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

Yang Wu, Jian Zeng, Futao Zhang, Zhihong Zhu, Ting Qi, Zhili Zheng, Luke R. Lloyd-Jones, Riccardo E. Marioni, Nicholas G. Martin, Grant W. Montgomery, Ian J. Deary, Naomi R. Wray, Peter M. Visscher, Allan F. McRae and Jian Yang ()
Additional contact information
Yang Wu: The University of Queensland
Jian Zeng: The University of Queensland
Futao Zhang: The University of Queensland
Zhihong Zhu: The University of Queensland
Ting Qi: The University of Queensland
Zhili Zheng: The University of Queensland
Luke R. Lloyd-Jones: The University of Queensland
Riccardo E. Marioni: University of Edinburgh
Nicholas G. Martin: QIMR Berghofer Medical Research Institute
Grant W. Montgomery: The University of Queensland
Ian J. Deary: University of Edinburgh
Naomi R. Wray: The University of Queensland
Peter M. Visscher: The University of Queensland
Allan F. McRae: The University of Queensland
Jian Yang: The University of Queensland

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03371-0

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