Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci

Taisuke Ishikawa¹, Tatsuo Masuda^{2

3

4}, Tsuyoshi Hachiya⁵, Christian Dina⁶, Floriane Simonet⁶, Yuki Nagata^{7

8}, Michael W T Tanck⁹, Kyuto Sonehara^{2

10}, Charlotte Glinge^{11

12

13

14}, Rafik Tadros^{11

12

15}, Apichai Khongphatthanayothin^{16

17

18}, Tzu-Pin Lu¹⁹, Chihiro Higuchi^{7

20}, Tadashi Nakajima²¹, Kenshi Hayashi²², Yoshiyasu Aizawa²³, Yukiko Nakano²⁴, Akihiko Nogami²⁵, Hiroshi Morita²⁶, Seiko Ohno^{27

28}, Takeshi Aiba²⁹, Christian Krijger Juárez^{11

12}, John Mauleekoonphairoj¹⁶, Yong Poovorawan³⁰, Jean-Baptiste Gourraud^{6

14}, Wataru Shimizu³¹, Vincent Probst^{6

14}, Minoru Horie²⁸, Arthur A M Wilde^{12

14

32}, Richard Redon⁶, Jyh-Ming Jimmy Juang^{33

34}, Koonlawee Nademanee^{16

35}, Connie R Bezzina^{11

12

14}, Julien Barc^{6

14}, Toshihiro Tanaka^{7

8}, Yukinori Okada^{2

10

36

37}, Jean-Jacques Schott^{6

14}, Naomasa Makita^{38

39}

Affiliations

¹ Omics Research Center, National Cerebral and Cardiovascular Center, Suita, Japan.
² Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
³ StemRIM Institute of Regeneration-Inducing Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
⁴ Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Japan.
⁵ Institute for Biomedical Sciences, Iwate Medical University, Iwate, Japan.
⁶ L'institut du thorax, Nantes Université, CHU Nantes, CNRS, INSERM, Nantes, France.
⁷ Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
⁸ Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University, Tokyo, Japan.
⁹ Epidemiology and Data Science, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands.
¹⁰ Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
¹¹ Department of Experimental Cardiology, Amsterdam UMC location University of Amsterdam, Heart Centre, Amsterdam, The Netherlands.
¹² Heart Failure & Arrhythmias, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.
¹³ Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
¹⁴ European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART https://guardheart.ern-net.eu).
¹⁵ Montreal Heart Institute, Universite de Montreal, Cardiovascular Genetics Centre, Montreal, Quebec, Canada.
¹⁶ Department of Medicine, Center of Excellence in Arrhythmia Research Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
¹⁷ Department of Pediatrics, Division of Cardiology Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
¹⁸ Department of Cardiology, Bangkok Hospital, Bangkok, Thailand.
¹⁹ Department of Public Health, Institute of Health Data Analytics and Statistics, National Taiwan University, Taipei, Taiwan.
²⁰ Artificial Intelligence Center for Health and Biomedical Research, National Institutes of Biomedical Innovation, Health and Nutrition, Settsu, Japan.
²¹ Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan.
²² Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
²³ Department of Cardiovascular Medicine, International University of Health and Welfare, Narita, Japan.
²⁴ Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
²⁵ Department of Cardiology, University of Tsukuba, Tsukuba, Japan.
²⁶ Department of Cardiovascular Therapeutics, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
²⁷ Medical Genome Center, National Cerebral and Cardiovascular Center, Suita, Japan.
²⁸ Department of Cardiovascular Medicine, Shiga University of Medical Sciences, Otsu, Japan.
²⁹ Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
³⁰ Center of Excellence in Clinical Virology Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
³¹ Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.
³² Department of Cardiology, Amsterdam UMC location University of Amsterdam, Heart Centre, Amsterdam, The Netherlands.
³³ Cardiovascular Center, Heart Failure Center and Department of Internal Medicine, Division of Cardiology, National Taiwan University Hospital, Taipei, Taiwan.
³⁴ Department of Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
³⁵ Pacific Rim Electrophysiology Research Institute, Bumrungrad International Hospital, Bangkok, Thailand.
³⁶ Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
³⁷ Laboratory of Statistical Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan.
³⁸ Department of Cardiology, Sapporo Teishinkai Hospital, N33, E1, Sapporo 065-0033, Japan.
³⁹ Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 6-1, Kishibe Shimmachi, 564-8565 Suita, Japan.

PMID: 38747976
DOI: 10.1093/eurheartj/ehae251

Meta-Analysis

Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci

Taisuke Ishikawa et al. Eur Heart J. 2024.

. 2024 Jul 9;45(26):2320-2332.

doi: 10.1093/eurheartj/ehae251.

