Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits.
Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits.
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DOI：
10.1038/s41467-018-03371-0
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发表时间：
2018-03-02
影响因子：
16.6
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Wu Y;Zeng J;Zhang F;Zhu Z;Qi T;Zheng Z;Lloyd-Jones LR;Marioni RE;Martin NG;Montgomery GW;Deary IJ;Wray NR;Visscher PM;McRae AF;Yang J
确定GWAS发现的潜在关联的基因和调控元件对于理解复杂性状(包括疾病)的病因学至关重要。在这里，我们展示了一种分析范式，为后续的功能研究优先考虑GWA基因座的基因和调控元件。我们进行了一项综合分析，使用来自多个组学研究的汇总水平的SNP数据来检测与基因表达和表型相关的DNA甲基化(DNaM)位点，这些位点通过共享的遗传效应(即多效性)来实现。我们确定了7858个dNaM位点和2733个基因之间的多效性关联。这些dNaM位点富含增强子和启动子，其中40%被定位到远端基因。进一步的多效性关联分析将甲基组和转录组与12个复杂性状联系在一起，确定了149个dNaM位点和66个基因，表明了一种合理的机制，即遗传变异对表型的影响是通过dNaM对转录的遗传调节来调节的。在GWAS基因座上鉴定致病基因仍然是一项具有挑战性的任务。在这里，使用SMR和Heidi方法整合Gwas、eQTL和mQTL数据，Wu等人。将DNA甲基化位点映射到转录组，从而确定12个人类复杂特征的功能相关基因的优先顺序。
The identification of genes and regulatory elements underlying the associations discovered by GWAS is essential to understanding the aetiology of complex traits (including diseases). Here, we demonstrate an analytical paradigm of prioritizing genes and regulatory elements at GWAS loci for follow-up functional studies. We perform an integrative analysis that uses summary-level SNP data from multi-omics studies to detect DNA methylation (DNAm) sites associated with gene expression and phenotype through shared genetic effects (i.e., pleiotropy). We identify pleiotropic associations between 7858 DNAm sites and 2733 genes. These DNAm sites are enriched in enhancers and promoters, and >40% of them are mapped to distal genes. Further pleiotropic association analyses, which link both the methylome and transcriptome to 12 complex traits, identify 149 DNAm sites and 66 genes, indicating a plausible mechanism whereby the effect of a genetic variant on phenotype is mediated by genetic regulation of transcription through DNAm. The identification of the causal gene at a GWAS locus remains to be a challenging task. Here, using the SMR & HEIDI method to integrate GWAS, eQTL and mQTL data, Wu et al. map DNA methylation sites to the transcriptome and thereby prioritize functionally relevant genes for 12 human complex traits.
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影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
64.5
作者：
Boyle EA;Li YI;Pritchard JK
通讯作者：
Pritchard JK
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
4.6
作者：
Bakshi A;Zhu Z;Vinkhuyzen AA;Hill WD;McRae AF;Visscher PM;Yang J
通讯作者：
Yang J
影响因子：
2.7
作者：
Kuonen, D
通讯作者：
Kuonen, D