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Integrative analysis of transcriptome-wide association study data and mRNA expression profiles identified candidate genes and pathways associated with atrial fibrillation

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Abstract

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia characterized by extensive structural, contractile and electrophysiological remodeling. The genetic basis of AF remained elusive until now. Transcriptome-wide association study (TWAS) was conducted by FUSION tool using gene expression weights of 7 tissues combined with a large-scale genome-wide association study (GWAS) dataset of AF, totally involving 8180 AF cases and 28,612 controls. Significant genes identified by TWAS were then subjected to gene ontology (GO) and pathway enrichment analysis. The genome-wide mRNA gene expression profiling of AF was compared with the results of TWAS to detect common genes shared by TWAS and mRNA expression profiling of AF. TWAS detected a group of candidate genes with PTWAS values < 0.05 across the seven tissues for AF, such as CMAH (PTWAS = 3.15 × 10–25 for whole blood), INCENP (PTWAS = 1.77 × 10–22 for artery aorta), CMAHP (PTWAS = 4.57 × 10–20 for artery aorta). Pathway enrichment analysis identified multiple candidate pathways, such as protein K48-linked ubiquitination (P value = 0.0124), positive regulation of leukocyte chemotaxis (P value = 0.0046) and fatty acid degradation (P value = 0.0295). Further comparing the GO results of TWAS and mRNA expression profiling, 2 common GO terms were identified, including actin binding (PTWAS = 0.0446, PmRNA = 7.00 × 10–4) and extracellular matrix (PTWAS = 0.0037, PmRNA = 3.00 × 10–6). We detected multiple novel candidate genes, GO terms and pathways for AF, providing novel clues for understanding the genetic mechanism of AF.

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Acknowledgements

This work was supported by the National Natural Scientific Foundation of China (81472925, 81673112); the Key projects of international cooperation among governments in scientific and technological innovation (2016YFE0119100); the Natural Science Basic Research Plan in Shaanxi Province of China (2017JZ024);Program for Tackling Key Problems in Shannxi Provincial Science and Technology (2016SF-288); and the Fundamental Research Funds for the Central Universities.

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Author notes

  1. Lu Zhang and Li Liu contributed equally to this work.

  2. Feng Zhang takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

Authors and Affiliations

  1. Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, School of Public Health, Health Science Center, Xi’an Jiaotong University, Xi’an, People’s Republic of China

    Lu Zhang, Li Liu, Mei Ma, Shiqiang Cheng, Bolun Cheng, Ping Li, Yan Wen, Yanan Du, Xiao Liang, Yan Zhao, Miao Ding, Qi Xin, Chujun Liang & Feng Zhang

  2. The Affiliated Children Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China

    Huimei Huang

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  1. Lu Zhang
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Contributions

LZ and LL drafted the manuscript, FZ designed the study. MM, SC, YZ, HH, XL and PL performed the statistical analyses. YW, BC, CL, MD, QX and YD provided feasible advice on data analysis and drafting manuscript. All authors read and approved the final manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Feng Zhang.

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Zhang, L., Liu, L., Ma, M. et al. Integrative analysis of transcriptome-wide association study data and mRNA expression profiles identified candidate genes and pathways associated with atrial fibrillation. Heart Vessels 34, 1882–1888 (2019). https://doi.org/10.1007/s00380-019-01418-w

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  • DOI: https://doi.org/10.1007/s00380-019-01418-w

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