Abstract
Functionally altered biological mechanisms arising from disease-associated polymorphisms remain difficult to characterize when those variants are intergenic, or, fall between genes. The speaker and his research group 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, they predicted 3,870 inter-intra and inter-intra SNP pairs with convergent biological mechanisms (FDR<0.05). These prioritized SNP pairs with overlapping messenger RNA targets or similar functional annotations were more likely to be associated with the same disease than unrelated pathologies (OR>12). They 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<10-4). Using ENCODE data sets, The speaker and his group further statistically validated that the biological mechanisms shared within prioritized SNP pairs are frequently governed by matching transcription factor binding sites and long-range chromatin interactions. These results provide a 'roadmap' of disease mechanisms and therapeutic targets emerging from GWAS and further identify candidate therapeutic targets among downstream effectors of intergenic SNPs.
About the speaker
Prof Yves A. Lussier received his bachelor degree in Engineering in 1985 and MD in 1989, both from the University of Sherbrooke. After serving as an attending physician at the University of Sherbrooke Hospital, he joined Columbia University and became an Assistant Professor in 2001. Prof Lussier furthered his career in the University of Chicago and the University of Illinois at Chicago. In 2013, he joined the University of Arizona and is currently the Professor of Medicine.
Prof Lussier’s research focuses on the use of knowledge technologies and ontologies to accurately individualize the understanding, prediction, and treatments of these diseases. His research group also conducts hypothesis-driven translational research in biomedical informatics.
Prof Lussier was elected a Fellow of American College of Medical Informatics (ACMI) in 2005 and was appointed as the General Chair of the 2009 American Medical Informatics Association (AMIA) Summit on Translational Bioinformatics. He serves on the editorial board of the Journal of Biomedical Informatics, Journal of the American Medical Informatics Association, and on the Journal of Personalized Medicine. Prof Lussier was also invited to the White House Precision Medicine Initiative summit in 2016.
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