Abstract
Atrial fibrillation (AF) affects more than 33 million individuals worldwide1 and has a complex heritability2. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
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Change history
20 July 2018
In the version of this article initially published, Supplementary Tables 1, 2, 6, 8, 10 and 19–22 and the Supplementary Note were omitted from the supplementary PDF. The supplementary PDF now includes these items.
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Acknowledgements
A full list of acknowledgments appears in the Supplementary Notes.
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C.R., M.D.C., E.J.B., K.L.L., S.A.L., P.T.E. and H.L. drafted and finalized the manuscript. H.J.C., E.A.D., B.L.K., B. Weijs, S. Kääb, M.M.-N., B.N., K.S., M.F.S., J.L., A.A., L.Y.C., K.L., S.A., D.C., G.P., L. Risch, S. Thériault, T.T., C. Schurman, S.A.S., J.C.D., D.M.R., Q.S.W., C.R., M.D.C., K.G.A., B.R.D., N.G., S. Kathiresan, L.M., P.L.H., J.B., M.K.C., J.D.S., H. Sun, D.R.V.W., T.M.B., J.C.B., J.A.B., G.A., M.S.O., L. Refsgaard, J.H.S., D.F., R.J., S. Shah, P.K., R.B.S., T.E., M.T.-L., E.J.B., B. Wang, K.L.L., M. Kähönen, T.L., I.E.C., I.C.V.G., B.G., M. Rienstra, J.E.S., P.V.D.H., N.V., H.L.B., S.C.D., R.G., B.L., S. Saba, A.A.S., R.W., H.C., R.N.L., N.L.S., K.L.W., S.R.H., B.M.P., N.S., J. Carlquist, M.J.C., S. Knight, M.E.K., W.M., P.A., O.M., M.O.-M., X.G., H.J.L., J.I.R., K.D.T., S.H.C., N.R.T., S.A.L., P.T.E., C.N.-C., M.A.R., C.D.A., P.N., J.J.G.S., H. Schunkert, T.P.C., K.B.M., I.F., J.J.W.J., P.W.M., R.N., S. Trompet, O.H.F., A. Hofman, M. Kavousi, M.N.N., B.H. Stricker, A.G.U., R.P.G., J.J.-C., S.L.P., S.M., A. Hamsten, J.P.K., G.M.M., C.R.P., A.P.M., S.G., E. Ingelsson, H.L., D.D., J.A.M., M.M.B.S., Z.T.Y., C. Shaffer, P.E.W., C.M.A., D.I.C., R.K.S., J.W., M. Dichgans and R.M. contributed to and revised the manuscript. H.J.C., E.A.D., B.L.K., B. Weijs, S. Kääb, M.M.-N., B.N., K.S., M.F.S., V.G., T.B.H., L.J.L., A.V.S., M.E., J. Hernesniemi, J.L., I.S., A.A., D.E.A., N.A.B., E.B., L.Y.C., M.L., E.Z.S., S.A., D.C., G.P., L. Risch, S. Thériault, K.I., Y.K., M. Kubo, S.-K.L., T.T., E.B.B., R.J.F.L., Y.L., C. Schurman, S.A.S., J.C.D., D.M.R., Q.S.W., C.R., M.D.C., L.-C.W., K.G.A., N.G., S. Kathiresan, L.M., P.L.H., J.B., M.K.C., J.D.S., H. Sun, D.R.V.W., T.M.B., J.C.B., J.A.B., M.-L.L., J. Sinisalo, E.V., G.A., M.S.O., L. Refsgaard, J.H.S., D.F., R.J., A. Sun, P.K., H.O., R.B.S., T.Z., T.E., M.T.-L., E.J.B., B. Wang, K.L.L., M. Kähönen, T.L., L.-P.L., K.N., I.E.C., A. Tveit, B.G., J.E.S., N.V., H.L.B., S.C.D., R.G., B.L., S. Saba, A.A.S., R.W., A.C., C.H., L.J.H., J. Huffman, S.P., D.P., B.H. Smith, H.C., E. Ipek, S.N., R.N.L., N.L.S., K.L.W., S.R.H., B.M.P., N.S., J. Carlquist, M.J.C., S. Knight, E.-K.C., H.E.L., H.-N.P., J. Shim, P.-S.Y., G.D., J. Huang, M.E.K., P.A., O.M., M.O.-M., Y.-D.C., X.G., K.D.T., J.Y., S.A.L., P.T.E., C.N.-C., M.A.R., J.R., N.R., C.D.A., P.N., J.J.G.S., A.K., T.K., H. Schunkert, L.Z., T.P.C., S.M.D., K.B.M., M.P.M., D.J.R., I.F., J.J.W.J., S. Trompet, O.H.F., A. Hofman, M. Kavousi, M.N.N., B.H. Stricker, A.G.U., M. Dörr, S.B.F., A. Teumer, U.V., S.W., J.W.C., R.P.G., J.J.-C., P.K.-W., J.P., S.L.P., M. Ribasés, A. Slowik, D.W., B.B.W., A.R.V.R.H., J.E.K., A.J.M., A.P., S.M., A.N., A. Hamsten, P.K.M., N.L.P., J.P.K., G.M.M., C.R.P., J. Cook, L.L., C.M.L., A.M., A.P.M., S.G., E. Ingelsson, N.E., K.T., H.L., D.D.M., D.D., J.A.M., M.M.B.S., Z.T.Y., C. Shaffer, P.E.W., C.M.A., D.I.C., P.M.R., M. Dichgans and R.M. contributed to study-specific GWAS by providing phenotype data or performing data analyses. C.R., M.D.C. and S.L.P. performed meta-analyses. N.R.T., P.T.E., T.P.C., K.B.M., M.P.M. and H.L. contributed samples sequencing or performed left atrial eQTL analyses. C.R., M.D.C., L.-C.W., K.L.L., S.H.C., N.R.T. and H.L. performed downstream analyses. K.I., T.T., K.L.L., S.R.H., S.A.L. and P.T.E. conceived designed and supervised the overall project.
