Systematic Post-Genome Wide Association Study Analysis by Combining Genetic and Expression Profiles in Nasopharyngeal Carcinoma

In the past decade, genome‐wise association studies (GWASs) have successfully identified thousands of genetic variants underlying susceptibility to complex diseases. However, most of the variants identified do not directly link to causal genes as well as provide evidence on how the variants affect downstream biological processes and finally lead to the disease. Therefore, in the post‐GWAS era there are two critical challenges ‐‐ discovery of true causal genes and functionally characterization of the associations through combining GWAS findings with other molecular data. Previously, we have successfully performed several full investigations of any possible susceptible loci in nasopharyngeal carcinoma (NPC), including GWAS, copy number variation (CNV) analysis and genome‐wide single nucleotide polymorphism (SNP)‐SNP interaction analysis. Just like other complex diseases, there are still two unsolved problems in NPC susceptibility analysis: First, although the importance of human leukocyte antigen (HLA) genes and major histocompatibility complex (MHC) region to NPC susceptibility were well recognized, whether there is another non‐HLA causal gene located within this region is still unknown. From our GWAS and meta‐analysis, the MHC region might also relate to differences in NPC incidences in different regions. A gender‐specific CNV related to NPC susceptibility also located in this region. To untie the mystery of MHC region, a deep sequencing analysis of this region will provide closer understanding. Second, we still don’t know how the susceptible variants affect disease status through influencing subsequent biological process. We can try to answer this question through analyze the effect of genetic variation on gene expression in NPC tissues through expression quantitative trait loci (eQTL) analysis. Systematic investigation of eQTLs in combination of our previous GWAS and SNP‐SNP interaction results will provide insights to the genetic effect of tumourigenesis and may also serve as a prognostic predictor in clinical applications. Therefore, in this proposal, we intend to answer above questions by accomplish the following specific aims in next three years: Aim 1. Identification of NPC putative causal variants within MHC region Aim 2. Identification of putative regulatory drivers in NPC

Project ID:PC10601-0231
External Project ID:MOST104-2314-B182-033-MY3