Abstract

We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of east Asian ancestry from the AGEN-BP consortium followed up with de novo genotyping (n = 10,518) and further replication (n = 20,247) in east Asian samples. We identified genome-wide significant (P < 5 × 10−8) associations with SBP or DBP, which included variants at four new loci (ST7L-CAPZA1, FIGN-GRB14, ENPEP and NPR3) and a newly discovered variant near TBX3. Among the five newly discovered variants, we obtained significant replication in the independent samples for all of these loci except NPR3. We also confirmed seven loci previously identified in populations of European descent. Moreover, at 12q24.13 near ALDH2, we observed strong association signals (P = 7.9 × 10−31 and P = 1.3 × 10−35 for SBP and DBP, respectively) with ethnic specificity. These findings provide new insights into blood pressure regulation and potential targets for intervention.

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Acknowledgements

The authors acknowledge the essential role of the Asian Genetic Epidemiology Network (AGEN) in developing and supporting this manuscript. AGEN members include the Cardio-metabolic Genome Epidemiology (CAGE) Network, Genetic Epidemiology Network of Salt-Sensitivity (GenSalt), Korean Association Resource (KARE) Project, Shanghai Hypertension Study, Singapore Malay Eye Survey (SiMES), Singapore Prospective Study (SP2) Program, Suita Study and Taiwan Super Control Study.

CAGE: The CAGE Network Studies were supported by grants for the Core Research for Evolutional Science and Technology (CREST) from the Japan Science Technology Agency; the Program for Promotion of Fundamental Studies in Health Sciences, National Institute of Biomedical Innovation Organization (NIBIO); KAKENHI (Grant-in-Aid for Scientific Research) on Priority Areas 'Applied Genomics' from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and the Grant of National Center for Global Health and Medicine (NCGM).

GenSalt: The Genetic Epidemiology Network of Salt Sensitivity is supported by research grants (U01HL072507, R01HL087263 and R01HL090682) from the National Heart, Lung, and Blood Institute, National Institutes of Health (Bethesda, Maryland, USA). T.N.K. is supported partially by Award Number K12HD043451 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Bethesda, Maryland, USA).

KARE: KARE and HEXA-shared control studies were supported by grants from Korea Centers for Disease Control & Prevention, Republic of Korea (4845-301, 4851-302, 4851-307).

Shanghai: This work was supported by the Chinese National Key Program for Basic Research (grants 973:2004CB518603, 2006CB503804 and 2009CB521905) and Chinese National High Tech Program (grants 863:2009AA022703 and 2006AA02Z179) and the Ministry of Science and Technology, National Natural Science Foundation (30871361).

SiMES: The Singapore Malay Eye Study (SiMES) was funded by the National Medical Research Council (NMRC 0796/2003 and NMRC/STaR/0003/2008) and the Biomedical Research Council (BMRC, 09/1/35/19/616).

SP2: The Singapore Prospective Study Program (SP2) was funded through grants from the Biomedical Research Council of Singapore (BMRC 05/1/36/19/413 and 03/1/27/18/216) and the National Medical Research Council of Singapore (NMRC/1174/2008). Y.Y.T. acknowledges support from the Singapore National Research Foundation (NRF-RF-2010-05). E.S.T. also receives additional support from the National Medical Research Council through a clinician scientist award (NMRC/CSA/008/2009).

Suita/Ehime Study: The Ehime Study was supported by Grants for Scientific Research (Priority Areas 'Medical Genome Science (Millennium Genome Project)' and 'Applied Genomics') from the Ministry of Education, Culture, Sports, Science and Technology, Japan; a Grants-in-Aid (H15-longevity-005, H17-longevity-003, H16-kenko-001, H18-longevity (kokusai)) from the Ministry of Health, Labor and Welfare, Health and Labor Sciences Research Grants, Japan; a Science and Technology Incubation Program in Advanced Regions, Japan Science and Technology Agency; and the Japan Atherosclerosis Prevention Fund.

Taiwan Super Control Study: This study was supported by Academia Sinica Genomic Medicine Multicenter Study; National Research Program for Genomic Medicine, National Science Council, Taiwan (National Clinical Core, NSC97-3112-B-001-014; and National Genotyping Center, NSC97-3112-B-001-015).

Author information

Author notes

    • Norihiro Kato
    • , Fumihiko Takeuchi
    • , Yasuharu Tabara
    • , Tanika N Kelly
    • , Min Jin Go
    • , Xueling Sim
    • , Wan Ting Tay
    • , Chien-Hsiun Chen
    • , Yi Zhang
    • , Ken Yamamoto
    • , Tomohiro Katsuya
    •  & Mitsuhiro Yokota

    These authors contributed equally to this work.

    • Toshio Ogihara
    • , Dingliang Zhu
    • , Naoharu Iwai
    • , Jer-Yuarn Wu
    • , Yik Ying Teo
    • , E Shyong Tai
    • , Yoon Shin Cho
    •  & Jiang He

    These authors jointly directed this work.

Affiliations

  1. Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.

    • Norihiro Kato
    • , Fumihiko Takeuchi
    •  & Masato Isono
  2. Department of Basic Medical Research and Education, Ehime University Graduate School of Medicine, Toon, Japan.

    • Yasuharu Tabara
  3. Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.

    • Tanika N Kelly
    •  & Jiang He
  4. Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex, Chungcheongbuk-do, Korea.