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Competing interests
P.T.E is the PI on a grant from Bayer to the Broad Institute focused on the genetics and therapeutics of AF. B.M.P. serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. P.K. receives research support from the European Union, the British Heart Foundation, the Leducq Foundation, the Medical Research Council (UK) and the German Centre for Cardiovascular Research, and from several drug and device companies active in AF, and has received honoraria from several such companies. P.K. is also listed as an inventor on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). K.L. is an employee of Bayer. The genotyping of participants in the Broad AF study and the expression analysis of LA tissue samples were supported by a grant from Bayer to the Broad Institute. S.N. is a consultant to Biosense Webster, Siemens and Cardiosolv. S.N. also receives research grants from NIH/NHLBI, Siemens, Biosense Webster and Imricor. S. Kathiresan has received grant support from Bayer and Amarin; holds equity in San Therapeutics and Catabasis; and has received personal fees for participation in scientific advisory boards for Catabasis, Regeneron Genetics Center, Merck, Celera, Genomics PLC, Corvidia Therapeutics and Novo Ventures. S. Kathiresan also received personal fees for consulting services from Novartis, AstraZeneca, Alnylam, Eli Lilly Company, Leerink Partners, Merck, Noble Insights, Bayer, Ionis Pharmaceuticals, Novo Ventures, Haug Partners LLC and Genetic Modifiers Newco, Inc. S.A.L. receives sponsored research support from Bristol Myers Squibb, Bayer, Biotronik and Boehringer Ingelheim, and has consulted for St. Jude Medical/Abbott and Quest Diagnostics. The remaining authors have no disclosures.
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Integrated Supplementary Information
Supplementary Figure 1 Quantile–quantile plot of combined ancestry meta-analysis.
Quantile–quantile plot of combined ancestry meta-analysis for n = 12,149,979 included variants and λGC = 1.0948.
Supplementary Figure 2 Venn diagram for genes near sentinel variants from combined ancestry meta-analysis within enriched gene sets, by functional groups.
The Venn diagram shows genes that are within enriched gene set from the gene set enrichment analysis and within 500 kb of a sentinel variant. The genes were manually grouped into functional categories based on their corresponding gene sets. The diagram shows the overlap between the genes and the functional categories.
Supplementary Figure 3 Manhattan plot of European-ancestry meta-analysis.
The plot shows novel (red and purple) and known (blue) genetic loci associated with AF at a significance level of P < 1 × 10–8 (dotted line) for the European-ancestry meta-analysis (n = 537,409). The significance level accounts for multiple testing of independent variants with MAF ≥0.1% using a Bonferroni correction. P values (two-sided) were derived from a meta-analysis using a fixed-effects model with an inverse-variance-weighted approach. Loci in purple did not reach genome-wide significance in the combined ancestry meta-analysis. Gene labels correspond to the nearest gene(s). The y axis has a break between –log10 (P) of 25 and 400 to emphasize the novel loci.
Supplementary Figure 4 Quantile–quantile plot of European-ancestry meta-analysis.
Quantile–quantile plot of European-ancestry meta-analysis for n = 9,362,422 included variants and λGC = 1.1194.
Supplementary Figure 5 Manhattan plot of African-American meta-analysis.
The plot shows known (blue) genetic loci associated with AF at a significance level of P < 1 × 10–8 (dotted line), for the African-American-ancestry meta-analysis (n = 8,967). The significance level accounts for multiple testing of independent variants with MAF ≥ 0.1% using a Bonferroni correction. P values (two-sided) were derived from a meta-analysis using a fixed-effects model with an inverse-variance-weighted approach. The gene label corresponds to the nearest gene.
