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.

Details

Title
Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits
Author
Wu, Yang 1 ; Zeng, Jian 1   VIAFID ORCID Logo  ; Zhang, Futao 1 ; Zhu, Zhihong 1 ; Ting Qi 1 ; Zheng, Zhili 2 ; Lloyd-Jones, Luke R 1 ; Marioni, Riccardo E 3 ; Martin, Nicholas G 4 ; Montgomery, Grant W 1   VIAFID ORCID Logo  ; Deary, Ian J 5 ; Wray, Naomi R 6   VIAFID ORCID Logo  ; Visscher, Peter M 6   VIAFID ORCID Logo  ; McRae, Allan F 1 ; Yang, Jian 6   VIAFID ORCID Logo 

1  Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia 
2  Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia; The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China 
3  Medical Genetics Section, Centre for Genomics and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK; Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK 
4  Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia 
5  Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK 
6  Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia; Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia 
Pages
1-14
Publication year
2018
Publication date
Mar 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-03371-0
ProQuest document ID
2009878032
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.