Multi-ethnic genome-wide association study for atrial fibrillation

Carolina Roselli; Mark D Chaffin; Lu-Chen Weng; Stefanie Aeschbacher; Gustav Ahlberg; Christine M Albert; Peter Almgren; Alvaro Alonso; Christopher D Anderson; Krishna G Aragam; Dan E Arking; John Barnard; Traci M Bartz; Emelia J Benjamin; Nathan A Bihlmeyer; Joshua C Bis; Heather L Bloom; Eric Boerwinkle; Erwin B Bottinger; Jennifer A Brody; Hugh Calkins; Archie Campbell; Thomas P Cappola; John Carlquist; Daniel I Chasman; Lin Y Chen; Yii-Der Ida Chen; Eue-Keun Choi; Seung Hoan Choi; Ingrid E Christophersen; Mina K Chung; John W Cole; David Conen; James Cook; Harry J Crijns; Michael J Cutler; Scott M Damrauer; Brian R Daniels; Dawood Darbar; Graciela Delgado; Joshua C Denny; Martin Dichgans; Marcus Dörr; Elton A Dudink; Samuel C Dudley; Nada Esa; Tonu Esko; Markku Eskola; Diane Fatkin; Stephan B Felix; Ian Ford; Oscar H Franco; Bastiaan Geelhoed; Raji P Grewal; Vilmundur Gudnason; Xiuqing Guo; Namrata Gupta; Stefan Gustafsson; Rebecca Gutmann; Anders Hamsten; Tamara B Harris; Caroline Hayward; Susan R Heckbert; Jussi Hernesniemi; Lynne J Hocking; Albert Hofman; Andrea R V R Horimoto; Jie Huang; Paul L Huang; Jennifer Huffman; Erik Ingelsson; Esra Gucuk Ipek; Kaoru Ito; Jordi Jimenez-Conde; Renee Johnson; J Wouter Jukema; Stefan Kääb; Mika Kähönen; Yoichiro Kamatani; John P Kane; Adnan Kastrati; Sekar Kathiresan; Petra Katschnig-Winter; Maryam Kavousi; Thorsten Kessler; Bas L Kietselaer; Paulus Kirchhof; Marcus E Kleber; Stacey Knight; Jose E Krieger; Michiaki Kubo; Lenore J Launer; Jari Laurikka; Terho Lehtimäki; Kirsten Leineweber; Rozenn N Lemaitre; Man Li; Hong Euy Lim; Henry J Lin; Honghuang Lin; Lars Lind; Cecilia M Lindgren; Marja-Liisa Lokki; Barry London; Ruth J F Loos; Siew-Kee Low; Yingchang Lu; Leo-Pekka Lyytikäinen; Peter W Macfarlane; Patrik K Magnusson; Anubha Mahajan; Rainer Malik; Alfredo J Mansur; Gregory M Marcus; Lauren Margolin; Kenneth B Margulies; Winfried März; David D McManus; Olle Melander; Sanghamitra Mohanty; Jay A Montgomery; Michael P Morley; Andrew P Morris; Martina Müller-Nurasyid; Andrea Natale; Saman Nazarian; Benjamin Neumann; Christopher Newton-Cheh; Maartje N Niemeijer; Kjell Nikus; Peter Nilsson; Raymond Noordam; Heidi Oellers; Morten S Olesen; Marju Orho-Melander; Sandosh Padmanabhan; Hui-Nam Pak; Guillaume Paré; Nancy L Pedersen; Joanna Pera; Alexandre Pereira; David Porteous; Bruce M Psaty; Sara L Pulit; Clive R Pullinger; Daniel J Rader; Lena Refsgaard; Marta Ribasés; Paul M Ridker; Michiel Rienstra; Lorenz Risch; Dan M Roden; Jonathan Rosand; Michael A Rosenberg; Natalia Rost; Jerome I Rotter; Samir Saba; Roopinder K Sandhu; Renate B Schnabel; Katharina Schramm; Heribert Schunkert; Claudia Schurman; Stuart A Scott; Ilkka Seppälä; Christian Shaffer; Svati Shah; Alaa A Shalaby; Jaemin Shim; M Benjamin Shoemaker; Joylene E Siland; Juha Sinisalo; Moritz F Sinner; Agnieszka Slowik; Albert V Smith; Blair H Smith; J Gustav Smith; Jonathan D Smith; Nicholas L Smith; Elsayed Z Soliman; Nona Sotoodehnia; Bruno H Stricker; Albert Sun; Han Sun; Jesper H Svendsen; Toshihiro Tanaka; Kahraman Tanriverdi; Kent D Taylor; Maris Teder-Laving; Alexander Teumer; Sébastien Thériault; Stella Trompet; Nathan R Tucker; Arnljot Tveit; Andre G Uitterlinden; Pim Van Der Harst; Isabelle C Van Gelder; David R Van Wagoner; Niek Verweij; Efthymia Vlachopoulou; Uwe Völker; Biqi Wang; Peter E Weeke; Bob Weijs; Raul Weiss; Stefan Weiss; Quinn S Wells; Kerri L Wiggins; Jorge A Wong; Daniel Woo; Bradford B Worrall; Pil-Sung Yang; Jie Yao; Zachary T Yoneda; Tanja Zeller; Lingyao Zeng; Steven A Lubitz; Kathryn L Lunetta; Patrick T Ellinor

