Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits

被引：361

作者：

Wu, Yang ^{[1
]}

Zeng, Jian ^{[1
]}

Zhang, Futao ^{[1
]}

Zhu, Zhihong ^{[1
]}

Qi, Ting ^{[1
]}

Zheng, Zhili ^{[1
,2
]}

Lloyd-Jones, Luke R. ^{[1
]}

Marioni, Riccardo E. ^{[3
,4
]}

Martin, Nicholas G. ^{[5
]}

Montgomery, Grant W. ^{[1
]}

Deary, Ian J. ^{[4
]}

Wray, Naomi R. ^{[1
,6
]}

Visscher, Peter M. ^{[1
,6
]}

McRae, Allan F. ^{[1
]}

Yang, Jian ^{[1
,6
]}

机构：

[1] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia

[2] Wenzhou Med Univ, Sch Ophthalmol & Optometry, Hosp Eye, Wenzhou 325027, Zhejiang, Peoples R China

[3] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh EH4 2XU, Midlothian, Scotland

[4] Univ Edinburgh, Dept Psychol, Ctr Cognit Ageing & Cognit Epidemiol, 7 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland

[5] QIMR Berghofer Med Res Inst, Genet & Computat Biol, Brisbane, Qld 4029, Australia

[6] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

英国医学研究理事会; 美国国家卫生研究院; 英国生物技术与生命科学研究理事会; 澳大利亚研究理事会;

关键词：

EPIGENOME-WIDE ASSOCIATION; DNA METHYLATION; SUSCEPTIBILITY LOCI; GENETIC-VARIATION; DISEASE; VARIANT; GWAS; METAANALYSIS; EXPRESSION; RISK;

D O I：

10.1038/s41467-018-03371-0

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

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