Li H, Achour I, Bastarache L, Berghout J, Gardeux V, Li J, Lee Y, Pesce L, Yang X, Ramos KS, Foster I, Denny JC, Moore JH, Lussier YA. Integrative genomics analyses unveil downstream biological effectors of disease-specific polymorphisms buried in intergenic regions. NPJ genomic medicine. 1(1). PMID: 27482468 [PubMed] PMCID: PMC4966659 NIHMSID: NIHMS804551.
Functionally altered biological mechanisms arising from disease-associated polymorphisms, remain difficult to characterize 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 modeling 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 (FDR12). We additionally confirmed synergistic and antagonistic genetic interactions for a subset of prioritized 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 p