Manuel Mattheisen

Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases. / Gusev, Alexander; Lee, S Hong; Trynka, Gosia; Finucane, Hilary; Vilhjálmsson, Bjarni Jóhann; Xu, Han; Zang, Chongzhi; Ripke, Stephan; Bulik-Sullivan, Brendan; Stahl, Eli; Kähler, 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; Schizophrenia Working Group of the Psychiatric Genomics Consortium (Manuel Mattheisen and Jakob Grove, members).

In: American Journal of Human Genetics, Vol. 95, No. 5, 2014, p. 535-52.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Gusev, A, Lee, SH, Trynka, G, Finucane, H, Vilhjálmsson, BJ, Xu, H, Zang, C, Ripke, S, Bulik-Sullivan, B, Stahl, E, Kähler, AK, Hultman, CM, Purcell, SM, McCarroll, SA, Daly, M, Pasaniuc, B, Sullivan, PF, Neale, BM, Wray, NR, Raychaudhuri, S, Price, AL & Schizophrenia Working Group of the Psychiatric Genomics Consortium (Manuel Mattheisen and Jakob Grove, members) 2014, 'Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases', American Journal of Human Genetics, vol. 95, no. 5, pp. 535-52. https://doi.org/10.1016/j.ajhg.2014.10.004

APA

Gusev, A., Lee, S. H., Trynka, G., Finucane, H., Vilhjálmsson, B. J., Xu, H., Zang, C., Ripke, S., Bulik-Sullivan, B., Stahl, E., Kähler, A. K., Hultman, C. M., Purcell, S. M., McCarroll, S. A., Daly, M., Pasaniuc, B., Sullivan, P. F., Neale, B. M., Wray, N. R., ... Schizophrenia Working Group of the Psychiatric Genomics Consortium (Manuel Mattheisen and Jakob Grove, members) (2014). Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases. American Journal of Human Genetics, 95(5), 535-52. https://doi.org/10.1016/j.ajhg.2014.10.004

CBE

Gusev A, Lee SH, Trynka G, Finucane H, Vilhjálmsson BJ, Xu H, Zang C, Ripke S, Bulik-Sullivan B, Stahl E, Kähler AK, Hultman CM, Purcell SM, McCarroll SA, Daly M, Pasaniuc B, Sullivan PF, Neale BM, Wray NR, Raychaudhuri S, Price AL, Schizophrenia Working Group of the Psychiatric Genomics Consortium (Manuel Mattheisen and Jakob Grove, members). 2014. Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases. American Journal of Human Genetics. 95(5):535-52. https://doi.org/10.1016/j.ajhg.2014.10.004

MLA

Vancouver

Gusev A, Lee SH, Trynka G, Finucane H, Vilhjálmsson BJ, Xu H et al. Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases. American Journal of Human Genetics. 2014;95(5):535-52. https://doi.org/10.1016/j.ajhg.2014.10.004

Author

Gusev, Alexander ; Lee, S Hong ; Trynka, Gosia ; Finucane, Hilary ; Vilhjálmsson, Bjarni Jóhann ; Xu, Han ; Zang, Chongzhi ; Ripke, Stephan ; Bulik-Sullivan, Brendan ; Stahl, Eli ; Kähler, 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 ; Schizophrenia Working Group of the Psychiatric Genomics Consortium (Manuel Mattheisen and Jakob Grove, members). / 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. 535-52.

Bibtex

@article{82408ffaccbc4084b328df48665ea7ff,
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 = "Alexander Gusev and Lee, {S Hong} and Gosia Trynka and Hilary Finucane and Vilhj{\'a}lmsson, {Bjarni J{\'o}hann} 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 {Schizophrenia Working Group of the Psychiatric Genomics Consortium (Manuel Mattheisen and Jakob Grove, members)} and Manuel Mattheisen and Jakob Grove",
note = "Copyright {\textcopyright} 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.",
year = "2014",
doi = "10.1016/j.ajhg.2014.10.004",
language = "English",
volume = "95",
pages = "535--52",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "5",

}

RIS

TY - JOUR

T1 - Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases

AU - Gusev, Alexander

AU - Lee, S Hong

AU - Trynka, Gosia

AU - Finucane, Hilary

AU - Vilhjálmsson, Bjarni Jóhann

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 - Schizophrenia Working Group of the Psychiatric Genomics Consortium (Manuel Mattheisen and Jakob Grove, members)

AU - Mattheisen, Manuel

AU - Grove, Jakob

N1 - Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. 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.

U2 - 10.1016/j.ajhg.2014.10.004

DO - 10.1016/j.ajhg.2014.10.004

M3 - Journal article

C2 - 25439723

VL - 95

SP - 535

EP - 552

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 5

ER -