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

Author

Listed:
  • 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
    Wenzhou Medical University)

  • Luke R. Lloyd-Jones

    (The University of Queensland)

  • Riccardo E. Marioni

    (University of Edinburgh
    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
    The University of Queensland)

  • Peter M. Visscher

    (The University of Queensland
    The University of Queensland)

  • Allan F. McRae

    (The University of Queensland)

  • Jian Yang

    (The University of Queensland
    The University of Queensland)

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.

Suggested Citation

  • 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., 2018. "Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03371-0
    DOI: 10.1038/s41467-018-03371-0
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    Cited by:

    1. Gianluca Ursini & Pasquale Di Carlo & Sreya Mukherjee & Qiang Chen & Shizhong Han & Jiyoung Kim & Maya Deyssenroth & Carmen J. Marsit & Jia Chen & Ke Hao & Giovanna Punzi & Daniel R. Weinberger, 2023. "Prioritization of potential causative genes for schizophrenia in placenta," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Marie C. Sadler & Chiara Auwerx & Kaido Lepik & Eleonora Porcu & Zoltán Kutalik, 2022. "Quantifying the role of transcript levels in mediating DNA methylation effects on complex traits and diseases," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Chris Wallace, 2021. "A more accurate method for colocalisation analysis allowing for multiple causal variants," PLOS Genetics, Public Library of Science, vol. 17(9), pages 1-11, September.
    4. Denis A Baird & Jimmy Z Liu & Jie Zheng & Solveig K Sieberts & Thanneer Perumal & Benjamin Elsworth & Tom G Richardson & Chia-Yen Chen & Minerva M Carrasquillo & Mariet Allen & Joseph S Reddy & Philip, 2021. "Identifying drug targets for neurological and psychiatric disease via genetics and the brain transcriptome," PLOS Genetics, Public Library of Science, vol. 17(1), pages 1-26, January.
    5. Zhen Qiao & Julia Sidorenko & Joana A. Revez & Angli Xue & Xueling Lu & Katri Pärna & Harold Snieder & Peter M. Visscher & Naomi R. Wray & Loic Yengo, 2023. "Estimation and implications of the genetic architecture of fasting and non-fasting blood glucose," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    6. Yordi J. Vegte & Ruben N. Eppinga & M. Yldau Ende & Yanick P. Hagemeijer & Yuvaraj Mahendran & Elias Salfati & Albert V. Smith & Vanessa Y. Tan & Dan E. Arking & Ioanna Ntalla & Emil V. Appel & Claudi, 2023. "Genetic insights into resting heart rate and its role in cardiovascular disease," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    7. Lei Li & Xuelian Ma & Ya Cui & Maxime Rotival & Wenyan Chen & Xudong Zou & Ruofan Ding & Yangmei Qin & Qixuan Wang & Lluis Quintana-Murci & Wei Li, 2023. "Immune-response 3′UTR alternative polyadenylation quantitative trait loci contribute to variation in human complex traits and diseases," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    8. Alesha A. Hatton & Fei-Fei Cheng & Tian Lin & Ren-Juan Shen & Jie Chen & Zhili Zheng & Jia Qu & Fan Lyu & Sarah E. Harris & Simon R. Cox & Zi-Bing Jin & Nicholas G. Martin & Dongsheng Fan & Grant W. M, 2024. "Genetic control of DNA methylation is largely shared across European and East Asian populations," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    9. Fengzhe Xu & Evan Yi-Wen Yu & Xue Cai & Liang Yue & Li-peng Jing & Xinxiu Liang & Yuanqing Fu & Zelei Miao & Min Yang & Menglei Shuai & Wanglong Gou & Congmei Xiao & Zhangzhi Xue & Yuting Xie & Sainan, 2023. "Genome-wide genotype-serum proteome mapping provides insights into the cross-ancestry differences in cardiometabolic disease susceptibility," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    10. Jayshree Advani & Puja A. Mehta & Andrew R. Hamel & Sudeep Mehrotra & Christina Kiel & Tobias Strunz & Ximena Corso-Díaz & Madeline Kwicklis & Freekje Asten & Rinki Ratnapriya & Emily Y. Chew & Dena G, 2024. "QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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