Abstract:

Atherosclerotic cardiovascular diseases (ASCVDs) and associated vascular dementia (VaD) are major contributors to global morbidity and mortality, disproportionately affecting women at younger ages compared to men. However, key aspects of their molecular pathology and gender differences remain poorly understood. The plasma proteome provides a dynamic window into understanding the molecular pathophysiology of these diseases, yet its complexity challenges traditional statistical models, which struggle to capture the complex, interconnected nature of ASCVD and VaD.
Methods: This PhD research aims to address these challenges by applying biologically informed neural networks (BINNs) and instrumental variable approaches to integrate genomic and proteomic data, with the goal of refining risk stratification and identifying causal molecular pathways associated with ASCVD and VaD. Using two extensively phenotyped population-based cohorts, the study will map genetic loci for regulation of protein expression and molecular pathways for ASCVD and VaD, with a particular focus on sex-specific aspects. Additionally, the project will evaluate the performance of different proteomics platforms on suboptimally handled blood samples, providing guidance for future biobank-based research with a specific wish to conduct ASCVD research on a unique female cohort with 30 years of follow-up.
Significance: This study will provide novel insights into the genetic and proteomic architecture of ASCVDs and VaD and pave the way for large-scale MS-based proteomics research using biobank samples.