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

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

Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization

La sequía de la península de Yucatán

La sequía es uno de los fenómenos naturales más difíciles de estudiar debido a que no se cuenta con una definición lo suficientemente clara ni con los recursos técnicos para poder predecirla. Es un problema que, en el mundo, se ha incrementado en las últimas décadas como consecuencia del cambio climático. En México, la sequía afecta a más personas que cualquier otra contingencia natural, por lo que se requiere estudiarla para poder prevenir y mitigar sus efectos. En la península de Yucatán (PY), zona privilegiada por tener un vasto manto acuífero, la sequía no se presenta de manera tan catastrófica como en otros estados de la república. La sequía produce pérdidas y bajo rendimiento de cultivos, cabezas de ganado y colmenas, disminución de la calidad de los productos, así como incremento en los costos de producción, lo que produce reducción en el ingreso de los productores. A nivel de los organismos operadores no se registra baja en la disponibilidad de agua durante la época de sequía y sólo se reporta su disminución para consumo humano en algunas localidades en donde el acuífero se encuentra muy profundo o la calidad natural del agua no es adecuada para consumo humano. Sin embargo, al depender la PY casi en su totalidad del acuífero para el abasto del agua, su disponibilidad podría disminuir súbitamente por problemas en la infraestructura del sistema operador o de contaminación (importante por la permeabilidad del sustrato geológico y porque no existen sistemas de drenaje y potabilización de agua suficientes)

Nested inversion polymorphisms predispose chromosome 22q11.2 to meiotic rearrangements [RETRACTED]

Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A–D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A–B 22q11.2 deletion carry inversions of LCR22B–D or LCR22C–D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders

Complete sequence of the 22q11.2 allele in 1,053 subjects with 22q11.2 deletion syndrome reveals modifiers of conotruncal heart defects

The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression

Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization