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

Gusev, Alexander and Lee, S. Hong and Trynka, Gosia and Finucane, Hilary and Vilhjálmsson, Bjarni J. and Xu, Han and Zang, Chongzhi and Ripke, Stephan and Bulik-Sullivan, Brendan and Stahl, Eli and Kähler, Anna K. and Hultman, Christina M. and Purcell, Shaun M. and McCarroll, Steven A. and Daly, Mark and Pasaniuc, Bogdan and Sullivan, Patrick F. and Neale, Benjamin M. and Wray, Naomi R. and Raychaudhuri, Soumya and Price, Alkes L. and Knight, Jo (2014) Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. American Journal of Human Genetics, 95 (5). pp. 535-552. ISSN 0002-9297

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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.

Item Type:
Journal Article
Journal or Publication Title:
American Journal of Human Genetics
Additional Information:
Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/2700/2716
Subjects:
ID Code:
80069
Deposited By:
Deposited On:
15 Jun 2016 13:44
Refereed?:
Yes
Published?:
Published
Last Modified:
03 Apr 2020 03:28