Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases
Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases
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DOI：
10.1016/j.ajhg.2014.10.004
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发表时间：
2014-11-06
影响因子：
9.8
通讯作者：
Price, Alkes L.
中科院分区：
文献类型：
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作者：
Gusev, Alexander;Lee, S. Hong;Price, Alkes L.
已知调控和编码变体富含复杂疾病的全基因组关联研究（GWAS）确定的关联，但其对性状遗传力的贡献目前尚不清楚。我们应用方差分量法对11种常见疾病的基因型数据进行插补，以将由基因型SNP（h（g）（2））解释的遗传力划分为不同功能类别（同时考虑由于连锁不平衡导致的共享方差）。广泛的模拟表明，与GWAS汇总统计的当前估计值相比，方差分量方法在广泛的复杂疾病结构下准确地划分了遗传性。在11种疾病中，来自217种细胞类型的DNA酶I超敏位点（DHS）跨越了16%的插补SNP（和24%的基因型SNP），但平均79%（SE = 8%）的h（g）（2）由插补SNP解释（5.1 x富集; p = 3.7 x 10（-17））和38%（SE = 4%）的h（g）（2）来自基因型SNP（1.6 x富集，p = 1.0 x 10（-4））。在增强子DHS和细胞类型特异性DHS处观察到进一步富集。相比之下，跨越1%基因组的编码变异解释了
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 (h(g)(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 h(g)(2) from imputed SNPs (5.1 x enrichment; p = 3.7 x 10(-17)) and 38% (SE = 4%) of h(g)(2) 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