Supplementary Figure 6 Quantile–quantile plot of African-American-ancestry meta-analysis.
Quantile–quantile plot of African-American-ancestry meta-analysis for n = 8,640,046 included variants and λGC = 0.997.
Supplementary Figure 7 Regional plots for 4q25 for European, Japanese and African American ancestry and pairwise LD between sentinel variants at 4q25.
a–c, Regional plots of 4q25 for European-ancestry results (a, n = 537,409), Japanese-ancestry results (b, n = 36,792) and African-American-ancestry results (c, n = 8,967). LD is shown based on the 1000 Genomes phase 1 v3 reference, using the populations EUR (a), ASN (b) and AFR (c). d, Pairwise LD (r2) for the sentinel variants based on the LD from the 1000 Genomes phase 1 v3 reference for EUR (n = 379), ASN (n = 286) and AFR (n = 246) ancestry. 1000G, 1000 Genomes; AA, African American; AFR, African; ASN, Asian; EUR, European; JAP, Japanese; LD, linkage disequilibrium.
Supplementary Figure 8 Forest plots of odds ratios, and allele frequency plots, by ancestry for sentinel variants with significant heterogeneity.
a–c, Forest plots of odds ratios and pie charts of allele frequencies across ancestries (EUR, n = 537,409; JAP, n = 36,792; AA, n = 8,967; BRAZ, n = 1,664; HISP, n = 3,358) for sentinel variants with significant heterogeneity, close to PITX2 (a), NEURL (b) and ZFHX3 (c). Shown are odds ratios with 95% confidence intervals. Frequencies of the effect allele are depicted in blue; frequencies of the reference allele are depicted in orange. AA, African American; BRAZ, Brazilian; EUR, European; HISP, Hispanic; JAP, Japanese.
Supplementary Figure 9 Enrichment of atrial fibrillation–associated loci across ChromHMM regulatory regions.
a,b, Percent overlap of loci with regulatory regions (promoter, enhancer, DNase) based on the Roadmap Epigenomics Consortium 25-state model across all tissues (a) and cardiac tissues (b). Each locus includes sentinel variant and proxies with r2 > 0.6. The P values were derived from one-tailed permutation tests (n = 1,000). 1000 Genomes control loci were matched to atrial fibrillation sentinel SNPs via SNPSnap (n = 93,000). Atrial fibrillation–associated loci are from the combined ancestry analysis (n = 93). The sentinel SNP for one AF locus could not be matched in SNPSnap and was excluded from this analysis. The box plot depicts the following values: the center represents the median, the top and bottom of the box represent the first and third quartile, the whiskers reach to 1.5 times the interquartile range, and data points outside the whiskers are plotted as outliers. *P = 0.001. 1000G, 1000 Genomes; AF, atrial fibrillation.
Supplementary information
Supplementary Text, Figures and Tables
Supplementary Figures 1–9, Supplementary Tables 1, 2, 6, 8, 10 and 19–22, and Supplementary Notes
Supplementary Table 3
Known loci in combined ancestry meta-analysis
Supplementary Table 4
Gene set enrichment analysis results for combined ancestry meta-analysis
Supplementary Table 5
Novel and known loci in ancestry-specific meta-analyses
Supplementary Table 7
Loci with multiple signals identified by conditional and joint analysis for European-ancestry meta-analysis
Supplementary Table 9
Chromatin states for sentinel variants and proxies from Roadmap Epigenomics across all tissues and heart
Supplementary Table 11
Significant cis-eQTLs for sentinel variants from combined ancestry meta-analysis in GTEx heart tissues
Supplementary Table 12
Probable AF susceptibility genes for loci from combined ancestry meta-analysis
Supplementary Table 13
Transcriptome-wide results based on summary-level data from combined ancestry meta-analysis
Supplementary Table 14
Association to diseases and traits in NHGRI-EBI GWAS catalog for sentinel variants or proxies from combined ancestry meta-analysis
Supplementary Table 15
PheWAS results in UK Biobank for sentinel variants from combined ancestry meta-analysis
Supplementary Table 16
134 loci associated with atrial fibrillation
Supplementary Table 17
Baseline summary for GWAS
Supplementary Table 18
GWAS summary on genotyping, QC, imputation and analysis per study
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Roselli, C., Chaffin, M.D., Weng, LC. et al. Multi-ethnic genome-wide association study for atrial fibrillation. Nat Genet 50, 1225–1233 (2018). https://doi.org/10.1038/s41588-018-0133-9
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DOI: https://doi.org/10.1038/s41588-018-0133-9
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