Multi-Ethnic Genome-wide Association Study for Atrial Fibrillation

TLDR: This large, multi-ethnic genome-wide association study identifies 97 loci significantly associated with atrial fibrillation that are enriched for genes involved in cardiac development, electrophysiology, structure and contractile function.

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.

Figures

Table 1. Novel loci in combined-ancestry meta-analysis

Figure 2. Manhattan plot of combined-ancestry meta-analysis

Figure 3. Volcano plot of MetaXcan results from human heart tissues.

Figure 4. Cross-trait associations of AF risk variants with AF risk factors in the UK Biobank.

Figure 1. Study and analysis flowchart

Full text

University of Birmingham
Multi-ethnic genome-wide association study for
atrial fibrillation
Roselli, Carolina; Chaffin, Mark D ; Weng, Lu-Chen ; Aeschbacher, Stefanie; Ahlberg, Gustav
; Albert, Christine M.; Almgren, Peter; Alonso, Alvaro; Anderson, Christopher D ; Aragam,
Krishna G; Arking, Dan E; Barnard, John; Bartz, Traci M ; Benjamin, Emelia J; Bihlmeyer,
Nathan A ; Bis, Joshua C; Bloom, Heather L ; Boerwinkle, Eric; Bottinger, Erwin P; Brody,
Jennifer A
DOI:
10.1038/s41588-018-0133-9
License:
None: All rights reserved
Document Version
Peer reviewed version
Citation for published version (Harvard):
Roselli, C, Chaffin, MD, Weng, L-C, Aeschbacher, S, Ahlberg, G, Albert, CM, Almgren, P, Alonso, A, Anderson,
CD, Aragam, KG, Arking, DE, Barnard, J, Bartz, TM, Benjamin, EJ, Bihlmeyer, NA, Bis, JC, Bloom, HL,
Boerwinkle, E, Bottinger, EP, Brody, JA, Calkins, H, Campbell, A, Cappola, TP, Carlquist, J, Chasman, DL,
Chen, LY, Chen, Y-DI, Choi, E-K, Choi, SH, Christophersen, IE, Chung, MK, Cole, JW, Conen, D, Cook, J,
Crijns, HJ, Cutler, MJ, Damrauer, SM, Daniels, BR, Darbar, D, Delgado, G, Denny, JC, Dichgans, M, Dorr, M,
Dudink, EA, Dudley, SC, Esa, N, Esko, T, Eskola, M, Fatkin, D, Felix, SB, Ford, I, Franco, OH, Geelhoed, B,
Grewal, R, Gudnason, V, Guo, X, Gupta, N, Gustafsson, S, Gutmann, R, Hamsten, A, Harris, TB, Hayward, C,
Heckbert, SR, Hernesniemi , J, Hocking, LJ, Hofman, A, Horimoto, ARVR, Huang, J, Huang, PL, Huffman, J,
Ingelsson, E, Gucuk Ipek, E, Ito, K, Jimenez-Conde, J, Johnson, R, Wouter Jukema, J, Kaab, S, Kähönen, M,
Kamatani, Y, Kane, JP, Kastrati, A, Kathiresan, S, Katschnig-Winter, P, Kavousi, M, Kessler, T, Kietselaer, BL,
Kirchhof, P, Kleber, ME, Knight, S, Krieger, JE, Kubo, M, Launer, LJ, Laurikka, J, Lehtimäki, T, Leineweber, K,
Lemaitre, RN, Li, M, Lim, HE, Lin, HJ, Lin, H, Lind, L, Lindgren, CM, Lokki, M-L, London, B, Loos, RJF, Low, S-
K, Lu, Y, Lyytikäinen, L-P, Macfarlane, PW, Magnusson, PK, Mahajan, A, Malik, R, Mansur, AJ, Marcus, GM,
Margolin, L, Margulies, KB, März, W, McManus, DD, Melander, O, Mohanty, S, Montgomery, JA, Morley, MP,
Morris, AP, Müller-Nurasyid, M, Natale, A, Nazarian, S, Neumann, B, Newton-Cheh, C, Niemeijer, MN, Nikus, K,
Nilsson, PM, Noordam, R, Oellers, H, Olesen, MS, Orho-Melander, M, Padmanabhan, S, Pak, H-N, Pare, G,
Pedersen, NL, Pera, J, Pereira, A, Porteous, D, Psaty, BM, Pulit, SL, Pullinger, CR, Rader, DJ, Refsgaard, L,
Ribases, M, Ridker, PM, Rienstra, M, Risch, L, Roden, D, Rosand, J, Rosenberg, MA, Rost, N, Rotter, JI, Saba,
S, Sandhu, RK, Schnabel, RB, Schramm, K, Schunkert, H, Schurman, C, Scott, SA, Seppala, I, Shaffer, C,
Shah, SH, Shalaby, AA, Shim, J, Shoemaker, MB, Siland, JE, Sinisalo, J, Sinner, MF, Slowik, A, Smith, AV,
Smith, BH, Smith, JG, Smith, JD, Smith, NL, Soliman, EZ, Sotoodehnia, N, Stricker, BH, Sun, A, Sun, H,
Svendsen, JH, Tanaka, T, Tanriverdi, K, Taylor, KD, Teder-Laving, M, Teumer, A, Theriault, S, Trompet, S,
Tucker, NR, Tveit, A, Uitterlinden, AG, Van der Harst, P, Van Gelder, IC, Van Wagoner, DR, Verweij, N,
Vlachopoulou, E, Volker, U, Wang, B, Weeke, PE, Weijs, B, Weiss, R, Weiss, S, Wells, Q, Wiggins, KL, Wong,
J, Woo, D, Worrall, BB, Yang, P-S, Yao, J, Yoneda, ZT, Zeller, T, Zeng, L, Lubitz, SA, Lunetta, KL & Ellinor, PT
2018, 'Multi-ethnic genome-wide association study for atrial fibrillation', Nature Genetics, vol. 50, no. 9, pp.
1225–1233. https://doi.org/10.1038/s41588-018-0133-9
Link to publication on Research at Birmingham portal
Publisher Rights Statement:
Final Version of Record available at: https://doi.org/10.1038/s41588-018-0133-9

