We introduce an approach to identify disease-relevant tissues and cell types by analyzing gene expression data together with genome-wide association study (GWAS) summary statistics. Our approach uses stratified linkage disequilibrium (LD) score regression to test whether disease heritability is enriched in regions surrounding genes with the highest specific expression in a given tissue. We applied our approach to gene expression data from several sources together with GWAS summary statistics for 48 diseases and traits (average N = 169,331) and found significant tissue-specific enrichments (false discovery rate (FDR) < 5%) for 34 traits. In our analysis of multiple tissues, we detected a broad range of enrichments that recapitulated known biology. In our brain-specific analysis, significant enrichments included an enrichment of inhibitory over excitatory neurons for bipolar disorder, and excitatory over inhibitory neurons for schizophrenia and body mass index. Our results demonstrate that our polygenic approach is a powerful way to leverage gene expression data for interpreting GWAS signals.
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We are thankful to R. Herbst, E. Hodis, F. Hormozdiari, M. Kanai, T. Pers, S. Riesenfeld, J. Ulirsch and A. Veres for helpful comments. This research was conducted using the UK Biobank Resource (application number: 16549). This research was funded by NIH grants R01 MH107649 (H.K.F., S.G., B.M.N., A.L.P.), R01 MH109978 (A.G., A.L.P.), U01 CA194393 (H.K.F., A.L.P.) and U01 HG009379 (S.R., A.L.P.). H.K.F. was also supported by the Fannie and John Hertz Foundation and by Eric and Wendy Schmidt. Data on neuron types were generated as part of the PsychENCODE Consortium, supported by: U01MH103392 (S. Akbarian, Icahn School of Medicine at Mount Sinai; P. Sklar, Icahn School of Medicine at Mount Sinai), U01MH103365 (F. Vaccarino, Yale University; M. Gerstein, Yale University; S. Weissman, Yale University), U01MH103346 (P. Farnham, University of Southern California; J. A. Knowles, University of Southern California), U01MH103340 (C. Liu, SUNY Upstate Medical University; K. White, University of Chicago), U01MH103339 (N. Sestan, Yale University; M. State, University of California, San Francisco), R21MH109956 (A. Jaffe, Lieber Institute for Brain Development), R21MH105881 (D. Pinto, Icahn School of Medicine at Mount Sinai), R21MH105853 (A. Jaffe, Lieber Institute for Brain Development; D. Weinberger, Lieber Institute for Brain Development), R21MH103877 (S. Dracheva, Icahn School of Medicine at Mount Sinai; S. Akbarian, Icahn School of Medicine at Mount Sinai), R21MH102791 (A. Jaffe, Lieber Institute for Brain Development), R01MH111721 (F. Goes, Johns Hopkins University; T. Hyde, Lieber Institute for Brain Development), R01MH110928 (M. State, University of California, San Francisco; S. Sanders, University of California, San Francisco; J. Willsey, University of California, San Francisco), R01MH110927 (D. Geschwind, University of California, Los Angeles), R01MH110926 (N. Sestan, Yale University), R01MH110921 (P. Sklar, Icahn School of Medicine at Mount Sinai), R01MH110920 (C. Liu, SUNY Upstate Medical University), R01MH110905 (K. White, University of Chicago), R01MH109715 (D. Pinto, Icahn School of Medicine at Mount Sinai), R01MH109677 (P. Roussos, Icahn School of Medicine at Mount Sinai), R01MH105898, (P. Zandi, Johns Hopkins University; T. M. Hyde, Lieber Institute for Brain Development), R01MH094714, (D. Geschwind, University of California, Los Angeles), P50MH106934, (N. Sestan, Yale University), R01MH105472 (G. Crawford, Duke University; P. Sullivan, University of North Carolina).
The authors declare no competing interests.
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Finucane, H.K., Reshef, Y.A., Anttila, V. et al. Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types. Nat Genet 50, 621–629 (2018). https://doi.org/10.1038/s41588-018-0081-4
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