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

doi: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

Medicine

Research output: Contribution to journal › Article › peer-review

437 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 (h_g 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 h_g ² from imputed SNPs (5.1× enrichment; p = 3.7 × 10^-17) and 38% (SE = 4%) of h_g 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 h_g 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 language	English
Pages (from-to)	535-552
Number of pages	18
Journal	American Journal of Human Genetics
Volume	95
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2014.10.004
Publication status	Published - 2014

Bibliographical note

Funding Information:
This study made use of data generated by the Wellcome Trust Case Control Consortium (WTCCC) and the Wellcome Trust Sanger Institute. A full list of the investigators who contributed to the generation of the WTCCC data is available at www.wtccc.org.uk . Funding for the WTCCC project was provided by the Wellcome Trust under award 076113. We thank Manolis Kellis, Abhishek Sarkar, Joe Pickrell, X. Shirley Liu, Nick Patterson, Sara Lindstrom, Peter Kraft, and Shamil Sunyaev for helpful discussions and Amy Williams for assistance with HAPI-UR. This research was funded by NIH grants R01 MH101244, R03 HG006731, and 1U01HG0070033, the Doris Duke Clinical Scientist Development Award, and NIH fellowship F32 GM106584. G.T. was supported by the Rubicon grant from the Netherlands Organization for Scientific Research. H.F. was supported by the Fannie and John Hertz Foundation. We also acknowledge grant funding from the Australian Research Council (DE130100614 and FT0991360) and the National Health and Medical Research Council (613602 and 1050218).

Publisher Copyright:
© 2014 by The American Society of Human Genetics. All rights reserved.

ASJC Scopus Subject Areas

Genetics
Genetics(clinical)

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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10.1016/j.ajhg.2014.10.004

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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

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 et al.
In: American Journal of Human Genetics, Vol. 95, No. 5, 2014, p. 535-552.

Research output: Contribution to journal › Article › peer-review

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

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;95(5):535-552. doi: 10.1016/j.ajhg.2014.10.004

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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 Guiqing Cai and Sandra Meier",

note = "Funding Information: This study made use of data generated by the Wellcome Trust Case Control Consortium (WTCCC) and the Wellcome Trust Sanger Institute. A full list of the investigators who contributed to the generation of the WTCCC data is available at www.wtccc.org.uk . Funding for the WTCCC project was provided by the Wellcome Trust under award 076113. We thank Manolis Kellis, Abhishek Sarkar, Joe Pickrell, X. Shirley Liu, Nick Patterson, Sara Lindstrom, Peter Kraft, and Shamil Sunyaev for helpful discussions and Amy Williams for assistance with HAPI-UR. This research was funded by NIH grants R01 MH101244, R03 HG006731, and 1U01HG0070033, the Doris Duke Clinical Scientist Development Award, and NIH fellowship F32 GM106584. G.T. was supported by the Rubicon grant from the Netherlands Organization for Scientific Research. H.F. was supported by the Fannie and John Hertz Foundation. We also acknowledge grant funding from the Australian Research Council (DE130100614 and FT0991360) and the National Health and Medical Research Council (613602 and 1050218). Publisher Copyright: {\textcopyright} 2014 by The American Society of Human Genetics. All rights reserved.",

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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 - Cai, Guiqing

AU - Meier, Sandra

N1 - Funding Information: This study made use of data generated by the Wellcome Trust Case Control Consortium (WTCCC) and the Wellcome Trust Sanger Institute. A full list of the investigators who contributed to the generation of the WTCCC data is available at www.wtccc.org.uk . Funding for the WTCCC project was provided by the Wellcome Trust under award 076113. We thank Manolis Kellis, Abhishek Sarkar, Joe Pickrell, X. Shirley Liu, Nick Patterson, Sara Lindstrom, Peter Kraft, and Shamil Sunyaev for helpful discussions and Amy Williams for assistance with HAPI-UR. This research was funded by NIH grants R01 MH101244, R03 HG006731, and 1U01HG0070033, the Doris Duke Clinical Scientist Development Award, and NIH fellowship F32 GM106584. G.T. was supported by the Rubicon grant from the Netherlands Organization for Scientific Research. H.F. was supported by the Fannie and John Hertz Foundation. We also acknowledge grant funding from the Australian Research Council (DE130100614 and FT0991360) and the National Health and Medical Research Council (613602 and 1050218). Publisher Copyright: © 2014 by The American Society of Human Genetics. All rights reserved.

PY - 2014

Y1 - 2014

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.

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

Abstract

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