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Partitioning heritability by functional annotation using genome-wide association summary statistics

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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Figure 1: Simulation results for null calibration and power.
Figure 2: Simulation results for model misspecification.
Figure 3: Simulation results for ranking cell type groups and cell types.
Figure 4: Enrichment estimates for the 24 main annotations, averaged over nine independent traits.
Figure 5: Enrichment estimates for selected annotations and traits.
Figure 6: Enrichment of cell type groups.
Figure 7: Comparison of stratified LD score regression to other methods for identifying enriched cell types.

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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.

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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.

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

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A full list of members appears in the Supplementary Note.

A full list of members appears in the Supplementary Note.

A full list of members appears in the Supplementary Note.

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Finucane, H., Bulik-Sullivan, B., Gusev, A. et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat Genet 47, 1228–1235 (2015). https://doi.org/10.1038/ng.3404

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