T13. epigenetic factors influencing co-morbidity of insulin-related somatic and brain disorders

The PRIME (Prevention and Remediation of Insulin Multimorbidity in Europe) project aims to investigate the correlation between insulin-related somatic disorders and brain disorders. Previous research within the project has demonstrated shared genetic factors among these disorders. Besides genetic factors, environmental factors may also contribute to their development. Cells can respond and adapt to environmental changes by modifying their gene expression, a process influenced by epigenetic mechanisms like chromatin remodeling. We utilized the H-MAGMA software to conduct gene-based analysis incorporating chromatin interaction profiles (Hi-C data) from human brain tissues. This approach allowed us to extract valuable biological insights from genome-wide association study (GWAS) summary statistics. Epigenetic analyses were performed on 21 pairs of three insulin-related somatic diseases and seven neuropsychiatric disorders using cross-disorder GWAS summary statistics and chromatin interaction profiles from human brain tissues. Our analysis revealed significant gene-based associations for all pairs of disorders. We identified several genes that were shared across multiple disorders, which are known to have relevant neurobiological functions and have previously been associated with the investigated disorders. Notable genes among the frequently overlapping ones include RHOA, IHO1, NDUFAF3, PKHD1, CCDC71, TMEM219, AMT, ARIH2, NPIPB11, QRICH1, TAOK2, and BANK1, showing significant associations across various disorder pairs. RHOA, CCDC71, and TAOK2 have previously been linked to both somatic insulin-related disorders and neurodevelopmental disorders. Subsequently, we performed a Gene Ontology analysis on genes that were significant in at least three disorder pairs in our cross-disorder analyses (n=420 genes). The Gene Ontology analysis indicated enrichment in three major biological process domains ("epigenetics," immune system, and mitochondrial organization), as well as a few minor domains. These findings suggest the potential involvement of these processes in the multimorbidity between somatic and brain insulin-related disorders. In the ``epigenetics'' domain specifically, we identified genes associated with covalent chromatin modifications, histone modifications, lysine acetylation, and various protein modifications. Importantly, the enrichment of genes in the epigenetics-related domain is independent of the original use of the H-MAGMA method. Our findings provide valuable insights into the intricate relationship between somatic and brain insulin-related disorders, emphasizing the significance of epigenetic factors. The results support previous findings within the PRIME project and contribute to the understanding of shared genetic and environmental factors underlying these disorders. Further research is necessary to validate these findings and explore the mechanisms behind the comorbidity observed between somatic and brain insulin-related disorders. The insights gained from this study have the potential to aid in the development of targeted interventions and personalized medicine approaches for individuals with co-occurring somatic and psychiatric disorders.