TY - JOUR
T1 - Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases
AU - SWE-SCZ Consortium
AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium
AU - Psychosis Endophenotypes International Consortium
AU - Wellcome Trust Case Control 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 J.
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 - Davidson, Michael
AU - Weiser, Mark
N1 - 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.
UR - http://www.scopus.com/inward/record.url?scp=84922273141&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2014.10.004
DO - 10.1016/j.ajhg.2014.10.004
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C2 - 25439723
AN - SCOPUS:84922273141
SN - 0002-9297
VL - 95
SP - 535
EP - 552
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -