Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

An Erratum to this article was published on 27 July 2017

This article has been updated

Abstract

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death1,2. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups3,4,5,6,7. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery8.

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Figure 1: Study flowchart.
Figure 2: Manhattan plot of the combined-ancestry GWAS meta-analyses.
Figure 3: Regional plots from the combined-ancestry GWAS meta-analysis.

Change history

  • 11 May 2017

    In the version of this article initially published online, the authors were incorrectly defined as members of the AFGen consortium in the author list. The members of the consortium are listed in the Supplementary Note. The error has been corrected in the print, PDF and HTML versions of this article.

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Acknowledgements

A full list of acknowledgments appears in the Supplementary Note.

Author information

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Contributions

I.E.C., C.R., X.Y., T.T., K.L.L., E.J.B., S.A.L., M.R., B.G., and P.T.E. wrote and edited the manuscript. All authors contributed to and discussed the results and commented on the manuscript. GWAS and ExWAS analyses: A.V.S., N.A.B., M.M.-N., I.S., C.S., P.E.W., S.A., S. Thériault, J.A.B., J.C.B., H.L., J. Huffman, J.Y., X.G., F.R., M.N.N., D.E.A., G.P., S.-K.L., Y.K., M. Kähönen, A.C.P., A.R.H., J.S., L.-P.L., M.A., M.E.K., J.G.S., R.M., S.G., S. Trompet, M.D., S.W., J.A.W., D.I.C., M.V.P., Q.Y., T.B.H., M.F.S., J.S., D.R.v.W. Individual data set quality control and GWAS and ExWAS meta-analyses: I.E.C., K.L.L., C.R., X.Y., M.R., B.G., Y.P.H., N.V., J.E.S. Replication in METASTROKE and Neuro-CHARGE: Q.Y., J.C.H., S.D., G.C., B.B.W. Replication in UK Biobank: S.K., D.K., C.N.-C. Replication in BioBank Japan: S.-K.L., Y.K., M. Kubo, T.T. Replication in African-American population: R.D., D.J.R., S.H.S., A.S. CCAF eQTL analyses: J.B., M.K.C., D.v.W., J.D.S. Functional annotation: I.E.C., S.H.C., L.-C.W., M. Li, C.R., M.C., N.R.T., S.C. Pathway analyses: H.L.

Corresponding author

Correspondence to Patrick T Ellinor.

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Competing interests

P.T.E. is the principal investigator on a grant from Bayer HealthCare to the Broad Institute focused on the genetics and therapeutics of atrial fibrillation. The remaining authors have no disclosures.

Additional information

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

Integrated supplementary information

Supplementary Figure 1 QQ plot for the combined-ancestry GWAS meta-analysis.

QQ plot displaying the observed versus the expected –log10 of the P value for each variant tested in the combined-ancestry GWAS meta-analysis. λ represents the genomic inflation factor.

Supplementary Figure 2 Regional plots from combined-ancestry ExWAS meta-analysis.

The most significant variant at each locus is plotted (purple, diamond-shaped) and identified by rsID. Each dot in the plots represents a single variant present in our results, and the color of the dot indicates the degree of linkage disequilibrium with the most significant variant, as shown in the top left color chart in each panel. The lower part of each panel shows the locations of genes in the respective loci. r2, degree of linkage disequilibrium; chr., chromosome. Regional plots were created using LocusZoom.

Supplementary Figure 3 QQ plot for the combined-ancestry ExWAS meta-analysis.

QQ plot displaying the observed versus the expected –log10 of the P value for each variant tested in the combined-ancestry ExWAS meta-analysis. λ represents the genomic inflation factor.

Supplementary Figure 4 Manhattan plot of results from African-American-ancestry GWAS meta-analysis.

Genetic loci that have also previously been associated with atrial fibrillation through GWAS are highlighted in blue. The dashed line represents the significance threshold (5 × 10–8). The gene names represent the gene in closest proximity to the most significant variant at each locus.

Supplementary Figure 5 Manhattan plot of results from European-ancestry GWAS meta-analysis.

New genetic loci for atrial fibrillation are highlighted in red, whereas loci that have also previously been associated with atrial fibrillation through GWAS are highlighted in blue. The dashed line represents the significance threshold (5 × 10–8). The gene names represent the gene in closest proximity to the most significant variant at each locus. There is a break in the y axis to increase the resolution of the genetic loci near the genome-wide significance threshold.

Supplementary Figure 6 Manhattan plot of results from Asian-ancestry GWAS meta-analysis.