Authors

Affiliations

¹ Omics Research Center, National Cerebral and Cardiovascular Center, Suita, Japan.
² Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
³ StemRIM Institute of Regeneration-Inducing Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
⁴ Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Japan.
⁵ Institute for Biomedical Sciences, Iwate Medical University, Iwate, Japan.
⁶ L'institut du thorax, Nantes Université, CHU Nantes, CNRS, INSERM, Nantes, France.
⁷ Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
⁸ Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University, Tokyo, Japan.
⁹ Epidemiology and Data Science, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands.
¹⁰ Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
¹¹ Department of Experimental Cardiology, Amsterdam UMC location University of Amsterdam, Heart Centre, Amsterdam, The Netherlands.
¹² Heart Failure & Arrhythmias, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.
¹³ Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
¹⁴ European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART https://guardheart.ern-net.eu).
¹⁵ Montreal Heart Institute, Universite de Montreal, Cardiovascular Genetics Centre, Montreal, Quebec, Canada.
¹⁶ Department of Medicine, Center of Excellence in Arrhythmia Research Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
¹⁷ Department of Pediatrics, Division of Cardiology Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
¹⁸ Department of Cardiology, Bangkok Hospital, Bangkok, Thailand.
¹⁹ Department of Public Health, Institute of Health Data Analytics and Statistics, National Taiwan University, Taipei, Taiwan.
²⁰ Artificial Intelligence Center for Health and Biomedical Research, National Institutes of Biomedical Innovation, Health and Nutrition, Settsu, Japan.
²¹ Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan.
²² Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
²³ Department of Cardiovascular Medicine, International University of Health and Welfare, Narita, Japan.
²⁴ Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
²⁵ Department of Cardiology, University of Tsukuba, Tsukuba, Japan.
²⁶ Department of Cardiovascular Therapeutics, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
²⁷ Medical Genome Center, National Cerebral and Cardiovascular Center, Suita, Japan.
²⁸ Department of Cardiovascular Medicine, Shiga University of Medical Sciences, Otsu, Japan.
²⁹ Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
³⁰ Center of Excellence in Clinical Virology Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
³¹ Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.
³² Department of Cardiology, Amsterdam UMC location University of Amsterdam, Heart Centre, Amsterdam, The Netherlands.
³³ Cardiovascular Center, Heart Failure Center and Department of Internal Medicine, Division of Cardiology, National Taiwan University Hospital, Taipei, Taiwan.
³⁴ Department of Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
³⁵ Pacific Rim Electrophysiology Research Institute, Bumrungrad International Hospital, Bangkok, Thailand.
³⁶ Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
³⁷ Laboratory of Statistical Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan.
³⁸ Department of Cardiology, Sapporo Teishinkai Hospital, N33, E1, Sapporo 065-0033, Japan.
³⁹ Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 6-1, Kishibe Shimmachi, 564-8565 Suita, Japan.

PMID: 38747976
DOI: 10.1093/eurheartj/ehae251

Abstract

Background and aims: Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans. Genome-wide association studies (GWAS) have revealed its polygenic architecture mainly in European populations. The aim of this study was to identify novel BrS-associated loci and to compare allelic effects across ancestries.

Methods: A GWAS was conducted in Japanese participants, involving 940 cases and 1634 controls, followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3760 cases and 11 635 controls). The novel loci were characterized by fine-mapping, gene expression, and splicing quantitative trait associations in the human heart.

Results: The Japanese-specific GWAS identified one novel locus near ZSCAN20 (P = 1.0 × 10-8), and the cross-ancestry meta-analysis identified 17 association signals, including six novel loci. The effect directions of the 17 lead variants were consistent (94.1%; P for sign test = 2.7 × 10-4), and their allelic effects were highly correlated across ancestries (Pearson's R = .91; P = 2.9 × 10-7). The genetic risk score derived from the BrS GWAS of European ancestry was significantly associated with the risk of BrS in the Japanese population [odds ratio 2.12 (95% confidence interval 1.94-2.31); P = 1.2 × 10-61], suggesting a shared genetic architecture across ancestries. Functional characterization revealed that a lead variant in CAMK2D promotes alternative splicing, resulting in an isoform switch of calmodulin kinase II-δ, favouring a pro-inflammatory/pro-death pathway.

Conclusions: This study demonstrates novel susceptibility loci implicating potentially novel pathogenesis underlying BrS. Despite differences in clinical expressivity and epidemiology, the polygenic architecture of BrS was substantially shared across ancestries.

Keywords: SCN5A; Brugada syndrome; Cross-ancestry meta-analysis; Genetic risk score; Genome-wide association studies.

© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

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Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci

Affiliations

Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci

Authors

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Abstract

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