doi:10.1038/s41588-018-0133-9

Multi-ethnic genome-wide association study for atrial fibrillation

Carolina Roselli, Mark D Chaffin, Lu-Chen Weng, Stefanie Aeschbacher, Gustav Ahlberg, Christine M Albert, Peter Almgren, Alvaro Alonso, Christopher D Anderson, Krishna G Aragam, Dan E Arking, John Barnard, Traci M Bartz, Emelia J Benjamin, Nathan A Bihlmeyer, Joshua C Bis, Heather L Bloom, Eric Boerwinkle, Erwin B Bottinger, Jennifer A BrodyHugh Calkins, Archie Campbell, Thomas P Cappola, John Carlquist, Daniel I Chasman, Lin Y Chen, Yii-Der Ida Chen, Eue-Keun Choi, Seung Hoan Choi, Ingrid E Christophersen, Mina K Chung, John W Cole, David Conen, James Cook, Harry J Crijns, Michael J Cutler, Scott M Damrauer, Brian R Daniels, Dawood Darbar, Graciela Delgado, Joshua C Denny, Martin Dichgans, Marcus Dörr, Elton A Dudink, Samuel C Dudley, Nada Esa, Tonu Esko, Markku Eskola, Diane Fatkin, Stephan B Felix, Ian Ford, Oscar H Franco, Bastiaan Geelhoed, Raji P Grewal, Vilmundur Gudnason, Xiuqing Guo, Namrata Gupta, Stefan Gustafsson, Rebecca Gutmann, Anders Hamsten, Tamara B Harris, Caroline Hayward, Susan R Heckbert, Jussi Hernesniemi, Lynne J Hocking, Albert Hofman, Andrea R V R Horimoto, Jie Huang, Paul L Huang, Jennifer Huffman, Erik Ingelsson, Esra Gucuk Ipek, Kaoru Ito, Jordi Jimenez-Conde, Renee Johnson, J Wouter Jukema, Stefan Kääb, Mika Kähönen, Yoichiro Kamatani, John P Kane, Adnan Kastrati, Sekar Kathiresan, Petra Katschnig-Winter, Maryam Kavousi, Thorsten Kessler, Bas L Kietselaer, Paulus Kirchhof, Marcus E Kleber, Stacey Knight, Jose E Krieger, Michiaki Kubo, Lenore J Launer, Jari Laurikka, Terho Lehtimäki, Kirsten Leineweber, Rozenn N Lemaitre, Man Li, Hong Euy Lim, Henry J Lin, Honghuang Lin, Lars Lind, Cecilia M Lindgren, Marja-Liisa Lokki, Barry London, Ruth J F Loos, Siew-Kee Low, Yingchang Lu, Leo-Pekka Lyytikäinen, Peter W Macfarlane, Patrik K Magnusson, Anubha Mahajan, Rainer Malik, Alfredo J Mansur, Gregory M Marcus, Lauren Margolin, Kenneth B Margulies, Winfried März, David D McManus, Olle Melander, Sanghamitra Mohanty, Jay A Montgomery, Michael P Morley, Andrew P Morris, Martina Müller-Nurasyid, Andrea Natale, Saman Nazarian, Benjamin Neumann, Christopher Newton-Cheh, Maartje N Niemeijer, Kjell Nikus, Peter Nilsson, Raymond Noordam, Heidi Oellers, Morten S Olesen, Marju Orho-Melander, Sandosh Padmanabhan, Hui-Nam Pak, Guillaume Paré, Nancy L Pedersen, Joanna Pera, Alexandre Pereira, David Porteous, Bruce M Psaty, Sara L Pulit, Clive R Pullinger, Daniel J Rader, Lena Refsgaard, Marta Ribasés, Paul M Ridker, Michiel Rienstra, Lorenz Risch, Dan M Roden, Jonathan Rosand, Michael A Rosenberg, Natalia Rost, Jerome I Rotter, Samir Saba, Roopinder K Sandhu, Renate B Schnabel, Katharina Schramm, Heribert Schunkert, Claudia Schurman, Stuart A Scott, Ilkka Seppälä, Christian Shaffer, Svati Shah, Alaa A Shalaby, Jaemin Shim, M Benjamin Shoemaker, Joylene E Siland, Juha Sinisalo, Moritz F Sinner, Agnieszka Slowik, Albert V Smith, Blair H Smith, J Gustav Smith, Jonathan D Smith, Nicholas L Smith, Elsayed Z Soliman, Nona Sotoodehnia, Bruno H Stricker, Albert Sun, Han Sun, Jesper H Svendsen, Toshihiro Tanaka, Kahraman Tanriverdi, Kent D Taylor, Maris Teder-Laving, Alexander Teumer, Sébastien Thériault, Stella Trompet, Nathan R Tucker, Arnljot Tveit, Andre G Uitterlinden, Pim Van Der Harst, Isabelle C Van Gelder, David R Van Wagoner, Niek Verweij, Efthymia Vlachopoulou, Uwe Völker, Biqi Wang, Peter E Weeke, Bob Weijs, Raul Weiss, Stefan Weiss, Quinn S Wells, Kerri L Wiggins, Jorge A Wong, Daniel Woo, Bradford B Worrall, Pil-Sung Yang, Jie Yao, Zachary T Yoneda, Tanja Zeller, Lingyao Zeng, Steven A Lubitz, Kathryn L Lunetta, Patrick T Ellinor

