Abstract

Obesity is a risk factor for a wide variety of health problems. In a genome-wide association study (GWAS) of body mass index (BMI) in Japanese people (n = 173,430), we found 85 loci significantly associated with obesity (P < 5.0 × 10−8), of which 51 were previously unknown. We conducted trans-ancestral meta-analyses by integrating these results with the results from a GWAS of Europeans and identified 61 additional new loci. In total, this study identifies 112 novel loci, doubling the number of previously known BMI-associated loci. By annotating associated variants with cell-type-specific regulatory marks, we found enrichment of variants in CD19+ cells. We also found significant genetic correlations between BMI and lymphocyte count (P = 6.46 × 10−5, rg = 0.18) and between BMI and multiple complex diseases. These findings provide genetic evidence that lymphocytes are relevant to body weight regulation and offer insights into the pathogenesis of obesity.

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Acknowledgements

We would like to acknowledge the staff of the TMM, the JPHC and the BBJ for collecting samples and clinical information. We are grateful to the staff of the RIKEN Center for Integrative Medical Sciences for genotyping and data management. We thank S.K. Low, K. Suzuki and M. Horikoshi for advice on statistical analyses, and A.P. Morris for providing us with the MANTRA software. This study was funded by the BioBank Japan project (M.A., Y.O., M. Kanai, A.T., Y.M., M.H., K.M., M. Kubo and Y.K.) and Tohoku Medical Megabank project (T.H., K.T., A.S., A.H., N.M. and M.Y.), which is supported by the Ministry of Education, Culture, Sports, Sciences and Technology of Japanese government and the Japan Agency for Medical Research and Development. The JPHC Study has been supported by the National Cancer Research and Development Fund (2010–present) and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (1989–2010) (M. Iwasaki., T.Y., N.S. and S.T.). GWAS of psychiatric disorders were the results of the Strategic Research Program for Brain Sciences (SRPBS) from the Japan Agency for Medical Research and Development (A.T., M. Ikeda, N.I., M. Kubo and Y.K.).

Author information

Affiliations

  1. Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

    • Masato Akiyama
    • , Yukinori Okada
    • , Masahiro Kanai
    • , Atsushi Takahashi
    •  & Yoichiro Kamatani
  2. Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.

    • Yukinori Okada
  3. Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.

    • Yukinori Okada
  4. Laboratory for Omics Informatics, Omics Research Center, National Cerebral and Cardiovascular Center, Osaka, Japan.

    • Atsushi Takahashi
  5. Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

    • Yukihide Momozawa
  6. Department of Psychiatry, Fujita Health University School of Medicine, Aichi, Japan.

    • Masashi Ikeda
    •  & Nakao Iwata
  7. Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.

    • Shiro Ikegawa
  8. Institute of Medical Science, the University of Tokyo, Tokyo, Japan.

    • Makoto Hirata
  9. Graduate school of Frontier Sciences, the University of Tokyo, Tokyo, Japan.

    • Koichi Matsuda
  10. Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.

    • Motoki Iwasaki
    • , Taiki Yamaji
    •  & Norie Sawada
  11. Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan.

    • Tsuyoshi Hachiya
    • , Kozo Tanno
    •  & Atsushi Shimizu
  12. Department of Hygiene and Preventive Medicine, School of Medicine, Iwate Medical University, Iwate, Japan.

    • Kozo Tanno
  13. Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.

    • Atsushi Hozawa
    • , Naoko Minegishi
    •  & Masayuki Yamamoto
  14. Graduate School of Medicine, Tohoku University, Sendai, Japan.

    • Atsushi Hozawa
    • , Naoko Minegishi
    •  & Masayuki Yamamoto
  15. Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.

    • Shoichiro Tsugane
  16. RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

    • Michiaki Kubo
  17. Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

    • Yoichiro Kamatani

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Contributions

M.A., Y.K. and M. Kubo conceived and designed the study. K.M., M.H. and M. Kubo collected and managed the BBJ sample. M. Iwasaki, T.Y., N.S. and S.T. collected and managed JPHC sample and information. T.H., K.T., A.S., A.H., N.M. and M.Y. collected and managed the TMM sample. Y.M. and M. Kubo performed genotyping. M.A., M. Kanai, Y.K. and A.T. performed statistical analysis. S.I., M. Ikeda and N.I. contributed to data acquisition. Y.O., A.T., Y.K. and M. Kubo supervised the study. M.A., Y.O., Y.K. and M. Kubo wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Yoichiro Kamatani.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–14 and Supplementary Note.

  2. 2.

    Life Sciences Reporting Summary

  3. 3.

    Supplementary Data Set 1

    Regional association plots of newly identified loci.

  4. 4.

    Supplementary Data Set 2

    Regional association plots of previously reported loci.

  5. 5.

    Supplementary Data Set 3

    Regional association plots of trans-ethnic meta-analysis.

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    Supplementary Tables

    Supplementary Tables 1–27 (excel)

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DOI

https://doi.org/10.1038/ng.3951

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