Integrative genomics analyses unveil downstream biological effectors of disease-specific polymorphisms buried in intergenic regions

Haiquan Li, Ikbel Achour, Lisa Bastarache, Joanne Berghout, Vincent Gardeux, Jianrong Li, Younghee Lee, Lorenzo Pesce, Xinan Yang, Kenneth Ramos, Ian Foster, Joshua C. Denny, Jason H. Moore, Yves A Lussier

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 of intergenic SNPs.

Original languageEnglish (US)
Article number16006
Journalnpj Genomic Medicine
Volume1
DOIs
StatePublished - Apr 27 2016

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Intergenic DNA
Genomics
Single Nucleotide Polymorphism
Genome-Wide Association Study
Entropy
Gene Ontology
Quantitative Trait Loci
Urinary Bladder Neoplasms
Chromatin
Rheumatoid Arthritis
Alzheimer Disease
Transcription Factors
Binding Sites
Pathology
Messenger RNA
Genes

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Genetics(clinical)

Cite this

Integrative genomics analyses unveil downstream biological effectors of disease-specific polymorphisms buried in intergenic regions. / Li, Haiquan; Achour, Ikbel; Bastarache, Lisa; Berghout, Joanne; Gardeux, Vincent; Li, Jianrong; Lee, Younghee; Pesce, Lorenzo; Yang, Xinan; Ramos, Kenneth; Foster, Ian; Denny, Joshua C.; Moore, Jason H.; Lussier, Yves A.

In: npj Genomic Medicine, Vol. 1, 16006, 27.04.2016.

Research output: Contribution to journalArticle

Li, Haiquan ; Achour, Ikbel ; Bastarache, Lisa ; Berghout, Joanne ; Gardeux, Vincent ; Li, Jianrong ; Lee, Younghee ; Pesce, Lorenzo ; Yang, Xinan ; Ramos, Kenneth ; 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. In: npj Genomic Medicine. 2016 ; Vol. 1.
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