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

Am J Hum Genet
Authors
Keywords
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

Year of Publication
2014
Journal
Am J Hum Genet
Volume
95
Issue
5
Pages
535-52
Date Published
2014 Nov 06
ISSN
1537-6605
URL
DOI
10.1016/j.ajhg.2014.10.004
PubMed ID
25439723
PubMed Central ID
PMC4225595
Links
Grant list
F32 GM106584 / GM / NIGMS NIH HHS / United States
G0601635 / Medical Research Council / United Kingdom
T32 MH020030 / MH / NIMH NIH HHS / United States
1U01HG0070033 / HG / NHGRI NIH HHS / United States
076113 / Wellcome Trust / United Kingdom
R03 HG006731 / HG / NHGRI NIH HHS / United States
R01 AR063759 / AR / NIAMS NIH HHS / United States
R01 GM105857 / GM / NIGMS NIH HHS / United States
R01 MH101244 / MH / NIMH NIH HHS / United States
U01 MH094432 / MH / NIMH NIH HHS / United States
MR/L010305/1 / Medical Research Council / United Kingdom
G0800509 / Medical Research Council / United Kingdom
U01 MH096296 / MH / NIMH NIH HHS / United States