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1225-1233
Number of pages	9
Journal	Nature Genetics
Volume	50
Issue number	9
DOIs	https://doi.org/10.1038/s41588-018-0133-9
Publication status	Published - 1 Sept 2018
Externally published	Yes

Keywords

Atrial Fibrillation/ethnology
Case-Control Studies
Ethnicity/genetics
Genetic Predisposition to Disease
Genome-Wide Association Study/methods
Humans
Quantitative Trait Loci
Transcriptome

Access to Document

10.1038/s41588-018-0133-9

Cite this

Roselli, C., Chaffin, M. D., Weng, L.-C., Aeschbacher, S., Ahlberg, G., Albert, C. M., Almgren, P., Alonso, A., Anderson, C. D., Aragam, K. G., Arking, D. E., Barnard, J., Bartz, T. M., Benjamin, E. J., Bihlmeyer, N. A., Bis, J. C., Bloom, H. L., Boerwinkle, E., Bottinger, E. B., ... Ellinor, P. T. (2018). Multi-ethnic genome-wide association study for atrial fibrillation. Nature Genetics, 50(9), 1225-1233. https://doi.org/10.1038/s41588-018-0133-9

@article{e7ac075ff0814e9d941dd5de1a53f384,

title = "Multi-ethnic genome-wide association study for atrial fibrillation",

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.",

keywords = "Atrial Fibrillation/ethnology, Case-Control Studies, Ethnicity/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study/methods, Humans, Quantitative Trait Loci, Transcriptome",

