4. Discussion
death
ADVERSE EVENTS, INFLAMMATORY RESPONSE
In this study, we identified new potential genetic determinants of SOS at the SNP, gene, and pathway levels using a new multi-omics data analysis pipeline integrating data from two different experiments. We analyzed In the LCLs treated with busulfan, we found several upregulated pathways, which are mainly involved in the inflammatory response, signaling by interleukins and interferon-gamma, We identified new genetic markers in significant association with SOS, using the WES data, after the application of filtering steps to increase the homogeneity of the genetic dataset. Our data workflow reduced the number of individuals from the unfiltered WES dataset by 34.5% and the number of SNPs by 12.4%. Our pipeline thus generated a more homogenous sample at the cost of a smaller sample size. This workflow allowed us to identify through the analyses at the gene level 12 genes in significant association with SOS. None of these genes was identified in the previously published study, where a different strategy was used with a focus on single SNPs and functional variants [Existing data suggest that the association of the currently identified genes with SOS could be meaningful. The combined test statistic allowed to integrate the expression results and the association metrics into a single statistic measure. We identified 35 genes that were found to be associated with SOS after correction for multiple testing. None of these genes was previously investigated for an association with SOS. The functional analysis of these genes, using the KEGG database revealed that many are involved in the The functional analysis using the Reactome database identified pathways mostly involved in programmed cell death. Additionally, gene sets linked to the integrin cell surface interactions were found (We estimated polygenic risk scores for the cases and the controls that were included in this study, using the SNPs that were found within the boundaries of the 35 genes that were associated with a significant combined test statistic. The difference in the distributions of the PRSs between the cases and the controls is highly significant. Classically, PRSs are estimated in another cohort than the one that was used to estimate the association metrics with the phenotype of interest. Here, our goal was to estimate the magnitude of differences in scores between our cases and our controls. The difference in scores between cases and controls was highly significant and underscores the notion that the SNPs we used to estimate those scores are good candidates for further validation. In a future study, selecting those SNPs that contributed most to the PRS should be tested or some of the SNPs could be further prioritized, choosing some specific functional categories, i.e. non-synonymous variants.The pipeline we developed and used in this study allowed us to identify genes and pathways in association with a rare clinical outcome with a limited number of patient samples, where machine learning-based approaches are inapplicable [There are some limitations to our approach that are associated with the assumptions that are made in the setup of this study. First, the hypothesis that the genes that are dysregulated in LCLs after busulfan exposure are more likely to carry variants which are modifiers of busulfan toxicity might not be true. The importance of transcriptomic changes after drug exposure was shown previously to correlate with adverse events after drug exposure [In this paper, we proposed a novel approach to unravel the genetic determinants of SOS by combining 