Title: Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases
year: 2014
Journal: Am J Hum Genet
Volume: 95
Issue: 5
Pages: 535-52
Epubdate: 03/12/2014
date: 01/11/2006
Alternate Journal: American journal of human genetics
ISSN: 01/02/9297
DOI: 10.1016/j.ajhg.2014.10.004
PMCID: PMC4225595
Accession Number: 25439723
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 (5.1x enrichment; p = 3.7 x 10(-17)) and 38% (SE = 4%) of hg(2) from genotyped SNPs (1.6x enrichment, p = 1.0 x 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.
Notes: 1537-6605
Gusev, Alexander
Lee, S Hong
Trynka, Gosia
Finucane, Hilary
Vilhjalmsson, Bjarni J
Xu, Han
Zang, Chongzhi
Ripke, Stephan
Bulik-Sullivan, Brendan
Stahl, Eli
Schizophrenia Working Group of thePsychiatric
Genomics Consortium
SWE-SCZ Consortium
Kahler, Anna K
Hultman, Christina M
Purcell, Shaun M
McCarroll, Steven A
Daly, Mark
Pasaniuc, Bogdan
Sullivan, Patrick F
Neale, Benjamin M
Wray, Naomi R
Raychaudhuri, Soumya
Price, Alkes L
076113/Wellcome Trust/United Kingdom
1U01HG0070033/HG/NHGRI NIH HHS/United States
F32 GM106584/GM/NIGMS NIH HHS/United States
R01 AR063759/AR/NIAMS NIH HHS/United States
R01 GM105857/GM/NIGMS NIH HHS/United States
R01 MH101244/MH/NIMH NIH HHS/United States
R03 HG006731/HG/NHGRI NIH HHS/United States
T32 MH020030/MH/NIMH NIH HHS/United States
U01 MH094432/MH/NIMH NIH HHS/United States
U01 MH096296/MH/NIMH NIH HHS/United States
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
United States
Am J Hum Genet. 2014 Nov 6
95(5):535-52. doi: 10.1016/j.ajhg.2014.10.004. Epub 2014 Nov 6.
URI: https://open-access.imh.com.sg/handle/123456789/4701
Authors Address: Harvard School of Public Health, Boston, MA 02115, USA. Electronic address: agusev@hsph.harvard.edu.
The University of Queensland, Queensland Brain Institute, Brisbane, QLD 4072, Australia.
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.
Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Harvard School of Public Health, Boston, MA 02115, USA.
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02115, 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.Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.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.Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.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.Department of Pathology and Laboratory Medicine, Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.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.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.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.
Translated author: NLM
Translated title: eng
Appears in Collections:2014




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