author = "Carolina Roselli and Chaffin, {Mark D} and Lu-Chen Weng and Stefanie Aeschbacher and Gustav Ahlberg and Albert, {Christine M} and Peter Almgren and Alvaro Alonso and Anderson, {Christopher D} and Aragam, {Krishna G} and Arking, {Dan E} and John Barnard and Bartz, {Traci M} and Benjamin, {Emelia J} and Bihlmeyer, {Nathan A} and Bis, {Joshua C} and Bloom, {Heather L} and Eric Boerwinkle and Bottinger, {Erwin B} and Brody, {Jennifer A} and Hugh Calkins and Archie Campbell and Cappola, {Thomas P} and John Carlquist and Chasman, {Daniel I} and Chen, {Lin Y} and Chen, {Yii-Der Ida} and Eue-Keun Choi and Choi, {Seung Hoan} and Christophersen, {Ingrid E} and Chung, {Mina K} and Cole, {John W} and David Conen and James Cook and Crijns, {Harry J} and Cutler, {Michael J} and Damrauer, {Scott M} and Daniels, {Brian R} and Dawood Darbar and Graciela Delgado and Denny, {Joshua C} and Martin Dichgans and Marcus D{\"o}rr and Dudink, {Elton A} and Dudley, {Samuel C} and Nada Esa and Tonu Esko and Markku Eskola and Diane Fatkin and Felix, {Stephan B} and Ian Ford and Franco, {Oscar H} and Bastiaan Geelhoed and Grewal, {Raji P} and Vilmundur Gudnason and Xiuqing Guo and Namrata Gupta and Stefan Gustafsson and Rebecca Gutmann and Anders Hamsten and Harris, {Tamara B} and Caroline Hayward and Heckbert, {Susan R} and Jussi Hernesniemi and Hocking, {Lynne J} and Albert Hofman and Horimoto, {Andrea R V R} and Jie Huang and Huang, {Paul L} and Jennifer Huffman and Erik Ingelsson and Ipek, {Esra Gucuk} and Kaoru Ito and Jordi Jimenez-Conde and Renee Johnson and Jukema, {J Wouter} and Stefan K{\"a}{\"a}b and Mika K{\"a}h{\"o}nen and Yoichiro Kamatani and Kane, {John P} and Adnan Kastrati and Sekar Kathiresan and Petra Katschnig-Winter and Maryam Kavousi and Thorsten Kessler and Kietselaer, {Bas L} and Paulus Kirchhof and Kleber, {Marcus E} and Stacey Knight and Krieger, {Jose E} and Michiaki Kubo and Launer, {Lenore J} and Jari Laurikka and Terho Lehtim{\"a}ki and Kirsten Leineweber and Lemaitre, {Rozenn N} and Man Li and Lim, {Hong Euy} and Lin, {Henry J} and Honghuang Lin and Lars Lind and Lindgren, {Cecilia M} and Marja-Liisa Lokki and Barry London and Loos, {Ruth J F} and Siew-Kee Low and Yingchang Lu and Leo-Pekka Lyytik{\"a}inen and Macfarlane, {Peter W} and Magnusson, {Patrik K} and Anubha Mahajan and Rainer Malik and Mansur, {Alfredo J} and Marcus, {Gregory M} and Lauren Margolin and Margulies, {Kenneth B} and Winfried M{\"a}rz and McManus, {David D} and Olle Melander and Sanghamitra Mohanty and Montgomery, {Jay A} and Morley, {Michael P} and Morris, {Andrew P} and Martina M{\"u}ller-Nurasyid and Andrea Natale and Saman Nazarian and Benjamin Neumann and Christopher Newton-Cheh and Niemeijer, {Maartje N} and Kjell Nikus and Peter Nilsson and Raymond Noordam and Heidi Oellers and Olesen, {Morten S} and Marju Orho-Melander and Sandosh Padmanabhan and Hui-Nam Pak and Guillaume Par{\'e} and Pedersen, {Nancy L} and Joanna Pera and Alexandre Pereira and David Porteous and Psaty, {Bruce M} and Pulit, {Sara L} and Pullinger, {Clive R} and Rader, {Daniel J} and Lena Refsgaard and Marta Ribas{\'e}s and Ridker, {Paul M} and Michiel Rienstra and Lorenz Risch and Roden, {Dan M} and Jonathan Rosand and Rosenberg, {Michael A} and Natalia Rost and Rotter, {Jerome I} and Samir Saba and Sandhu, {Roopinder K} and Schnabel, {Renate B} and Katharina Schramm and Heribert Schunkert and Claudia Schurman and Scott, {Stuart A} and Ilkka Sepp{\"a}l{\"a} and Christian Shaffer and Svati Shah and Shalaby, {Alaa A} and Jaemin Shim and Shoemaker, {M Benjamin} and Siland, {Joylene E} and Juha Sinisalo and Sinner, {Moritz F} and Agnieszka Slowik and Smith, {Albert V} and Smith, {Blair H} and Smith, {J Gustav} and Smith, {Jonathan D} and Smith, {Nicholas L} and Soliman, {Elsayed Z} and Nona Sotoodehnia and Stricker, {Bruno H} and Albert Sun and Han Sun and Svendsen, {Jesper H} and Toshihiro Tanaka and Kahraman Tanriverdi and Taylor, {Kent D} and Maris Teder-Laving and Alexander Teumer and S{\'e}bastien Th{\'e}riault and Stella Trompet and Tucker, {Nathan R} and Arnljot Tveit and Uitterlinden, {Andre G} and {Van Der Harst}, Pim and {Van Gelder}, {Isabelle C} and {Van Wagoner}, {David R} and Niek Verweij and Efthymia Vlachopoulou and Uwe V{\"o}lker and Biqi Wang and Weeke, {Peter E} and Bob Weijs and Raul Weiss and Stefan Weiss and Wells, {Quinn S} and Wiggins, {Kerri L} and Wong, {Jorge A} and Daniel Woo and Worrall, {Bradford B} and Pil-Sung Yang and Jie Yao and Yoneda, {Zachary T} and Tanja Zeller and Lingyao Zeng and Lubitz, {Steven A} and Lunetta, {Kathryn L} and Ellinor, {Patrick T}",

