Abstract

Clinical measurements can be viewed as useful intermediate phenotypes to promote understanding of complex human diseases. To acquire comprehensive insights into the underlying genetics, here we conducted a genome-wide association study (GWAS) of 58 quantitative traits in 162,255 Japanese individuals. Overall, we identified 1,407 trait-associated loci (P < 5.0 × 10−8), 679 of which were novel. By incorporating 32 additional GWAS results for complex diseases and traits in Japanese individuals, we further highlighted pleiotropy, genetic correlations, and cell-type specificity across quantitative traits and diseases, which substantially expands the current understanding of the associated genetics and biology. This study identified both shared polygenic effects and cell-type specificity, represented by the genetic links among clinical measurements, complex diseases, and relevant cell types. Our findings demonstrate that even without prior biological knowledge of cross-phenotype relationships, genetics corresponding to clinical measurements successfully recapture those measurements’ relevance to diseases, and thus can contribute to the elucidation of unknown etiology and pathogenesis.

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Acknowledgements

We acknowledge the staff of BBJ for their outstanding assistance in collecting samples and clinical information. We also thank the Tohoku Medical Megabank Project, the Japan Public Health Center–based Prospective (JPHC) Study, and the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study for their invaluable contributions to the case-control studies used in this study. We thank the staff of the Japan Scoliosis Clinical Research Group (JSCRG) for their support in recruiting patients to the AIS GWAS used in this study. We are grateful to H. Finucane for helpful discussions and assistance with LD score regression analysis. This research was supported by the Tailor-Made Medical Treatment Program (the BioBank Japan Project) of the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) and the Japan Agency for Medical Research and Development (AMED). The study of psychiatric disorders was supported by the Strategic Research Program for Brain Sciences (SRPBS) of AMED. M. Kanai was supported by a Nakajima Foundation Fellowship. Y.O. was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (grants 15H05670, 15H05907, 15H05911, 15K14429, 16H03269, and 16K15738), AMED (grants 16km0405206h0001, 16gm6010001h0001, and 17ek0410041h0001), Takeda Science Foundation, the Uehara Memorial Foundation, the Naito Foundation, Daiichi Sankyo Foundation of Life Science, and Senri Life Science Foundation.

Author information

Author notes

  1. These authors jointly supervised this work: Yukinori Okada and Yoichiro Kamatani.

Affiliations

  1. Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan

    • Masahiro Kanai
    •  & Yukinori Okada
  2. Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    • Masahiro Kanai
    • , Masato Akiyama
    • , Atsushi Takahashi
    • , Nana Matoba
    • , Yukinori Okada
    •  & Yoichiro Kamatani
  3. Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA

    • Masahiro Kanai
  4. Department of Genomic Medicine, Research Institute, 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. RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    • Michiaki Kubo
  11. Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Osaka, Japan

    • Yukinori Okada
  12. Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

    • Yoichiro Kamatani

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Contributions

M. Kanai, M.A., M. Kubo, Y.O., and Y.K. designed the study and wrote the manuscript. K.M., M.H., and M. Kubo collected and managed the BBJ samples. Y.M. and M. Kubo performed genotyping. M. Kanai, M.A., A.T., and N.M. performed statistical analysis. S.I., M.I., and N.I. contributed to data acquisition. Y.O. and Y.K. supervised the study. All authors contributed to and approved the final version of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Yukinori Okada or Yoichiro Kamatani.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–9 and Supplementary Note 1

  2. Life Sciences Reporting Summary

  3. Supplementary Tables

    Supplementary Tables 1–12

  4. Supplementary Dataset 1

    Manhattan, quantile–quantile, and LD score plots for the 58 quantitative traits

  5. Supplementary Dataset 2

    Regional plots for all identified trait-associated loci

About this article

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DOI

https://doi.org/10.1038/s41588-018-0047-6

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    • , Stefan T. Engelter
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    • , Vilmundur Gudnason
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    •  & Martin Dichgans

    Nature Genetics (2018)