Durante el ciclo de la vida, los individuos se ven expuestos a distintos factores tanto exógenos como endógenos, con diversas consecuencias sobre el comportamiento y el bienestar de los mismos. Entender la forma en que dichos factores afectan desenlaces de interés tanto a nivel individual como agregado, permite formular políticas públicas que mitiguen o potencien los efectos encontrados. En esta tesis analizo como factores socio-económicos, ambientales y genéticos afectan las decisiones de consumo y los niveles de salud de los individuos. En el primer capítulo de esta tesis, evalúo el efecto de una asignación gratuita de agua otorgada a hogares de bajos niveles socio-económicos en la ciudad de Bogotá (Colombia). Específicamente, evalúo el efecto de la asignación sobre las decisiones de consumo de agua de los individuos, encontrando que gracias a la intervención, los hogares incrementan su consumo de agua, al tiempo que experimentan una disminución en la factura del agua. Este resultado sugiere que la asignación funciona como una transferencia en efectivo. Adicionalmente, encuentro un incremento en el porcentaje de hogares que poseen un lavamanos; de esta forma el subsidio genera un incremento en el consumo de bienes durables relacionados con el consumo de agua. Finalmente, encuentro que entre la población más vulnerable, hay una disminución en la prevalencia de diarrea en menores de cinco años. En el segundo capítulo, analizo como la asociación entre variantes genéticas relacionadas con la obesidad y el índice de masa corporal (IMC) varía a lo largo del ciclo de la vida en varias cohortes poblacionales en Estados Unidos. Para tal fin empleo puntuaciones poligénicas, índices que resumen el riesgo genético de las personas hacia un elevado IMC. Encuentro que el efecto de las puntuaciones poligénicas del IMC sobre el IMC aumenta significativamente a medida que los adolescentes pasan a la edad adulta. Sin embargo, este no es el caso de las personas mayores de 55 años, cuya influencia genética en el IMC es notablemente estable a medida que avanzan hacia la vejez. Finalmente, en el último capítulo, evalúo el efecto que tienen los niveles de lluvia sobre medidas objetivas de salud mental en un país en vías de desarrollo. Usando un modelo de efectos y datos colombianos, encuentro que incrementos en los niveles de lluvia generan incrementos en el número de intentos de suicidios, en el número de personas tratadas por problemas de salud relacionados con el estrés y en el número de personas tratadas por depresión. A su vez encuentro una relación positiva entre niveles de lluvia y desempleo. Entre la población trabajadora, encuentro que incrementos en los niveles de lluvia únicamente afecta a los trabajadores del sector formal. Este resultado sugiere que los trabajadores del sector informal continúan trabajando aún bajo condiciones climáticas adversas.

Genetic and home chaos influences in early childhood have been independently associated with externalizing problems, characterized by inattentive, hyperactive, and aggressive behaviors. However, the Behavioral Genetics approach indicates that genetic and environmental influences, although independently effective, interact to produce behavior throughout development. Thus, this thesis uses two samples, the Early Growth and Development study (EGDS), n= 564, and the Avon Longitudinal Study of Parents and Children (ALSPAC), n= 8,952, and two genetically-sensitive approaches, a parent-child adoption approach and a polygenic scoring approach, to examine how genetic influences and home chaos interact in early childhood (age 3-4) to predict externalizing problems later in childhood (age 7). Results indicate that, although home chaos is correlated with later externalizing problems, the effect is reduced in the context of earlier externalizing, possibly suggesting that home chaos is most salient for concurrent, not later, externalizing problems. In addition, genetic influences were not predictive of externalizing problems in either study, nor was the interaction of home chaos and genetic influences. This pattern of results suggests that, although home chaos may be an important factor for concurrent externalizing problems, other factors, e.g., parenting style and prenatal risk, may be more salient than home chaos, especially in interaction with genetic effects. Further, failure to find genetic influence in this thesis suggest that accounting for the broad scope of genetic influences on complex traits like externalizing and the specific genetic risk for individual externalizing phenotypes is important in attempts to find genetic influence and interaction.

Schizophrenia is a severe psychiatric disorder associated with cognitive impairments. Polygenic risk for schizophrenia (SCZ-PGR) has been associated with poor performance in cognitive tasks, both in patients and in healthy individuals. It has also been suggested that schizophrenia is associated with accelerated aging. This study examines the association between SCZ-PGR and accelerated non-pathological cognitive aging by performing longitudinal analyses using linear mixed-effects models. We hypothesize that higher SCZ-PGR is associated with accelerated rate of cognitive decline in healthy elderly. The study sample consist of 1746 Caucasian individuals with genetic data. Their performance in general cognition, episodic memory, semantic memory and visuospatial memory was tested over 25 years. SCZ-PGR was significantly associated with poor cognitive function but was not associated with cognitive decline over time with any of the cognitive domains. Our results indicate that genetics of schizophrenia may not be associated with rate of cognitive aging. / Schizofreni är en svår psykiatrisk sjukdom som är associerad med kognitiv nedsättning. Polygenetisk risk för schizofreni (SCZ-PGR) har associerats med sämre resultat på kognitiva test, både hos schizofrenipatienter och friska individer. Det har även föreslagits att schizofreni är associerad med accelererat åldrande. Denna studie avser undersöka associationen mellan SCZPGR och accelererad icke-patologisk kognitivt åldrande genom att genomföra longitudinella analyser i lineära mixade-effekt-modeller. Vår hypotes är att högre SCZ-PGR är associerad med accelererad kognitivt åldrande hos friska. I denna studie ingår 1746 deltagare, där deltagarnas kognitiva förmåga testades under 25 år. Vi analyserade deras SCZ-PGR i relation till generell kognitiv förmåga, episodminne, semantiskt minne och visuo-spatialt minne, samt associationen mellan SCZ-PGR och förändringen av dessa variabler över tid. SCZ-PGR var signifikant associerad med sämre kognitiv förmåga, men inte med kognitiv försämring över tid. Dessa resultat indikerar att gener relaterade till schizofreni inte är associerade till kognitivt åldrande.

