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

Wellcome Trust Case Control Consortium, SWE-SCZ Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium, Psychosis Endophenotypes International Consortium

Research output: Contribution to journalArticle

240 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)535-552
Number of pages18
JournalAmerican Journal of Human Genetics
Volume95
Issue number5
DOIs
Publication statusPublished - 01-01-2014

Fingerprint

Single Nucleotide Polymorphism
Genome-Wide Association Study
Hypersensitivity
Exome
Linkage Disequilibrium
Schizophrenia
Genotype
Genome

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Wellcome Trust Case Control Consortium, SWE-SCZ Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium, & Psychosis Endophenotypes International Consortium (2014). Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. American Journal of Human Genetics, 95(5), 535-552. https://doi.org/10.1016/j.ajhg.2014.10.004
Wellcome Trust Case Control Consortium ; SWE-SCZ Consortium ; Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium ; Psychosis Endophenotypes International Consortium. / Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. In: American Journal of Human Genetics. 2014 ; Vol. 95, No. 5. pp. 535-552.
@article{ff8d5e976a9b4af2b0f74eb304c00edf,
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.",
author = "{Wellcome Trust Case Control Consortium} and {SWE-SCZ Consortium} and {Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium} and {Psychosis Endophenotypes International Consortium} and Alexander Gusev and Lee, {S. Hong} and Gosia Trynka and Hilary Finucane and Vilhj{\'a}lmsson, {Bjarni J.} and Han Xu and Chongzhi Zang and Stephan Ripke and Brendan Bulik-Sullivan and Eli Stahl and K{\"a}hler, {Anna K.} and Hultman, {Christina M.} and Purcell, {Shaun M.} and McCarroll, {Steven A.} and Mark Daly and Bogdan Pasaniuc and Sullivan, {Patrick F.} and Neale, {Benjamin M.} and Wray, {Naomi R.} and Soumya Raychaudhuri and Price, {Alkes L.} and Aiden Corvin and Walters, {James T.R.} and Farh, {Kai How} and Holmans, {Peter A.} and Phil Lee and Collier, {David A.} and Hailiang Huang and Pers, {Tune H.} and Ingrid Agartz and Esben Agerbo and Margot Albus and Madeline Alexander and Farooq Amin and Bacanu, {Silviu A.} and Martin Begemann and Belliveau, {Richard A.} and Judit Bene and Bergen, {Sarah E.} and Elizabeth Bevilacqua and Bigdeli, {Tim B.} and Black, {Donald W.} and B{\o}rglum, {Anders D.} and Richard Bruggeman and Buccola, {Nancy G.} and Buckner, {Randy L.} and William Byerley and Wiepke Cahn and Masashi Ikeda and Nakao Iwata",
year = "2014",
month = "1",
day = "1",
doi = "10.1016/j.ajhg.2014.10.004",
language = "English",
volume = "95",
pages = "535--552",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "5",

}

Wellcome Trust Case Control Consortium, SWE-SCZ Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium & Psychosis Endophenotypes International Consortium 2014, 'Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases', American Journal of Human Genetics, vol. 95, no. 5, pp. 535-552. https://doi.org/10.1016/j.ajhg.2014.10.004

Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. / Wellcome Trust Case Control Consortium; SWE-SCZ Consortium; Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium; Psychosis Endophenotypes International Consortium.

In: American Journal of Human Genetics, Vol. 95, No. 5, 01.01.2014, p. 535-552.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases

AU - Wellcome Trust Case Control Consortium

AU - SWE-SCZ Consortium

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium

AU - Psychosis Endophenotypes International Consortium

AU - Gusev, Alexander

AU - Lee, S. Hong

AU - Trynka, Gosia

AU - Finucane, Hilary

AU - Vilhjálmsson, Bjarni J.

AU - Xu, Han

AU - Zang, Chongzhi

AU - Ripke, Stephan

AU - Bulik-Sullivan, Brendan

AU - Stahl, Eli

AU - Kähler, Anna K.

AU - Hultman, Christina M.

AU - Purcell, Shaun M.

AU - McCarroll, Steven A.

AU - Daly, Mark

AU - Pasaniuc, Bogdan

AU - Sullivan, Patrick F.

AU - Neale, Benjamin M.

AU - Wray, Naomi R.

AU - Raychaudhuri, Soumya

AU - Price, Alkes L.

AU - Corvin, Aiden

AU - Walters, James T.R.

AU - Farh, Kai How

AU - Holmans, Peter A.

AU - Lee, Phil

AU - Collier, David A.

AU - Huang, Hailiang

AU - Pers, Tune H.

AU - Agartz, Ingrid

AU - Agerbo, Esben

AU - Albus, Margot

AU - Alexander, Madeline

AU - Amin, Farooq

AU - Bacanu, Silviu A.

AU - Begemann, Martin

AU - Belliveau, Richard A.

AU - Bene, Judit

AU - Bergen, Sarah E.

AU - Bevilacqua, Elizabeth

AU - Bigdeli, Tim B.

AU - Black, Donald W.

AU - Børglum, Anders D.

AU - Bruggeman, Richard

AU - Buccola, Nancy G.

AU - Buckner, Randy L.

AU - Byerley, William

AU - Cahn, Wiepke

AU - Ikeda, Masashi

AU - Iwata, Nakao

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84922273141&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84922273141&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2014.10.004

DO - 10.1016/j.ajhg.2014.10.004

M3 - Article

C2 - 25439723

AN - SCOPUS:84922273141

VL - 95

SP - 535

EP - 552

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 5

ER -

Wellcome Trust Case Control Consortium, SWE-SCZ Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium, Psychosis Endophenotypes International Consortium. Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. American Journal of Human Genetics. 2014 Jan 1;95(5):535-552. https://doi.org/10.1016/j.ajhg.2014.10.004