• genetic susceptibility
• single nucleotide polymorphisms
• pleiotropy scan
• multiple myeloma

Multiple myeloma (MM) is a malignancy of terminally differ¬entiated plasma cells, that originates from bone marrow cells. Patients typically present bone marrow infiltration of clonal plasma cells and overproduction of monoclonal protein detectable in the serum and/or urine, leading to end organ damage in more advanced MM stage. MM is the third haematological malignancy worldwide and it is still incurable, although sensible progress have been made in studying its pathogenesis and treatments for patients since its discovery. Genome-wide association studies (GWAS) have identified several genetic loci related to MM risk over the years, albeit they are a small number if compared to other cancer types. The large number of statistical tests and the necessity to avoid false positives association findings required by this investigation approach, implicates the establishment of a more restrictive significance threshold (Pvalue<5.00x10-8) which increases the chances of not observing true associations between single nucleotide polymorphisms (SNPs) and the disease. A possible strategy to avoid this problem is to reduce the number of SNPs based on a biological hypothesis and considering that also common genetic variants may be characterized by a genetic phenomenon named pleiotropy, i. e. the capability of a gene (or allele) to have an effect on several phenotypes, we conducted a pleiotropy scan analysis on MM cases and controls. The pleiotropic scan strategy tests only SNPs previously associated with human phenotypes to detect pleiotropic variants associated with the outcome of interest, as successfully done in other studies for various cancer types.
We downloaded from GWAS catalog (https://www.ebi.ac.uk/gwas/) the list of SNPs associated to any trait with a Pvalue<5.00x10-8 and all 59,858 unique SNP-trait associations were tested in the existing InterLymph MM GWAS data (2434 MM cases and 3446 controls). Thereafter a replication phase was conducted with the top 10 SNPs associated (Pvalue<10-4), excluding known MM risk loci. These SNPs were genotyped in the context of International Multiple Myeloma rESEarch (IMMEnSE) consortium containing 1955 MM cases and 1549 controls.
The genetic variant LOC105374037-rs1022206-T was found associated with an increased risk of developing MM both in InterLymph (OR= 1.18, 95%CI 1.09-1.28, Pvalue= 8.61x10-5) and IMMEnSE (OR= 1.17, 95%CI 1.04-1.31, Pvalue= 9.48x10-3). Finally, a meta-analysis between InterLymph and IMMEnSE results was conducted for rs1022206-T (OR= 1.18, 95%CI 1.10-1.26, Pvalue= 2.53x10-6, I2= 0.00%).
rs1022206 is an intronic variant of the uncharacterized ncRNA LOC105374037 known to be in high LD with rs6437923, which was discovered through GWAS to be associated with balding type 1 (Pvalue= 2.00x10-12). The functional role of rs1022206 is still unknown as well as its relation in the risk of developing MM.