Network nature of ligand-receptor interactions underlies disease comorbidity in the brain

Kavli Affiliate: Keri Martinowich

| Authors: Melissa Grant-Peters, Aine Fairbrother-Browne, Amy Hicks, Boyi Guo, Regina H. Reynolds, Louise A. Huuki-Myers, Nick Eagles, Jonathan Brenton, Sonia Garcia-Ruiz, Nicholas Wood, Sonia Gandhi, Keri Martinowich, Kristen Maynard, Leonardo Collado-Torres and Mina Ryten

| Summary:

Neurodegenerative disorders have overlapping symptoms and have high comorbidity rates, but this is not reflected in overlaps of risk genes. We have investigated whether ligand-receptor interactions (LRIs) are a mechanism by which distinct genes associated with disease risk can impact overlapping outcomes. We found that LRIs are likely disrupted in neurological disease and that the ligand-receptor networks associated with neurological diseases have substantial overlaps. Specifically, 96.8% of LRIs associated with disease risk are interconnected in a single LR network. These ligands and receptors are enriched for roles in inflammatory pathways and highlight the role of glia in cross-disease risk. Disruption to this LR network due to disease-associated processes (e.g. differential transcript use, protein misfolding) is likely to contribute to disease progression and risk of comorbidity. Our findings have implications for drug development, as they highlight the potential benefits and risks of pursuing cross-disease drug targets.

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