PO-057 Genetic interaction and pathway based discovery of key regulators in multiple myeloma

Abstract

IntroductionMultiple myeloma (MM) is a plasma cell dyscrasia characterised by proliferation of monoclonal plasma cells. As one of the most prevalent haematological malignancies, MM is genetically heterogeneous. Although 17 individual MM susceptibility loci have been identified, their inherent biological mechanism is sparsely understood. We carried out a polygenic interaction analysis with published whole-genome association studies (GWASs) to further characterise MM susceptibility with inflated genomic resolution in order to locate seemingly aberrant variations having temporal aggregation of risk.Material and methodsSingle nucleotide polymorphisms data from two MM GWAS representing 3999 cases and 7266 controls were subjected to genome-wide interaction analysis and followed-up with a meta-analysis. The identified loci were used for consequent gene set enrichment and tissue expression prioritisation to obtain functional evidence. Causal dependency between sentinel loci and functional variants was then interrogated with expression quantitative trait loci subject to summary data-based Mendelian randomization. Patient samples and relevant clinico-pathological information was obtained conditional on written informed consent and was subject to approval of corresponding ethical review boards at respective study centres in accordance with the tenets of Declaration of HelsinkiResults and discussionsA total of sixteen novel interacting pairs were identified along with indication of differential regulation in two principal signalling cascade families. Several previously identified and novel chromosomal regions influencing hematopoietic malignancies and contributing to pluripotent B-cell differentiation, survival, proliferation and apoptosis were identified. These loci were suggested to influence immune response and regulate immunoglobulin class-switch. Tissue/cell-type enrichment analysis showed that the genes associated with the identified loci were highly expressed in hemic-immune system tissue types and immune-related cell types.ConclusionOur polygenic interaction analysis renders novel insight into genetic susceptibility in MM. Related pathways provide some basic understanding of functional relation between discovered candidates as well as a biological basis of predisposition.