<p>Complex traits are influenced by genetic and environmental factors and their interactions. Most common human disorders such as cardiovascular, metabolic, autoimmune, and neurological diseases are complex. Understanding their genetic architecture and etiology is an important step to prevent, diagnose and treat these conditions. Genome Wide Association Studies (GWAS) have emerged as a powerful and widely used tool that can be used to explore and identify the genetic variants associated with complex traits. In this dissertation, we present some of the downstream applications of GWAS studies to analyze and understand the genetic risk and etiology of complex traits and provide important insights into the genetic architecture and background of several complex phenotypes. First, we examined whether prevalence of complex disorders around the world correlates to Polygenic Risk Scores (PRS). To do so, we determined the average PRS of 14 such complex disorders across 24 world populations using results of GWAS studies. We found variation in risk across populations and significant correlation was obtained between average disease risk and prevalence for seven of the studied disorders. Further exploring the power of PRS- based calculations, we performed a PRS - based phenome wide association study (PheWAS) for Tourette Syndrome (TS) and identified 57 phenotypic outcomes significantly associated with TS PRS. The strongest associations were found between TS PRS and mental health factors. Cross- disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. Furthermore, we performed a sex specific PheWAS that highlighted differences in associations of complex disorders with TS PRS in males and females. Finally, we used large- scale GWAS results to identify causal associations between different biological markers (proteins, metabolites, and microbes) and subcortical brain structure volumes using Mendelian Randomization (MR) analysis. We identified eleven proteins and six metabolites to be significantly associated with subcortical brain volume structures. Enrichment analysis indicated that the associated proteins were enriched for proteolytic functions and regulation of apoptotic pathways. Overall, our work demonstrates the power of GWAS studies to help disentangle the genetic basis of complex diseases and also provides important insights into the etiology of the studied complex traits. </p>

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Causal inference may help us to understand the underlying mechanisms and the risk factors of diseases. In Genetics, it is crucial to understand how the connectivity among variables is influenced by genetic and environmental factors. Family data have proven to be useful in elucidating genetic and environmental influences, however, few existing approaches are able of addressing structure learning of probabilistic graphical models (PGMs) and family data analysis jointly. We propose methodologies for learning, from observational Gaussian family data, the most likely PGM and its decomposition into genetic and environmental components. They were evaluated by a simulation study and applied to the Genetic Analysis Workshop 13 simulated data, which mimic the real Framingham Heart Study data, and to the metabolic syndrome phenotypes from the Baependi Heart Study. In neuroscience, one challenge consists in identifying interactions between functional brain networks (FBNs) - graphs. We propose a method to identify Granger causality among FBNs. We show the statistical power of the proposed method by simulations and its usefulness by two applications: the identification of Granger causality between the FBNs of two musicians playing a violin duo, and the identification of a differential connectivity from the right to the left brain hemispheres of autistic subjects. / Inferência causal pode nos ajudar a compreender melhor as relações de dependência direta entre variáveis e, assim, a identificar fatores de riscos de doenças. Em Genética, a análise de dados agrupados em famílias permite investigar influências genéticas e ambientais nas relações entre as variáveis. Neste trabalho, nós propomos métodos para aprender, a partir de dados Gaussianos agrupados em famílias, o mais provável modelo gráfico probabilístico (dirigido ou não dirigido) e também sua decomposição em dois componentes: genético e ambiental. Os métodos foram avaliados por simulações e aplicados tanto aos dados simulados do Genetic Analysis Workshop 13, que imitam características dos dados do Framingham Heart Study, como aos dados da síndrome metabólica do estudo Corações de Baependi. Em Neurociência, um desafio consiste em identificar interações entre redes funcionais cerebrais - grafos. Nós propomos um método que identifica causalidade de Granger entre grafos e, por meio de simulações, mostramos que o método tem alto poder estatístico. Além disso, mostramos sua utilidade por meio de duas aplicações: 1) identificação de causalidade de Granger entre as redes cerebrais de dois músicos enquanto tocam um dueto de violino e 2) identificação de conectividade diferencial do hemisfério cerebral direito para o esquerdo em indivíduos autistas.