note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = sep,

day = "1",

doi = "10.1038/s41588-018-0133-9",

language = "English",

volume = "50",

pages = "1225--1233",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "9",

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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, EB, Brody, JA, Calkins, H, Campbell, A, Cappola, TP, Carlquist, J, Chasman, DI, 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, Dörr, M, Dudink, EA, Dudley, SC, Esa, N, Esko, T, Eskola, M, Fatkin, D, Felix, SB, Ford, I, Franco, OH, Geelhoed, B, Grewal, RP, 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, Ipek, EG, Ito, K, Jimenez-Conde, J, Johnson, R, Jukema, JW, Kääb, 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, P, Noordam, R, Oellers, H, Olesen, MS, Orho-Melander, M, Padmanabhan, S, Pak, H-N, Paré, G, Pedersen, NL, Pera, J, Pereira, A, Porteous, D, Psaty, BM, Pulit, SL, Pullinger, CR, Rader, DJ, Refsgaard, L, Ribasés, M, Ridker, PM, Rienstra, M, Risch, L, Roden, DM, Rosand, J, Rosenberg, MA, Rost, N, Rotter, JI, Saba, S, Sandhu, RK, Schnabel, RB, Schramm, K, Schunkert, H, Schurman, C, Scott, SA, Seppälä, I, Shaffer, C, Shah, S, 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, Thériault, S, Trompet, S, Tucker, NR, Tveit, A, Uitterlinden, AG, Van Der Harst, P, Van Gelder, IC, Van Wagoner, DR, Verweij, N, Vlachopoulou, E, Völker, U, Wang, B, Weeke, PE, Weijs, B, Weiss, R, Weiss, S, Wells, QS, Wiggins, KL, Wong, JA, 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

