Obesity is a major risk factor for multiple common chronic diseases. The prevalence in European countries is high and a significant public health concern. This thesis aims to explore the obesity landscape in the Cooperative Health Research in South Tyrol (CHRIS) study. The first step was to characterise the obese CHRIS population, taking into account the established body mass index (BMI) classification from the World Health Organization (WHO) and looking at metabolically healthy and unhealthy obesity. We investigated the familial aggregation of these traits. We identified several families with significant familial aggregation and observed varying degrees of overlap for these traits in different families. The focus was then on implementing and applying a Genome-Wide Polygenic Score for obese participants. These scores were computed for individuals based on the presence of different genetic variants weighted according to their measured effects in genome-wide association studies (GWAS). We then paid attention to the targeted metabolomics data of the CHRIS study, to identify different serum metabolites associated with metabolically healthy/unhealthy obesity, using logistic regression and random forest methods to explore metabolic signatures to distinguish obesity into metabolically healthy and metabolically unhealthy obesity. Several biomarkers were shown to be related to obesity, many of which confirmed by existing evidence (such as BCAAs, tyrosine, and lysophosphatidylcholines).

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25001号 / 医博第5035号 / 新制||医||1070(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 近藤 尚己, 教授 古川 壽亮, 教授 森田 智視 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Developmental Dyslexia (DD), Attention Deficit Hyperactivity Disorder (ADHD), and Educational Attainment (EA) are highly prevalent conditions that have a significant impacton individuals' academic and social functioning. These conditions have a complex genetic basis and are often comorbid. To assess the polygenic architecture of these traits, psychiatric genetics researchers utilize a sophisticated tool known as polygenic scores (PGS). By combining numerous genes of individually modest effects, PGS summarizes an individual's genetic risk as a single score. In this study, we aimed to examine the association between PGS for ADHD and EA with typical DD traits. Using a meta-analytic approach, we analyzed data from earlier studies and found that PGS-ADHD accounts for 1.2% of the variance in DD, with a pooled effect size of r = -0.11 (95% CI = [-0.171, -0.050]). Similarly, PGS-EA accounted for 3.2% of the variance in DD, with a pooled effect size of r = 0.18 (95% CI = [0.070, 0.288]). