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Nat Genet. 2018 Apr;50(4):621-629. doi: 10.1038/s41588-018-0081-4. Epub 2018 Apr 9.

Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types.

Author information

1
Broad Institute of MIT and Harvard, Cambridge, MA, USA. finucane@broadinstitute.org.
2
Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, USA. finucane@broadinstitute.org.
3
Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA. finucane@broadinstitute.org.
4
Department of Computer Science, Harvard University, Cambridge, MA, USA.
5
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
6
Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
7
Bioinformatics and Integrative Genomics, Harvard University, Cambridge, MA, USA.
8
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
9
Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
10
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
11
Department of Genetics, Harvard Medical School, Boston, MA, USA.
12
Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
13
Harvard Society of Fellows, Harvard University, Cambridge, MA, USA.
14
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
15
Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
16
Partners Center for Personalized Genetic Medicine, Boston, MA, USA.
17
Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
18
Broad Institute of MIT and Harvard, Cambridge, MA, USA. aprice@hsph.harvard.edu.
19
Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA. aprice@hsph.harvard.edu.

Abstract

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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PMID:
29632380
PMCID:
PMC5896795
DOI:
10.1038/s41588-018-0081-4
[Indexed for MEDLINE]
Free PMC Article

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