Low overlap of plasma and CSF protein quantitative trait loci affects protein discovery for neurological disease

Plasma protein quantitative trait loci (pQTLs) have been integrated with genetic studies to prioritize proteins implicated in numerous human diseases. However, limited interaction between plasma and the central nervous system decreases the fluid's relevance for neurological disease. We compared the pQTL landscapes between plasma and cerebrospinal fluid (CSF), detecting widespread differences across fluids that translate to the identification and prioritization of proteins and pathways implicated in neurological disorders. Of almost 5000 CSF and plasma pQTLs, fewer than 30% were present in both fluids, demonstrating the importance of cross-context analyses to understand genetic regulation of protein abundance. We identified 427 associations between proteins and risk of 14 neurological traits, including 249 associations that were not found in previous studies. Only 69 of the associations were consistently detected in both fluids, demonstrating the information gained through the analysis of multiple bodily contexts. We further demonstrated that CSF proteogenomics captures more substantial disease overlap (for example, between Alzheimer's disease and dementia with Lewy bodies) and captures trait-relevant biology missed in plasma, including cell death and immune response signatures in Alzheimer's and multiple sclerosis. Through this work, we demonstrated the importance of analyzing less accessible but more trait-relevant contexts to fully understand human disease.