Abstract
Long non-coding RNAs (lncRNAs) serve as important controller of cellular functions via regulating RNA transcription, degradation and translation. However, what are the regulation patterns of lncRNAs on downstream mRNA and how the upstream genetic variants regulate lncRNAs are largely unknown. We first performed a comprehensive expression quantitative trait locus (eQTL) analysis (MatrixeQTL package, R) using genome-wide lncRNA expression and SNP genotype data from human peripheral blood mononuclear cells (PBMCs) of 43 unrelated individuals. Subsequently, multi-omics integrative network analysis was applied to construct SNP-lncRNA-mRNA (SLM) interaction networks. The causal inference test (CIT) was used to identify lncRNA-mediated (epi-) genetic regulation on mRNA expressions. Our eQTL analysis detected 707 pairs of cis-effect associations (p < 5.64E−06) and 6657 trans-effect associations (p < 3.51E−08), respectively. We also found that top significant cis-eSNPs were enriched around the lncRNA transcription start site regions, and that enrichment patterns of cis-eSNPs differs among different lncRNA sizes (small, medium and large).The constructed SLM interaction networks (1 primary networks and four small separate networks) showed various complex interaction patterns. Especially, the in-depth CIT detected 50 significant lncRNA-mediated SLM trios, and some hotspots (e.g., SNPs: rs926370, rs7716167 and rs16880521; lncRNAs: HIT000061975 and ENST00000579057.1). This study represents the first effort of dissecting the SLM interaction patterns in PBMCs by multi-omics integrative network analysis and causal inference test for clearing the regulation chain. The results provide novel insights into the regulation patterns of lncRNA, and may facilitate investigations of PBMC-related immune physiological process and immunological diseases in the future.
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Abbreviations
- 3′UTRs:
-
3′ Untranslated regions
- CIT:
-
Causal inference test
- DAVID:
-
The database for annotation, visualization, and integrated discovery
- elncRNA:
-
eQTL lncRNA
- eProbe:
-
eQTL probe
- eQTL:
-
Expression quantitative trait locus
- eSNP:
-
eQTL SNPs
- FDR:
-
False-discovery rate
- GO:
-
Gene ontology
- GWAS:
-
Genome-wide association studies
- KEGG:
-
Kyoto encyclopedia of genes and genomes
- LD:
-
Linkage disequilibrium
- lncR-eQTLs:
-
lncRNA eQTLs
- lncRNAs:
-
Long non-coding RNAs
- PBMCs:
-
Peripheral blood mononuclear cells
- PCC:
-
Pearson correlation coefficients
- RA:
-
Rheumatoid arthritis
- SLM:
-
SNP-lncRNA-mRNA
- SNPs:
-
Single nucleotide polymorphisms
- TES:
-
Transcription end site
- TFBS:
-
Transcription factor binding sites
- TSS:
-
Transcription start site
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Acknowledgements
The study was supported by Natural Science Foundation of China (81473046, 31271336, 81373010, 81502868, 31401079, 81401343, 81541068), the Natural Science Research Project of Jiangsu Provincial Higher Education (16KJA330001), the Natural Science Foundation of Jiangsu Province (BK20130300, BK20150346), the Project funded by China PostdoctoralScience Foundation (2014M551649),the Startup Fund from Soochow University (Q413900112, Q413900712), and a Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions.
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439_2017_1771_MOESM2_ESM.tif
Supplementary material 2 (TIFF 164 kb) Figure S1. Distribution of eQTL association significance (−log10 p value) for eSNPs against their distance (bp) from TSS in different types of lncRNA
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Xia, W., Zhu, XW., Mo, XB. et al. Integrative multi-omics analysis revealed SNP-lncRNA-mRNA (SLM) networks in human peripheral blood mononuclear cells. Hum Genet 136, 451–462 (2017). https://doi.org/10.1007/s00439-017-1771-1
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DOI: https://doi.org/10.1007/s00439-017-1771-1