Omics basis of human health: investigating plasma proteins and their genetic effects on complex traits

Abstract

Over the past decade, the advancements in technology and the growing amount of identified genetic variants have led to a high number of important discoveries in the field of precision medicine concerning human biology and pathophysiology. However, it became evident that genomics alone could not properly explain the onset and regulation of the specific molecular mechanisms of certain phenotypes. Studying omics helped complement this gap in genetic research, providing detailed information on the quantification of molecules that are involved in structural and functional processes in the organism. Specifically, protein production, levels, and regulation are dynamic and change during the course of one’s lifetime. This information has proven fundamental to understanding how certain proteins affect complex phenotypes such as neurological and psychiatric disorders.

In this thesis, I describe the three groups of analyses I conducted over the course of my doctoral programme on different sets of blood plasma proteins and over a broad range of neurological, psychiatric, cardiovascular, and electrophysiology phenotypes. The underlying mechanisms that trigger the onset of psychiatric and neurological conditions are often not limited to the nervous system, but rather stem from multi-system molecular triggers. The first part of the work I carried out aims at investigating the frequent co-occurrence and comorbidity of neurological and cardiovascular phenotypes by conducting a genome-wide association (GWA) meta-analysis of 183 neurology-related blood proteins on data from over 12000 individuals. The second part concerns the bivariate and multivariate analyses conducted on 276 cardiology and inflammatory proteins, while the third illustrates the contribution to consortia focussed on heart rate and electrophysiology. Results from the second and third parts of the work provided information that played an important role in understanding a part of the genetic mechanisms of the complex traits of interest.

Overall, the results presented in this thesis strongly support the notion that proteomics is an important tool to be used to study complex traits and drug discovery and development should focus on targeting protein synthesis and regulation. Furthermore, the results also support the notion that complex diseases involve more than one biological system, and in order to gain a better understanding of human pathology, it is fundamental to study the causes and effects across the entire organism.