    • Min Jin Go
    • , Young Jin Kim
    • , Jong-Young Lee
    • , Jae-Pil Jeon
    • , Sung Soo Kim
    • , Bok-Ghee Han
    •  & Yoon Shin Cho
  5. Centre for Molecular Epidemiology, National University of Singapore, Singapore.

    • Xueling Sim
    •  & Yik Ying Teo
  6. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

    • Wan Ting Tay
    • , Tin Aung
    •  & Tien Yin Wong
  7. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

    • Chien-Hsiun Chen
    • , Li-ching Chang
    • , Yuan-Tsong Chen
    •  & Jer-Yuarn Wu
  8. School of Chinese Medicine, China Medical University, Taichung, Taiwan.

    • Chien-Hsiun Chen
    •  & Jer-Yuarn Wu
  9. State Key Laboratory of Medical Genetics, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

    • Yi Zhang
    •  & Dingliang Zhu
  10. Shanghai Institute of Hypertension, Shanghai, China.

    • Yi Zhang
    •  & Dingliang Zhu
  11. Division of Genome Analysis, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.

    • Ken Yamamoto
  12. Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Japan.

    • Tomohiro Katsuya
  13. Department of Genome Science, Aichi-Gakuin University, School of Dentistry, Nagoya, Japan.

    • Mitsuhiro Yokota
  14. National University of Singapore Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore.

    • Rick Twee Hee Ong
    •  & Yik Ying Teo
  15. Department of Functional Pathology, Shimane University School of Medicine, Izumo, Japan.

    • Toru Nabika
  16. Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • Dongfeng Gu
  17. Chinese National Center for Cardiovascular Diseases, Beijing, China.

    • Dongfeng Gu
  18. Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, Suita, Japan.

    • Yoshihiro Kokubo
  19. Department of Genetics, Chinese National Human Genomic Center, Shanghai, China.

    • Wei Huang
  20. Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

    • Keizo Ohnaka
  21. Mukogawa Women's University Institute for World Health Development, Nishinomiya, Japan.

    • Yukio Yamori
  22. Division of Endocrinology and Diabetes, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

    • Eitaro Nakashima
  23. Department of Diabetes and Endocrinology, Chubu Rosai Hospital, Nagoya, Japan.

    • Eitaro Nakashima
  24. Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.

    • Cashell E Jaquish
  25. Institute of Human Genetics, University of California, San Francisco, California, USA.

    • Mark Seielstad
  26. Department of Epidemiology, University of Texas School of Public Health, Houston, Texas, USA.

    • James E Hixson
  27. Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon, Japan.

    • Tetsuro Miki
  28. Key Laboratory of Bioinformatics, Department of Automation, Tsinghua University, Beijing, China.

    • Xueya Zhou
    •  & Xuegong Zhang
  29. Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan.

    • Takao Sugiyama
    •  & Yik Ying Teo
  30. Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.

    • Jian Jun Liu
  31. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

    • Ryoichi Takayanagi
  32. Department of Ophthalmology, National University of Singapore, Singapore.

    • Tin Aung
    •  & Tien Yin Wong
  33. Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Yun Ju Sung
  34. Center for Eye Research Australia, University of Melbourne, Melbourne, Australia.

    • Tien Yin Wong
  35. Director, Shimane University Hospital, Izumo, Japan.

    • Shotai Kobayashi
  36. Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.

    • Toshio Ogihara
  37. Department of Genomic Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.

    • Naoharu Iwai
  38. Department of Statistics and Applied Probability, National University of Singapore, Singapore.

    • Yik Ying Teo
  39. Department of Epidemiology and Public Health, National University of Singapore, Singapore.

    • Yik Ying Teo
    •  & E Shyong Tai
  40. Department of Medicine, National University of Singapore, Singapore.

    • E Shyong Tai
  41. Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.

    • Jiang He

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Contributions

Principal investigators: N.K., J.H.

Project coordination leaders: N.K., J.H., Y.T.

Manuscript writing group: N.K., F.T., T.N.K., J.H., Y.Y.T., Y.S.C., E.S.T.

Project data management: T.N.K.

Genotyping and quality control: F.T., M.I., K.Y., Y.T., N.I., Y.K., X.S., W.T.T., Y.Y.T.

Phenotype collection, data management: CAGE: N.K., K.Y., T.K., T.N., M.Y., K.O., Y.Y., E.N., T.S., R.T., S.K., T.O.; GenSalt: T.N.K., D.G., J.H.; KARE: J.-P.J., S.S.K., Y.S.C.; Shanghai: Y.Z., X. Zhang, X. Zhou, D.Z.; SiMES/SP2: T.A., T.Y.W., E.S.T.; Suita: N.I., Y.K., Y.T., T.M.; Taiwan: C.-H.C., L.-c.C., Y.-T.C., J.-Y.W.

Genome-wide genotyping: CAGE: N.K., M.I.; GenSalt: J.E.H., Y.J.S.; KARE: J.-Y.L., B.-G.H., Y.S.C.; Shanghai: W.H.; SiMES/SP2: M.S., J.J.L.; Suita: N.I.; Taiwan: Y.-T.C., J.-Y.W.

Data analysis and data interpretation: N.K., F.T., T.N.K., Y.T., Y.Y.T., E.S.T., M.J.G., Y.J.K., X.S., W.T.T., R.T.H.O., C.-H.C., L.-c.C., C.E.J., J.H.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Norihiro Kato.

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DOI

https://doi.org/10.1038/ng.834

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