title: Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases.
abstract: Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs (hg(2)) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of hg(2) from imputed SNPs (5.1× enrichment; p = 3.7 × 10(-17)) and 38% (SE = 4%) of hg(2) from genotyped SNPs (1.6× enrichment, p = 1.0 × 10(-4)). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained <10% of hg(2) despite having the highest enrichment. We replicated these findings but found no significant contribution from rare coding variants in independent schizophrenia cohorts genotyped on GWAS and exome chips. Our results highlight the value of analyzing components of heritability to unravel the functional architecture of common disease.
authors.affiliation: Harvard School of Public Health, Boston, MA 02115, USA. Electronic address: agusev@hsph.harvard.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gusev
authors.affiliation: The University of Queensland, Queensland Brain Institute, Brisbane, QLD 4072, Australia.
authors.forename: S Hong
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Rheumatology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Partners Center for Personalized Genetic Medicine, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Gosia
authors.initials: G
authors.lastname: Trynka
authors.affiliation: Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Hilary
authors.initials: H
authors.lastname: Finucane
authors.affiliation: Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Bjarni J
authors.initials: BJ
authors.lastname: Vilhjálmsson
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02115, 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, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Bulik-Sullivan
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Stahl
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kähler
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Hultman
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Purcell
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: McCarroll
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Daly
authors.affiliation: Department of Pathology and Laboratory Medicine, Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Pasaniuc
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Sullivan
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Neale
authors.affiliation: The University of Queensland, Queensland Brain Institute, Brisbane, QLD 4072, Australia.
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Wray
authors.affiliation: Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Rheumatology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Partners Center for Personalized Genetic Medicine, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PL, UK.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.affiliation: Harvard School of Public Health, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: aprice@hsph.harvard.edu.
authors.forename: Alkes L
authors.initials: AL
authors.lastname: Price
mesh_terms: D003198:Computer Simulation; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics*; D008957:Models, Genetic; D016366:Open Reading Frames / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*