Evidence map›Paper›PMID 25439723›Full record

ArticleAmerican journal of human genetics2014

Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases.

Alexander Gusev, S Hong Lee, Gosia Trynka, Hilary Finucane, Bjarni J Vilhjálmsson, Han Xu, Chongzhi Zang, Stephan Ripke, Brendan Bulik-Sullivan, Eli Stahl and 15 more

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Article in American journal of human genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 387 papers, 4 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
387citing papers in PubMed, 4 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

387 citing papers in PubMed, 4 syntheses or guidelines pooled it.

  1. Pooled it
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  13. Functional Variant Discovery Identifies a Novel Genetic Link between SPRY2, Wood Smoke, and Asthma.American journal of respiratory cell and molecular biology · 2026
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327 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

25 authors.

Alexander GusevHarvard School of Public Health, Boston, MA 02115, USA. Electronic address: agusev@hsph.harvard.edu.
S Hong LeeThe University of Queensland, Queensland Brain Institute, Brisbane, QLD 4072, Australia.
Gosia TrynkaDivision 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.
Hilary FinucaneDepartment of Mathematics, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Bjarni J VilhjálmssonHarvard School of Public Health, Boston, MA 02115, USA.
Han XuDepartment of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02115, USA.
Chongzhi ZangDepartment of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02115, USA.
Stephan RipkeAnalytic 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.
Brendan Bulik-SullivanAnalytic 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.
Eli StahlDepartment of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
Schizophrenia Working Group of the Psychiatric Genomics Consortium
SWE-SCZ Consortium
Anna K KählerDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
Christina M HultmanDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
Shaun M PurcellAnalytic 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.
Steven A McCarrollStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Mark DalyProgram 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.
Bogdan PasaniucDepartment of Pathology and Laboratory Medicine, Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Patrick F SullivanDepartment 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.
Benjamin M NealeProgram 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.
Naomi R WrayThe University of Queensland, Queensland Brain Institute, Brisbane, QLD 4072, Australia.
Soumya RaychaudhuriDivision 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.
Alkes L PriceHarvard 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.
Schizophrenia Working Group of the Psychiatric Genomics Consortium
SWE-SCZ Consortium

Funding

Genomic Psychiatry CohortR01MH085548 · NIMH · UNIVERSITY OF SOUTHERN CALIFORNIA · PI PATO, CARLOS N, PATO, MICHELE T · 2008 to 2012
$16.3M
Statistical methods for studies of rare variantsR01MH101244 · NIMH · HARVARD MEDICAL SCHOOL · PI Benjamin Michael Neale, ALKES L PRICE · 2013 to 2026
$9.4M
4/4-Psychiatric GWAS Consortium:Genomic Follow-Up Next-Gen Sequencing & GenotypiU01MH096296 · NIMH · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI SKLAR, PAMELA · 2012 to 2015
$7.3M
Research Training: Psychiatric &Statistical GeneticsT32MH020030 · NIMH · VIRGINIA COMMONWEALTH UNIVERSITY · PI HERMINE H MAES, MICHAEL CHURTON NEALE · 1999 to 2026
$6.7M
Discovery and Functional Impact of Common and Rare Variants in RAR01AR063759 · NIAMS · BRIGHAM AND WOMEN'S HOSPITAL · PI Soumya Raychaudhuri · 2013 to 2026
$5.4M
2/4-Psychiatric GWAS Consortium: Genomic Follow-Up Next-Gen Sequencing & GenotypiU01MH094432 · NIMH · MASSACHUSETTS GENERAL HOSPITAL · PI DALY, MARK JOSEPH · 2012 to 2015
$3.0M
Improving Polygenic Prediction using Next-Generation Data SetsR01GM105857 · NIGMS · BRIGHAM AND WOMEN'S HOSPITAL · PI SUNYAEV, SHAMIL · 2014 to 2017
$2.0M
Heritability of complex traits via IBD and IBS in related and unrelated individuaR03HG006731 · NHGRI · HARVARD SCHOOL OF PUBLIC HEALTH · PI PRICE, ALKES L · 2013 to 2014
$162k
Fine-mapping heritability at known disease loci with correlated markersF32GM106584 · NIGMS · HARVARD SCHOOL OF PUBLIC HEALTH · PI GUSEV, ALEXANDER · 2013 to 2015
$159k
Chief Scientist Office SCD/12Medical Research Council G0601635Medical Research Council G0800509Medical Research Council MR/L010305/1NHGRI NIH HHS 1U01HG0070033NHGRI NIH HHS R03 HG006731NIAMS NIH HHS R01 AR063759NIGMS NIH HHS F32 GM106584NIGMS NIH HHS R01 GM105857NIMH NIH HHS R01 MH085548NIMH NIH HHS R01 MH101244NIMH NIH HHS T32 MH020030NIMH NIH HHS U01 MH094432NIMH NIH HHS U01 MH096296Wellcome TrustWellcome Trust 076113
6 · The paper itself

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.

Indexed as

Computer SimulationGenetic Diseases, InbornGenetic VariationGenome-Wide Association StudyHumansInheritance PatternsModels, GeneticOpen Reading FramesRegulatory Elements, Transcriptional

Identifiers

PMID25439723
PMCPMC4225595

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.