Partitioning heritability by functional annotation using genome-wide association summary statistics.
Partitioning heritability by functional annotation using genome-wide association summary statistics.
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DOI：
10.1038/ng.3404
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发表时间：
2015-11
期刊：
影响因子：
30.8
通讯作者：
Price AL
中科院分区：
文献类型：
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作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
近期的研究表明，基因组的某些功能类别对复杂疾病的遗传力贡献不成比例。在此，我们分析了一系列广泛的功能元件，包括细胞类型特异性元件，以评估它们在17种复杂疾病和性状的全基因组关联研究（GWAS）中对遗传力的多基因贡献，这些研究的平均样本量为73599。为了进行这项分析，我们引入了一种新方法，即分层LD分数回归，用于在考虑连锁标记的同时从GWAS汇总统计数据中划分遗传力。这种新方法在非常大的样本量下在计算上易于处理，并利用了全基因组信息。我们的研究结果包括：在许多性状中，保守区域的遗传力大幅富集；在FANTOM5增强子中，免疫疾病特异性的遗传力大幅富集；以及许多细胞类型特异性的富集，包括中枢神经系统细胞类型在体重指数、月经初潮年龄、受教育程度和吸烟行为方面的显著富集。
Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here, we analyze a broad set of functional elements, including cell-type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits with an average sample size of 73,599. To enable this analysis, we introduce a new method, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers. This new method is computationally tractable at very large sample sizes, and leverages genome-wide information. Our results include a large enrichment of heritability in conserved regions across many traits; a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers; and many cell-type-specific enrichments including significant enrichment of central nervous system cell types in body mass index, age at menarche, educational attainment, and smoking behavior.