Abstract

Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here we analyze a broad set of functional elements, including cell type–specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits with an average sample size of 73,599. To enable this analysis, we introduce a new method, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers. This new method is computationally tractable at very large sample sizes and leverages genome-wide information. Our findings include a large enrichment of heritability in conserved regions across many traits, a very large immunological disease–specific enrichment of heritability in FANTOM5 enhancers and many cell type–specific enrichments, including significant enrichment of central nervous system cell types in the heritability of body mass index, age at menarche, educational attainment and smoking behavior.

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Acknowledgements

We thank B. Bernstein, M. Finucane, A. Forrest, E. Hodis, D. Kotliar, X.S. Liu, M. Kellis, M. O'Donovan, B. Pasaniuc, A. Sandelin, A. Sarkar, P. Sullivan, B. Vilhjalmsson, A. Veres and the anonymous reviewers for helpful discussions and/or comments. This research was funded by US National Institutes of Health grants R01 MH101244, R01 HG006399, R03 CA173785, R21 CA182821, F32 GM106584 and U01 HG0070033. H.K.F. was also supported by the Fannie and John Hertz Foundation. G.T. is supported by the Wellcome Trust Sanger Institute (WT098051). Y.R. was supported by award T32 GM007753 from the National Institute of General Medical Sciences. S. Raychaudhuri is supported by funding from the Arthritis Foundation and by a Doris Duke Clinical Scientist Development Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health. This study made use of data generated by the Wellcome Trust Case Control Consortium (WTCCC) and the Wellcome Trust Sanger Institute. A full list of the investigators who contributed to the generation of the WTCCC data is available at http://www.wtccc.org.uk/. Funding for the WTCCC project was provided by the Wellcome Trust under award 076113.

Author information

Author notes

    • Hilary K Finucane
    •  & Brendan Bulik-Sullivan

    These authors contributed equally to this work.

    • Benjamin M Neale
    •  & Alkes L Price

    These authors jointly supervised this work.

Affiliations

  1. Department of Mathematics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Hilary K Finucane
  2. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

    • Hilary K Finucane
    • , Alexander Gusev
    • , Po-Ru Loh
    • , Sara Lindstrom
    •  & Alkes L Price
  3. Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Brendan Bulik-Sullivan
    • , Verneri Anttila
    • , Kyle Farh
    • , Stephan Ripke
    • , Mark J Daly
    •  & Benjamin M Neale
  4. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Brendan Bulik-Sullivan
    • , Verneri Anttila
    • , Stephan Ripke
    • , Mark J Daly
    •  & Benjamin M Neale
  5. Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Gosia Trynka
    • , Shaun Purcell
    •  & Soumya Raychaudhuri
  6. Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Gosia Trynka
    • , Shaun Purcell
    •  & Soumya Raychaudhuri
  7. Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.

    • Gosia Trynka
    •  & Soumya Raychaudhuri
  8. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Gosia Trynka
    • , Verneri Anttila
    • , Soumya Raychaudhuri
    • , Mark J Daly
    • , Nick Patterson
    • , Benjamin M Neale
    •  & Alkes L Price
  9. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.

    • Gosia Trynka
  10. Department of Computer Science, Harvard University, Cambridge, Massachusetts, USA.

    • Yakir Reshef
  11. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

    • Han Xu
    •  & Chongzhi Zang
  12. Epigenomics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Kyle Farh
  13. Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.

    • Felix R Day
    •  & John R B Perry
  14. Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA.

    • Shaun Purcell
    •  & Eli Stahl
  15. Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

    • Yukinori Okada
  16. Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

    • Yukinori Okada
  17. Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.

    • Soumya Raychaudhuri

Consortia

  1. ReproGen Consortium

    A full list of members appears in the Supplementary Note.

  2. Schizophrenia Working Group of the Psychiatric Genomics Consortium

    A full list of members appears in the Supplementary Note.

  3. The RACI Consortium

    A full list of members appears in the Supplementary Note.

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Contributions

H.K.F., B.B.-S., A.G., G.T., Y.R., P.-R.L., V.A., S. Raychaudhuri, M.J.D., N.P., B.M.N. and A.L.P. conceived and designed the experiments. H.K.F. and B.B.-S. performed the experiments, performed the statistical analysis and analyzed the data. H.X., C.Z., K.F., S. Ripke, F.R.D., S.P., E.S., S.L., J.R.B.P. and Y.O. contributed reagents. H.K.F., B.B.-S., B.M.N. and A.L.P. wrote the manuscript with feedback from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Hilary K Finucane or Brendan Bulik-Sullivan or Benjamin M Neale or Alkes L Price.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–9, Supplementary Tables 1–8 and Supplementary Note.

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DOI

https://doi.org/10.1038/ng.3404

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