Understanding protein complexes is crucial as they perform vital cellular functions through coordinated interactions among multiple proteins, unlike individual protein subunits. However, quantification of protein complexes is a highly challenging task. Here, we develop and apply both experimental assays and intelligent computational methods to generate the first high-throughput quantification of hundreds of protein complexes in human cohorts.
This study significantly advances proteomics by offering a detailed genetic atlas of human protein complexes. We identified thousands of genetic variants associated with these complexes, revealing hundreds of cis- and trans-associations. These findings highlight the strong effects of protein complex QTL (pcQTL) and their role in complex genetic regulation. Our analysis showed that higher heritability correlates with more detected pcQTL and greater phenotypic variance explained.
We discovered significant genetic links between protein complexes and human traits and diseases through colocalization and Mendelian randomization analyses. For instance, specific protein complexes showed protective effects against Alzheimer's disease and associations with immune-related conditions and cardiovascular diseases.
To explore therapeutic potential, we investigated protein markers as drug targets. Among the identified protein complexes, many protein subunits were linked to various diseases and health conditions. We identified over 100 drugs targeting these proteins, suggesting many drug-protein-complex-phenotype combinations for potential repurposing and new therapeutic strategies.
In summary, our research presents a comprehensive genetic atlas of human protein complexes, emphasizing the importance of studying protein complexes for understanding cellular functions, disease mechanisms, and therapeutic targets. This work paves the way for future innovations in diagnostics and precision medicine.