TY - JOUR

T1 - Multi-ethnic genome-wide association study for atrial fibrillation

AU - Roselli, Carolina

AU - Chaffin, Mark D

AU - Weng, Lu-Chen

AU - Aeschbacher, Stefanie

AU - Ahlberg, Gustav

AU - Albert, Christine M

AU - Almgren, Peter

AU - Alonso, Alvaro

AU - Anderson, Christopher D

AU - Aragam, Krishna G

AU - Arking, Dan E

AU - Barnard, John

AU - Bartz, Traci M

AU - Benjamin, Emelia J

AU - Bihlmeyer, Nathan A

AU - Bis, Joshua C

AU - Bloom, Heather L

AU - Boerwinkle, Eric

AU - Bottinger, Erwin B

AU - Brody, Jennifer A

AU - Calkins, Hugh

AU - Campbell, Archie

AU - Cappola, Thomas P

AU - Carlquist, John

AU - Chasman, Daniel I

AU - Chen, Lin Y

AU - Chen, Yii-Der Ida

AU - Choi, Eue-Keun

AU - Choi, Seung Hoan

AU - Christophersen, Ingrid E

AU - Chung, Mina K

AU - Cole, John W

AU - Conen, David

AU - Cook, James

AU - Crijns, Harry J

AU - Cutler, Michael J

AU - Damrauer, Scott M

AU - Daniels, Brian R

AU - Darbar, Dawood

AU - Delgado, Graciela

AU - Denny, Joshua C

AU - Dichgans, Martin

AU - Dörr, Marcus

AU - Dudink, Elton A

AU - Dudley, Samuel C

AU - Esa, Nada

AU - Esko, Tonu

AU - Eskola, Markku

AU - Fatkin, Diane

AU - Felix, Stephan B

AU - Ford, Ian

AU - Franco, Oscar H

AU - Geelhoed, Bastiaan

AU - Grewal, Raji P

AU - Gudnason, Vilmundur

AU - Guo, Xiuqing

AU - Gupta, Namrata

AU - Gustafsson, Stefan

AU - Gutmann, Rebecca

AU - Hamsten, Anders

AU - Harris, Tamara B

AU - Hayward, Caroline

AU - Heckbert, Susan R

AU - Hernesniemi, Jussi

AU - Hocking, Lynne J

AU - Hofman, Albert

AU - Horimoto, Andrea R V R

AU - Huang, Jie

AU - Huang, Paul L

AU - Huffman, Jennifer

AU - Ingelsson, Erik

AU - Ipek, Esra Gucuk

AU - Ito, Kaoru

AU - Jimenez-Conde, Jordi

AU - Johnson, Renee

AU - Jukema, J Wouter

AU - Kääb, Stefan

AU - Kähönen, Mika

AU - Kamatani, Yoichiro

AU - Kane, John P

AU - Kastrati, Adnan

AU - Kathiresan, Sekar

AU - Katschnig-Winter, Petra

AU - Kavousi, Maryam

AU - Kessler, Thorsten

AU - Kietselaer, Bas L

AU - Kirchhof, Paulus

AU - Kleber, Marcus E

AU - Knight, Stacey

AU - Krieger, Jose E

AU - Kubo, Michiaki

AU - Launer, Lenore J

AU - Laurikka, Jari

AU - Lehtimäki, Terho

AU - Leineweber, Kirsten

AU - Lemaitre, Rozenn N

AU - Li, Man

AU - Lim, Hong Euy

AU - Lin, Henry J

AU - Lin, Honghuang

AU - Lind, Lars

AU - Lindgren, Cecilia M

AU - Lokki, Marja-Liisa

AU - London, Barry

AU - Loos, Ruth J F

AU - Low, Siew-Kee

AU - Lu, Yingchang

AU - Lyytikäinen, Leo-Pekka

AU - Macfarlane, Peter W

AU - Magnusson, Patrik K

AU - Mahajan, Anubha

AU - Malik, Rainer

AU - Mansur, Alfredo J

AU - Marcus, Gregory M

AU - Margolin, Lauren

AU - Margulies, Kenneth B

AU - März, Winfried

AU - McManus, David D

AU - Melander, Olle

AU - Mohanty, Sanghamitra

AU - Montgomery, Jay A

AU - Morley, Michael P

AU - Morris, Andrew P

AU - Müller-Nurasyid, Martina

AU - Natale, Andrea

AU - Nazarian, Saman

AU - Neumann, Benjamin

AU - Newton-Cheh, Christopher

AU - Niemeijer, Maartje N

AU - Nikus, Kjell

AU - Nilsson, Peter

AU - Noordam, Raymond

AU - Oellers, Heidi

AU - Olesen, Morten S

AU - Orho-Melander, Marju

AU - Padmanabhan, Sandosh

AU - Pak, Hui-Nam

AU - Paré, Guillaume

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AU - Pera, Joanna

AU - Pereira, Alexandre

AU - Porteous, David

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AU - Pulit, Sara L

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AU - Rader, Daniel J

AU - Refsgaard, Lena

AU - Ribasés, Marta

AU - Ridker, Paul M

AU - Rienstra, Michiel

AU - Risch, Lorenz

AU - Roden, Dan M

AU - Rosand, Jonathan

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AU - Rost, Natalia

AU - Rotter, Jerome I

AU - Saba, Samir

AU - Sandhu, Roopinder K

AU - Schnabel, Renate B

AU - Schramm, Katharina

AU - Schunkert, Heribert

AU - Schurman, Claudia

AU - Scott, Stuart A

AU - Seppälä, Ilkka

AU - Shaffer, Christian

AU - Shah, Svati

AU - Shalaby, Alaa A

AU - Shim, Jaemin

AU - Shoemaker, M Benjamin

AU - Siland, Joylene E

AU - Sinisalo, Juha

AU - Sinner, Moritz F

AU - Slowik, Agnieszka

AU - Smith, Albert V

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AU - Woo, Daniel

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AU - Yang, Pil-Sung

AU - Yao, Jie

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N1 - Funding Information: 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. Publisher Copyright: © 2018, The Author(s).

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

AB - 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.

KW - Atrial Fibrillation/ethnology

KW - Case-Control Studies

KW - Ethnicity/genetics

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study/methods

KW - Humans

KW - Quantitative Trait Loci

KW - Transcriptome

UR - http://www.scopus.com/inward/record.url?scp=85048317620&partnerID=8YFLogxK

U2 - 10.1038/s41588-018-0133-9

DO - 10.1038/s41588-018-0133-9

M3 - Article

C2 - 29892015

SN - 1061-4036

VL - 50

SP - 1225

EP - 1233

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

Multi-ethnic genome-wide association study for atrial fibrillation

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