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

Gusev, Alexander, Lee, S. Hong, Trynka, Gosia, Finucane, Hilary, Vilhjálmsson, Bjarni J., Xu, Han, Zang, Chongzhi, Ripke, Stephan, Bulik-Sullivan, Brendan, Stahl, Eli, Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium, Kaehler, 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., Visscher, Peter M., Mowry, Bryan J., Psychosis Endophenotypes International Consortium and Wellcome Trust Case Control Consortium (2014) Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases. American Journal of Human Genetics, 95 5: 535-552. doi:10.1016/j.ajhg.2014.10.004

Author Gusev, Alexander
Lee, S. Hong
Trynka, Gosia
Finucane, Hilary
Vilhjálmsson, Bjarni J.
Xu, Han
Zang, Chongzhi
Ripke, Stephan
Bulik-Sullivan, Brendan
Stahl, Eli
Schizophrenia Working Group of the Psychiatric Genomics Consortium
SWE-SCZ Consortium
Kaehler, 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.
Visscher, Peter M.
Mowry, Bryan J.
Psychosis Endophenotypes International Consortium
Wellcome Trust Case Control Consortium
Title Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
Publication date 2014-11-01
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2014.10.004
Open Access Status DOI
Volume 95
Issue 5
Start page 535
End page 552
Total pages 18
Place of publication Cambridge, MA United States
Publisher Cell Press
Language eng
Formatted 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 (h2g) 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 ¼ 8%) of h2g from imputed SNPs (5.1 3 enrichment; p ¼ 3.7 3 10 -17 ) and 38% (SE ¼ 4%) of h2g from genotyped SNPs (1.6 3 enrichment, p ¼ 1.0 3 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 h2g 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.
Keyword Genome-Wide Association
Genotype Imputation
Prior Information
Dna Elements
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2015 Collection
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