title: 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.
authors.affiliation: Department of Mathematics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Hilary K
authors.initials: HK
authors.lastname: Finucane
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Bulik-Sullivan
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gusev
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Gosia
authors.initials: G
authors.lastname: Trynka
authors.affiliation: Department of Computer Science, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Yakir
authors.initials: Y
authors.lastname: Reshef
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Po-Ru
authors.initials: PR
authors.lastname: Loh
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Verneri
authors.identifier: http://orcid.org/0000-0002-0073-4675
authors.initials: V
authors.lastname: Anttila
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Chongzhi
authors.initials: C
authors.lastname: Zang
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Epigenomics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Farh
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Stephan
authors.identifier: http://orcid.org/0000-0003-3622-835X
authors.initials: S
authors.lastname: Ripke
authors.affiliation: Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Felix R
authors.identifier: http://orcid.org/0000-0003-3789-7651
authors.initials: FR
authors.lastname: Day
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Shaun
authors.initials: S
authors.lastname: Purcell
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Stahl
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Lindstrom
authors.affiliation: Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: John R B
authors.initials: JR
authors.lastname: Perry
authors.affiliation: Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.|Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Patterson
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Benjamin M
authors.identifier: http://orcid.org/0000-0003-1513-6077
authors.initials: BM
authors.lastname: Neale
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Alkes L
authors.initials: AL
authors.lastname: Price
mesh_terms: D000465:Algorithms; D003198:Computer Simulation; D004194:Disease / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006657:Histones / Q000378:metabolism; D006801:Humans; D040582:Inheritance Patterns; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide
chemical_list: D006657:Histones; D008239:Lysine