Pleiotropic Prioritization: Unraveling Shared Genetic Threads in Insomnia and Chronic Pain Through an Advanced Gene Prioritization Pipeline

Many chronic pain patients report co-occurring sleep disturbances, like insomnia, which have been linked to chronic pain development and exacerbation. Though these two complex conditions frequently co-occur, it is unclear whether these are distinct conditions or whether a common mechanism may underlie development of both. Using a bioinformatics approach, we identified potential pleiotropic genes associated with both phenotypes. As a first step, we developed a pipeline to prioritize genes implicated via single nucleotide variants (SNVs) associated with both insomnia and chronic pain phenotypes in genome-wide association studies (GWAS). This search resulted in 8 SNVs located in or between 11 genes. Using the Functional Mapping and Annotation database, FUMA v1.5.6, we identified 29 genes associated with our phenotypes of interest and then mapped these to their mouse orthologs using the DRSC integrative ortholog prediction tool (DIOPT v9.0) resulting in a final list of 26 mouse genes. Using previously published whole genome-sequencing data generated from multiple inbred mouse strains, we identified 86 variants within our prioritized mouse genes. Leveraging differential expression data between closely related mouse sub-strains to narrow this list to 5 genes, Mapt, Kansl1, Uqcc2, Grm4, and Dcc, implicated in insomnia and chronic pain in humans that contained 47 variants differing between sub-strains warranting further investigation. This pipeline facilitates the generation of novel hypotheses centered around common genetic mechanisms of risk for both insomnia and chronic pain. Follow-up studies examining how these genes interact together or independently as well as potential for these genes to encode pharmaceutical targets are warranted.