New genetic loci for atrial fibrillation are highlighted in red, whereas loci that have also previously been associated with atrial fibrillation through GWAS are highlighted in blue. The dashed line represents the significance threshold (5 × 10–8). The gene names represent the gene in closest proximity to the most significant variant at each locus.

Supplementary Figure 7 Manhattan plot of results from incident atrial fibrillation GWAS meta-analysis in Europeans.

Genetic loci that have also previously been associated with atrial fibrillation through GWAS are highlighted in blue. The dashed line represents the significance threshold (5 × 10–8). The gene names represent the gene in closest proximity to the most significant variant at each locus. There is a break in the y axis to increase the resolution of the genetic loci near the genome-wide significance threshold.

Supplementary Figure 8 Manhattan plot of results from prevalent atrial fibrillation GWAS meta-analysis in Europeans.

New genetic loci for atrial fibrillation are highlighted in red, whereas loci that have also previously been associated with atrial fibrillation through GWAS are highlighted in blue. The dashed line represents the significance threshold (5 × 10–8). The gene names represent the gene in closest proximity to the most significant variant at each locus. There is a break in the y axis to increase the resolution of the genetic loci near the genome-wide significance threshold.

Supplementary Figure 9 Distinct loci on chromosomes 1 and 10, as demonstrated using approximate joint and conditional association analysis in European-ancestry studies with GCTA software.

All conditional analyses were performed using the European-ancestry results only, with a European-ancestry reference population from the Framingham Heart Study. Regional plots were created using Locus Zoom software1 with LD information from the European ancestry 1000 Genomes reference population. (a,b) Regional plots of the independent signals at chromosome 1q24; the new METTL11B locus (a) and the replicated PRRX1 locus (b). (c,d) Regional plots of the independent signals at chromosome 10q24; the new SH3PXD2A locus (c) and the replicated NEURL1 locus (d).

Supplementary Figure 10 Atrial fibrillation–associated loci display pleiotropy across clinical, electrocardiographic, and echocardiographic cardiac phenotypes.

Diagram showing overlap of genetic associations between cardiac phenotypes, identified through interrogation of the NHGRI-EBI GWAS catalog2. Gene names are in italics and represent genetic loci identified through GWAS (Supplementary Table 13). AF, atrial fibrillation; HR, heart rate; LVIDD, left-ventricle internal diastolic diameter on echocardiography; PR-I, PR interval; PR-S, PR segment; QRS, QRS interval; QT, QT interval.

Supplementary Figure 11 Atrial fibrillation–associated loci are enriched for functional elements.

(af) Median overlap of loci by phastCons 46-way primate conserved elements (a), phastCons 46-way mammalian conserved elements (b), Roadmap Epigenomics cardiac H3K27ac gapped peaks (R atrium, L ventricle, R ventricle, aorta) (c), any Roadmap Epigenomics H3K27ac gapped peak (98 cell types) (d), ENCODE DNaseHS cardiac sites (cardiac fibroblasts, atrial fibroblasts, cardiac myocytes) (e), and ENCODE DNaseHS master sites (125 cell types) (f). *P < 0.05, **P < 0.01, ***P < 0.001, one-tailed bootstrapping (n = 1,000). Whiskers, interquartile range; AF, atrial fibrillation–associated loci (n = 24); GWAS, NHGRI-EBI GWAS catalog associated loci (n = 3,381); 1000G, 1000 Genomes control loci based on SNPsnap matched variants to atrial fibrillation GWAS hits (n = 9,093).

Supplementary Figure 12 Atrial fibrillation–associated loci are enriched for eQTLs.

The figure shows the proportion of loci with at least one GTEx eQTL for all tissues available in the GTEx database. Only the three top tissues showed significant enrichment of eQTLs for atrial fibrillation loci (pancreas, left ventricle, and tibial artery tissue) AF, atrial fibrillation–associated loci (n = 24); GWAS, NHGRI-EBI GWAS catalog associated loci (n = 3,381); 1000G, 1000 Genomes control loci based on SNPsnap matched variants to atrial fibrillation GWAS hits (n = 9,093).

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Supplementary Text and Figures

Supplementary Figures 1–12, Supplementary Tables 3–9, 12–16 and 21–29, and Supplementary Note. (PDF 4541 kb)

Supplementary Tables

Supplementary Tables 1, 2, 10, 11 and 17–20. (XLSX 268 kb)

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Christophersen, I., Rienstra, M., Roselli, C. et al. Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. Nat Genet 49, 946–952 (2017). https://doi.org/10.1038/ng.3843

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