L’hypercholestérolémie familiale à transmission autosomique dominante (ADH), caractérisée par une élévation des taux plasmatiques en cholestérol total et LDL-C, est due à des altérations de 4 gènes : LDLR, APOB, PCSK9 et APOE. L’objectif principal de cette thèse est d’identifier de nouveaux gènes impliqués dans l’ADH. L’identification de nouveaux gènes sera suivie de l’étude des mécanismes physiopathologiques liés à leurs mutations. Un deuxième objectif est de calculer le score génétique (GRS) chez tous les individus appartenant à 5 familles où une mutation FH a déjà été identifiée afin de déterminer si une forme polygénique expliquerait les cas de phénocopies observés. Parallèlement, nous avons mené une étude dans la population libanaise caractérisée par une fréquence élevée de dyslipidémie et qui représente un outil d’étude remarquable au plan génétique du fait de l’existence d’une forte homogénéité du fond génétique.Ce projet de recherche a permis de révéler un gène candidat pouvant être impliqué dans l’ADH : LRP6. De plus il a permis de remettre en question le rôle du récepteur LRP6 jusqu’à présent considéré comme un protagoniste important dans l’internalisation des LDL. Des études supplémentaires sont encore nécessaires afin de confirmer ou non l’implication de ce gène dans l’ADH et de déterminer son rôle exact dans le métabolisme du cholestérol. Concernant le score polygénique, nous avons montré que le GRS ne peut pas être considéré comme un outil de diagnostic pour différencier les sujets avec une hypercholestérolémie monogénique de ceux avec une hypercholestérolémie polygénique et ne peut pas être utilisé pour expliquer les cas de phénocopies / Atherosclerosis and its cardiovascular complications are the leading causes of morbidity and mortality in industrialized countries. Hypercholesterolemia is one of the major cardiovascular risk factors and it affects one in 20 subjects in the general population. Autosomal dominant hypercholesterolemia (ADH), characterized by elevated plasma total cholesterol and LDL-C levels, is due to alterations in 4 genes: LDLR, APOB, PCSK9 and APOE. The fundamental work of Brown and Goldstein revealed the important role of the mutations in the LDLR gene in ADH and contributed to the development of a major class of cholesterol-lowering drugs: statins. Similarly, the discovery by Abifadel et al. in 2003 of the first hypercholesterolemic mutations of PCSK9 was the starting point of an adventure which resulted, 12 years later, in the development of a new class of cholesterol-lowering drugs: anti-PCSK9 antibodies. The main objective of this thesis is to discover new genes, major genetic factors and modifiers involved in ADH. The identification of new genes will be followed by the study of the pathophysiological mechanisms linked to their mutations. A second objective of this work is to calculate the genetic risk score (GRS) in all individuals belonging to 5 families where a mutation responsible of the hypercholesterolemic phenotype has been already identified in order to determine whether a polygenic form would explain the phenocopies observed in these families. In parallel to these two projects, we conducted a study in the Lebanese population which is characterized by a high incidence of dyslipidemia. In this population, it is interesting to conduct genetic studies because of the existence of a limited number of sub-populations that constitute "genetic isolates" with a high homogeneity of their genetic background, making it easier to study many hereditary diseases such as familial hypercholesterolemia. The results obtained in this project revealed a candidate gene that could be involved in ADH: LRP6. Moreover, it allowed us to question about the exact role of the LRP6 receptor until now considered as an important protagonist in the internalization of LDL particles. Further studies are still needed to confirm whether or not this gene is involved in ADH and to determine its exact role in cholesterol metabolism. Concerning the genetic score, we have shown that the GRS does not seem to be a reliable diagnostic tool to identify polygenic hypercholesterolemia at the individual level. The 6-SNP score did not give us a clear answer and thus we cannot use the GRS to identify phenocopies within ADH families

Fisher’s adaptive sex ratio theory predicts that organisms should invest equally in sons and daughters and the sex ratio at conception should be 1:1. Hamilton’s theory predicts that organisms should adjust sex ratios based on the relative strength of competition within a mating group. Testing sex ratio and sex allocation theories requires variation in sex ratio. Different sex allocation and sex allocation adjustment mechanisms can produce skewed sex ratios. I used Tigriopus californicus, a harpacticoid copepod with extrabinomial variation in sex ratios, to test sex ratio evolution and socially-mediated sex determination. Using artificially selected sex-biased populations, the trajectory of population sex ratios were as expected under Fisher’s theory and sex ratios approached/reached 0.5 proportion males. Populations with overlapping generations had a slower rate of change towards 0.5 than populations with non-overlapping generations. I show that these data are supported by multiple different models: a mechanistic and simulation model. I tested socially-mediated sex determination using seawater conditioned with different local sex ratios of copepods. There were detectable effects found in both wild populations and isofemale lines. However, these effects may be trivial as differences were small between treatments. Sex determination in T. californicus is a complex mechanism, with multiple genetic and environmental components. The complex nature of sex determination in T. californicus and the dynamic nature of their habitat in highly ephemeral splash pools provide a possible explanation for the non-Fisherian sex ratios we see. / Graduate