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Frequently asked questions

Q1. What is the significance threshold for the proxies of sentinel variants?

The authors identified proxies of sentinel variants as variants in LD of r2 >0.6 based on the Broad AF LD reference file, using PLINK v1.90.14,15The authors meta-analyzed 111 variants from externally reported23 provisional loci within predominantly non-overlapping samples from the Broad AF Study, BBJ, EGCUT, PHB, SiGN and the Vanderbilt AF Registrywith METAL. 

Q2. What studies were previously not included in the primary AF GWAS discovery analyses?

Samples from the UK Biobank, the Broad AF Study, and thefollowing studies from the AFGen consortium: SiGN, EGCUT, PHB and the Vanderbilt Atrial FibrillationRegistry, were previously not included in primary AF GWAS discovery analyses. 

Q3. How many referents of Hispanic ancestry were analyzed?

The authors analyzed: 55,114 cases and 482,295 referentsof European ancestry, 1,307 cases and 7,660 referents of African American ancestry, 8,180 cases and3,081 referents of Hispanic ethnicity. 

Q4. What was the significance threshold for the heterogeneitytest?

The authors account for multiple testing across 94 variants using a Bonferroni correction, resulting in a significance threshold of P < 5.32x10-4 for the heterogeneitytest. 

Q5. How many ancestry groups were imputed to the siGN study?

12 Participants of the SiGN study were imputed to a combined reference panel consisting of 1000 Genomes phase 1 plus Genome of the Netherlands. 

Q6. How many mutations have been mapped in a variety of inherited arrhythmia?

30,31 Mutations in GJA5, KCNH2,SCN5A, KCNJ2, MYH7, NKX2-5, have been mapped in a variety of inherited arrhythmia, cardiomyopathy, or conduction system diseases. 

Q7. Where was the region significantly associated with AF in Europeans, Japanese, and African Americans?

The region most significantlyassociated with AF in Europeans, Japanese, and African Americans (Supplementary Figure S5-6) was onchromosome 4q25, upstream of the gene PITX2 (Supplementary Figure S7). 

Q8. How many loci were found with multiple AF signals?

In conditional and joint analyses of the European ancestry results, the authors found 11 loci with multiple,independent AF-associated signals. 

Q9. How many AF cases did Nielsen et al. report?

In recent pre-publication results, Nielsen et al., reported 111 loci from 60,620 AF cases and more than 970,000 referents,15 including more than 18,000 AF cases from their prior report. 

Q10. What is the conservative threshold for testing AF-associated loci?

This conservative threshold accounts for testingindependent variants with MAF ≥0.1% using a Bonferroni correction, while use of a more commonly utilized threshold of 5x10-8 resulted in the identification of an additional 10 loci (Supplementary TableS2). 

Q11. What was the significance cutoff for the ancestry specific meta-analyses?

For sentinel variants reaching genome-wide significance in the combined ancestry metaanalysis, the authors assessed if effect estimates were homogeneous across ancestries by calculating an I2Page 31 of 41statistic22 across ancestry specific meta-analyses. 

Q12. What was the meta-analysis of the Japanese and Hispanic studies?

19Summary level results were meta-analyzed jointly with METAL using a fixed effect model with inversevariance weighted approach, correcting for genomic control.20 Separate meta-analyses were conducted for each ancestry. 

Q13. What was the significance of the AF-associated loci?

Page 10 of 41The combined-ancestry meta-analysis revealed 94 AF-associated loci, 67 of which were novel atgenome-wide significance (P-value (P) < 1x10-8). 

Q14. What is the difference between the two meta-analyses?

As these meta-analysesare based on effect estimates and standard errors from both logistic regression and Cox proportionalhazards regression, the authors report variant effects as relative risk, calculated as the exponential of effectestimates. 

Q15. What was the effect of the combined-ancestry meta-analysis?

Among individuals of European ancestry, weidentified 3 additional loci associated with AF, each of which had a sub-threshold association (P < 1x10-6)in the combined-ancestry meta-analysis. 

Q16. What was the Statistical Significance of the eQTLs?

Statisticalsignificance was calculated with a permutation test from the perm package in R.Expression quantitative trait loci (eQTL)Variants identified from GWAS were assessed for overlap with eQTLs from two sources:1) Left atrial (LA) tissue from the Myocardial Applied Genomics Network (MAGNet) repository.