Abstract
Variations in blood protein levels have been linked to numerous complex diseases, including cardiovascular conditions. These associations highlight the intricate interplay between local and systemic factors in cardiovascular disease development, emphasizing the need for a comprehensive, systems-level understanding of its etiology. To address this, we develop a causal network inference framework using data from one of the largest serum proteomics studies to date, comprising measurements of 7523 serum proteins in the prospective, population-based Age, Gene/Environment Susceptibility-Reykjavik Study (AGES) cohort of 5376 older adults. Using cis-acting protein quantitative trait loci (pQTLs) as instrumental variables within a causal inference framework designed to mitigate hidden confounding, we identify 185 high-confidence causal serum protein subnetworks collectively interacting with 5611 targets. Several subnetworks, many forming hierarchical frameworks of directional relationships, are significantly associated with multiple cardiometabolic traits and with future risk of myocardial infarction and its long-term complication, heart failure.