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Title: Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases
Contributor(s): Gusev, Alexander (author); Lee, Sang Hong  (author); Schizophrenia Working Group of the Psychiatric Genomics Consortium, (author); SWE-SCZ Consortium, (author); Kahler, Anna K (author); Hultman, Christina M (author); Purcell, Shaun M (author); McCarroll, Steven A (author); Daly, Mark (author); Pasaniuc, Bogdan (author); Sullivan, Patrick F (author); Neale, Benjamin M (author); Trynka, Gosia (author); Wray, Naomi R (author); Raychaudhuri, Soumya (author); Price, Alkes L (author); Finucane, Hilary (author); Vilhjalmsson, Bjarni J (author); Xu, Han (author); Zang, Chongzhi (author); Ripke, Stephan (author); Bulik-Sullivan, Brendan (author); Stahl, Eli (author)
Publication Date: 2014
Open Access: Yes
DOI: 10.1016/j.ajhg.2014.10.004Open Access Link
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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 (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 = 8%) of h²g from imputed SNPs (5.13 enrichment; p = 3.7 x 10 ̄17) and 38% (SE = 4%) of h²g from genotyped SNPs (1.6 x enrichment, p = 1.0 x 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.
Publication Type: Journal Article
Source of Publication: American Journal of Human Genetics, 95(5), p. 535-552
Publisher: Cell Press
Place of Publication: United States of America
ISSN: 1537-6605
Fields of Research (FoR) 2008: 060412 Quantitative Genetics (incl. Disease and Trait Mapping Genetics)
110319 Psychiatry (incl. Psychotherapy)
060408 Genomics
Fields of Research (FoR) 2020: 310506 Gene mapping
320221 Psychiatry (incl. psychotherapy)
310509 Genomics
Socio-Economic Objective (SEO) 2008: 970106 Expanding Knowledge in the Biological Sciences
970111 Expanding Knowledge in the Medical and Health Sciences
920110 Inherited Diseases (incl. Gene Therapy)
Socio-Economic Objective (SEO) 2020: 280102 Expanding knowledge in the biological sciences
Peer Reviewed: Yes
HERDC Category Description: C1 Refereed Article in a Scholarly Journal
Appears in Collections:Journal Article

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