C.M.W., J.B., D.E.A., E.J.B., S.R.H. and S.K. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding authors

Correspondence to Patrick T Ellinor or Stefan Kääb.

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Competing interests

A.C. is a paid member of the Scientific Advisory Board of Affymetrix, a role that is managed by the Committee on Conflict of Interest of the Johns Hopkins University School of Medicine.

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Supplementary Note, Supplementary Tables 1–3 and Supplementary Figures 1 and 2 (PDF 998 kb)

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Ellinor, P., Lunetta, K., Glazer, N. et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet 42, 240–244 (2010). https://doi.org/10.1038/ng.537

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