TY - JOUR
T1 - Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases
AU - Gusev, Alexander
AU - Hong Lee, S.
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 - Schizophrenia Working Group of the Psychiatric Genomics Consortium
AU - O'Neill, Francis
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
N1 - Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
PY - 2014/11/6
Y1 - 2014/11/6
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 () 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 from imputed SNPs (5.1× enrichment; p = 3.7 × 10−17) and 38% (SE = 4%) of 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 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 () 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 from imputed SNPs (5.1× enrichment; p = 3.7 × 10−17) and 38% (SE = 4%) of 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 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 - Article
C2 - 25439723
SN - 0002-9297
VL - 95
SP - 535
EP - 552
JO - The American Journal of Human Genetics
JF - The American Journal of Human Genetics
IS - 5
ER -
