Identification of six new genetic loci associated with atrial fibrillation in the Japanese population

Abstract

Atrial fibrillation is the most common cardiac arrhythmia and leads to stroke. To investigate genetic loci associated with atrial fibrillation in the Japanese population, we performed a genome-wide association study (GWAS) that included 8,180 atrial fibrillation cases and 28,612 controls with follow-up in an additional 3,120 cases and 125,064 controls. We replicated previously reported loci and identified six new loci, near the KCND3, PPFIA4, SLC1A4CEP68, HAND2, NEBL and SH3PXD2A genes. Five of the six new loci were specifically associated with atrial fibrillation in the Japanese population after comparing our data to those from individuals of European ancestry, suggesting that there might be different genetic factors affecting susceptibility across ancestry groups. Our study discovered variants in the HAND2, KCND3 and NEBL genes, which are relevant to atrial fibrillation susceptibility. The involvement of PPFIA4 and SH3PXD2A in axon guidance also suggested a role in disease pathogenesis. Our findings may contribute to a better understanding of atrial fibrillation susceptibility and pathogenesis.

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Figure 1: Regional association plots for six new loci associated with atrial fibrillation in the Japanese population.

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Acknowledgements

We express our heartfelt gratitude to all the participants in this study. We would like to express our gratefulness to the staff of TMM, J-MICC, JPHC and BBJ for their outstanding assistance. We extend our appreciation to N. Miyagawa and other members of the Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences for their support. This study was in part supported by the Naito Foundation Natural Science Scholarship to T.T. This study was also funded by the BioBank Japan project and the Tohoku Medical Megabank project, which is supported by the Ministry of Education, Culture, Sports, Sciences and Technology Japan and the Japan Agency for Medical Research and Development. The JPHC Study has been supported by the National Cancer Research and Development Fund since 2010 and was supported by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan from 1989 to 2010. The J-MICC Study was supported by Grants-in-Aid for Scientific Research for Priority Areas of Cancer (17015018) and Innovative Areas (221S0001) and the JSPS KAKENHI Grant (16H06277) from the Japan Ministry of Education, Science, Sports, Culture and Technology. The following research institutions participated in the study: Chiba Cancer Center, University of Shizuoka, Nagoya City University, Aichi Cancer Center, Nagoya University, Shiga University of Medical Science, Kyoto Prefectural University of Medicine, University of Tokushima, Kyushu University, Saga University and Kagoshima University. This work was supported by grants from the US National Institutes of Health to P.T.E. (1RO1HL092577, R01HL128914, K24HL105780). P.T.E. is also supported by an Established Investigator Award from the American Heart Association (13EIA14220013) and by the Fondation Leducq (14CVD01).

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S.-K.L., K.I. and Y.K. wrote the manuscript. S.-K.L., A.T. and Y.K. conducted the data analyses. Y.E., K.O. and T.F. conducted replication genotyping, I.E.C., P.T.E. and the AFGen Consortium provided data from the AFGen Consortium. M.K. conducted SNP genotyping. Y.E., S.O., M.Y., M. Satoh, M. Sasaki, T.Y., M.I., S.T., K.T., M.N., K.W., H.T., T.F. and M.K. collected the samples. S.-K.L., A.T., K.I., Y.K. and T.T. designed the study.

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Correspondence to Kaoru Ito or Yoichiro Kamatani or Toshihiro Tanaka.

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

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Supplementary Text and Figures

Supplementary Figures 1–5, Supplementary Tables 1, 2 and 7–11, and Supplementary Note (PDF 3606 kb)

Supplementary Table 3

Association studies after adjusting for the effect of diabetes. (XLSX 52 kb)

Supplementary Table 4

Association studies after adjusting for the effect of myocardial infarction. (XLSX 49 kb)

Supplementary Table 5

Association studies after adjusting for the effect of heart failure. (XLSX 53 kb)

Supplementary Table 6

Association of atrial fibrillation variants with other traits according to the GWAS catalog (12 December 2016). (XLSX 49 kb)

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Low, SK., Takahashi, A., Ebana, Y. et al. Identification of six new genetic loci associated with atrial fibrillation in the Japanese population. Nat Genet 49, 953–958 (2017). https://doi.org/10.1038/ng.3842

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