Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Variants conferring risk of atrial fibrillation on chromosome 4q25

Abstract

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.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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

References

  1. 1

    Go, A. S. et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. J. Am. Med. Assoc. 285, 2370–2375 (2001)

    CAS  Article  Google Scholar 

  2. 2

    Miyasaka, Y. et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 114, 119–125 (2006)

    Article  Google Scholar 

  3. 3

    Arnar, D. O. et al. Familial aggregation of atrial fibrillation in Iceland. Eur. Heart J. 27, 708–712 (2006)

    Article  Google Scholar 

  4. 4

    Fox, C. S. et al. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. J. Am. Med. Assoc. 291, 2851–2855 (2004)

    CAS  Article  Google Scholar 

  5. 5

    Ellinor, P. T., Yoerger, D. M., Ruskin, J. N. & MacRae, C. A. Familial aggregation in lone atrial fibrillation. Hum. Genet. 118, 179–184 (2005)

    Article  Google Scholar 

  6. 6

    Chen, Y. H. et al. KCNQ1 gain-of-function mutation in familial fibrillation. Science 299, 251–254 (2003)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Yang, Y. et al. Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation. Am. J. Hum. Genet. 75, 899–905 (2004)

    CAS  Article  Google Scholar 

  8. 8

    Xia, M. et al. A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation. Biochem. Biophys. Res. Commun. 332, 1012–1019 (2005)

    CAS  Article  Google Scholar 

  9. 9

    Olson, T. M. et al. Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum. Mol. Genet. 15, 2185–2191 (2006)

    CAS  Article  Google Scholar 

  10. 10

    Hong, K., Bjerregaard, P., Gussak, I. & Brugada, R. Short QT syndrome and atrial fibrillation caused by mutation in KCNH2. J. Cardiovasc. Electrophysiol. 16, 394–396 (2005)

    Article  Google Scholar 

  11. 11

    Ellinor, P. T. et al. Mutations in the long QT gene, KCNQ1, are an uncommon cause of atrial fibrillation. Heart 90, 1487–1488 (2004)

    CAS  Article  Google Scholar 

  12. 12

    Ellinor, P. T., Petrov-Kondratov, V. I., Zakharova, E., Nam, E. G. & MacRae, C. A. Potassium channel gene mutations rarely cause atrial fibrillation. BMC Med. Genet. 7, 70 (2006)

    Article  Google Scholar 

  13. 13

    Franco, D. & Campione, M. The role of Pitx2 during cardiac development. Linking left–right signaling and congenital heart diseases. Trends Cardiovasc. Med. 13, 157–163 (2003)

    CAS  Article  Google Scholar 

  14. 14

    Faucourt, M., Houliston, E., Besnardeau, L., Kimelman, D. & Lepage, T. The pitx2 homeobox protein is required early for endoderm formation and nodal signaling. Dev. Biol. 229, 287–306 (2001)

    CAS  Article  Google Scholar 

  15. 15

    Mommersteeg, M. T. et al. Molecular pathway for the localized formation of the sinoatrial node. Circ. Res. 100, 354–362 (2007)

    CAS  Article  Google Scholar 

  16. 16

    The International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005)

  17. 17

    Waldo, A. L. The interrelationship between atrial fibrillation and atrial flutter. Prog. Cardiovasc. Dis. 48, 41–56 (2005)

    Article  Google Scholar 

  18. 18

    Zini, S. et al. Identification of metabolic pathways of brain angiotensin II and III using specific aminopeptidase inhibitors: predominant role of angiotensin III in the control of vasopressin release. Proc. Natl Acad. Sci. USA 93, 11968–11973 (1996)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Gretarsdottir, S. et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nature Genet. 35, 131–138 (2003)

    CAS  Article  Google Scholar 

  20. 20

    Falk, C. T. & Rubinstein, P. Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations. Ann. Hum. Genet. 51, 227–233 (1987)

    CAS  Article  Google Scholar 

  21. 21

    Mantel, N. & Haenszel, W. Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer Inst. 22, 719–748 (1959)

    CAS  PubMed  Google Scholar 

  22. 22

    Grant, S. F. et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nature Genet. 38, 320–323 (2006)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Yang, X. et al. Development and validation of stroke risk equation for Hong Kong Chinese patients with type 2 diabetes: the Hong Kong Diabetes Registry. Diabetes Care 30, 65–70 (2007)

    Article  Google Scholar 

  24. 24

    Baum, L. et al. Methylenetetrahydrofolate reductase gene A222V polymorphism and risk of ischemic stroke. Clin. Chem. Lab. Med. 42, 1370–1376 (2004)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Daniel F. Gudbjartsson or Kari Stefansson.

Ethics declarations

Competing interests

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

Supplementary information

Supplementary information

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

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gudbjartsson, D., Arnar, D., Helgadottir, A. et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 448, 353–357 (2007). https://doi.org/10.1038/nature06007

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing