Integrative genomics analyses unveil downstream biological effectors of disease-specific polymorphisms buried in intergenic regions
Abstract
Functionally altered biological mechanisms arising from disease-associated polymorphisms, remain difficult to characterise when those variants are intergenic, or, fall between genes. We sought to identify shared downstream mechanisms by which inter- and intragenic single-nucleotide polymorphisms (SNPs) contribute to a specific physiopathology. Using computational modelling of 2 million pairs of disease-associated SNPs drawn from genome-wide association studies (GWAS), integrated with expression Quantitative Trait Loci (eQTL) and Gene Ontology functional annotations, we predicted 3,870 inter–intra and inter–intra SNP pairs with convergent biological mechanisms (FDRo0.05). These prioritised SNP pairs with overlapping messenger RNA targets or similar functional annotations were more likely to be associated with the same disease than unrelated pathologies (OR412). We additionally confirmed synergistic and antagonistic genetic interactions for a subset of prioritised SNP pairs in independent studies of Alzheimer’s disease (entropy P = 0.046), bladder cancer (entropy P = 0.039), and rheumatoid arthritis (PheWAS case–control Po10 - 4 ). Using ENCODE data sets, we further statistically validated that the biological mechanisms shared within prioritised SNP pairs are frequently governed by matching transcription factor binding sites and long-range chromatin interactions. These results provide a ‘roadmap’ of disease mechanisms emerging from GWAS and further identify candidate therapeutic targets among downstream effectors ofmore »
- Authors:
-
[1];
[2];
[5];
[8]
- University of Arizona, Tucson, AZ (United States); University of Illinois, Chicago, IL (United States); University of Chicago, IL (United States)
- University of Arizona, Tucson, AZ (United States); University of Illinois, Chicago, IL (United States)
- Vanderbilt University, Nashville, TN (United States)
- University of Chicago, IL (United States)
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- University of Arizona, Tucson, AZ (United States)
- Dartmouth College, Hanover, NH (United States); University of Pennsylvania, Philadelphia, PA (United States)
- University of Arizona, Tucson, AZ (United States); University of Illinois, Chicago, IL (United States); University of Chicago, IL (United States); Argonne National Laboratory (ANL), Argonne, IL (United States)
- Publication Date:
- Research Org.:
- Univ. of Arizona, Tucson, AZ (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); University of Chicago; National Institutes of Health (NIH); University of Arizona; University of Illinois; Vanderbilt University
- OSTI Identifier:
- 1624015
- Grant/Contract Number:
- AC02-06CH11357; NIH 1S10RR029030-01; R01-LM010685; K22-LM008308; LM009012; LM010098; LM010685; NCI P30CA; UL1RR024975023074; UL1TR000050; UL1TR000445
- Resource Type:
- Accepted Manuscript
- Journal Name:
- npj Genomic Medicine
- Additional Journal Information:
- Journal Volume: 1; Journal Issue: 1; Journal ID: ISSN 2056-7944
- Publisher:
- Springer Nature
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; genetics; heredity
Citation Formats
Li, Haiquan, Achour, Ikbel, Bastarache, Lisa, Berghout, Joanne, Gardeux, Vincent, Li, Jianrong, Lee, Younghee, Pesce, Lorenzo, Yang, Xinan, Ramos, Kenneth S., Foster, Ian, Denny, Joshua C., Moore, Jason H., and Lussier, Yves A. Integrative genomics analyses unveil downstream biological effectors of disease-specific polymorphisms buried in intergenic regions. United States: N. p., 2016.
Web. doi:10.1038/npjgenmed.2016.6.
Li, Haiquan, Achour, Ikbel, Bastarache, Lisa, Berghout, Joanne, Gardeux, Vincent, Li, Jianrong, Lee, Younghee, Pesce, Lorenzo, Yang, Xinan, Ramos, Kenneth S., Foster, Ian, Denny, Joshua C., Moore, Jason H., & Lussier, Yves A. Integrative genomics analyses unveil downstream biological effectors of disease-specific polymorphisms buried in intergenic regions. United States. https://doi.org/10.1038/npjgenmed.2016.6
Li, Haiquan, Achour, Ikbel, Bastarache, Lisa, Berghout, Joanne, Gardeux, Vincent, Li, Jianrong, Lee, Younghee, Pesce, Lorenzo, Yang, Xinan, Ramos, Kenneth S., Foster, Ian, Denny, Joshua C., Moore, Jason H., and Lussier, Yves A. Wed .
"Integrative genomics analyses unveil downstream biological effectors of disease-specific polymorphisms buried in intergenic regions". United States. https://doi.org/10.1038/npjgenmed.2016.6. https://www.osti.gov/servlets/purl/1624015.
@article{osti_1624015,
title = {Integrative genomics analyses unveil downstream biological effectors of disease-specific polymorphisms buried in intergenic regions},
author = {Li, Haiquan and Achour, Ikbel and Bastarache, Lisa and Berghout, Joanne and Gardeux, Vincent and Li, Jianrong and Lee, Younghee and Pesce, Lorenzo and Yang, Xinan and Ramos, Kenneth S. and Foster, Ian and Denny, Joshua C. and Moore, Jason H. and Lussier, Yves A.},
abstractNote = {Functionally altered biological mechanisms arising from disease-associated polymorphisms, remain difficult to characterise when those variants are intergenic, or, fall between genes. We sought to identify shared downstream mechanisms by which inter- and intragenic single-nucleotide polymorphisms (SNPs) contribute to a specific physiopathology. Using computational modelling of 2 million pairs of disease-associated SNPs drawn from genome-wide association studies (GWAS), integrated with expression Quantitative Trait Loci (eQTL) and Gene Ontology functional annotations, we predicted 3,870 inter–intra and inter–intra SNP pairs with convergent biological mechanisms (FDRo0.05). These prioritised SNP pairs with overlapping messenger RNA targets or similar functional annotations were more likely to be associated with the same disease than unrelated pathologies (OR412). We additionally confirmed synergistic and antagonistic genetic interactions for a subset of prioritised SNP pairs in independent studies of Alzheimer’s disease (entropy P = 0.046), bladder cancer (entropy P = 0.039), and rheumatoid arthritis (PheWAS case–control Po10 - 4 ). Using ENCODE data sets, we further statistically validated that the biological mechanisms shared within prioritised SNP pairs are frequently governed by matching transcription factor binding sites and long-range chromatin interactions. These results provide a ‘roadmap’ of disease mechanisms emerging from GWAS and further identify candidate therapeutic targets among downstream effectors of intergenic SNPs.},
doi = {10.1038/npjgenmed.2016.6},
journal = {npj Genomic Medicine},
number = 1,
volume = 1,
place = {United States},
year = {Wed Apr 27 00:00:00 EDT 2016},
month = {Wed Apr 27 00:00:00 EDT 2016}
}
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Pathway-Based Approaches for Analysis of Genomewide Association Studies
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SCAN: SNP and copy number annotation
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PheWAS: demonstrating the feasibility of a phenome-wide scan to discover gene-disease associations
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Inference of Population Structure Using Multilocus Genotype Data
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NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins
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The Gene Ontology in 2010: extensions and refinements
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STRING v9.1: protein-protein interaction networks, with increased coverage and integration
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Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks
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journal, September 2012
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GENCODE: The reference human genome annotation for The ENCODE Project
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Linking disease associations with regulatory information in the human genome
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Annotation of functional variation in personal genomes using RegulomeDB
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Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits
journal, November 2013
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Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells
journal, March 2014
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- Science, Vol. 343, Issue 6175
The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans
journal, May 2015
- Ardlie, K. G.; Deluca, D. S.; Segre, A. V.
- Science, Vol. 348, Issue 6235
Emergence of Scaling in Random Networks
journal, October 1999
- Barabási, Albert-László; Albert, Réka
- Science, Vol. 286, Issue 5439
CTCF Controls Expression and Chromatin Architecture of the Human Major Histocompatibility Complex Class II Locus
journal, June 2010
- Majumder, Parimal; Boss, Jeremy M.
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Complex-disease networks of trait-associated single-nucleotide polymorphisms (SNPs) unveiled by information theory
journal, March 2012
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A Neighborhood-Wide Association Study (NWAS): Example of prostate cancer aggressiveness
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Novel disease syndromes unveiled by integrative multiscale network analysis of diseases sharing molecular effectors and comorbidities
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A Neighborhood-Wide Association Study (NWAS): Example of prostate cancer aggressiveness
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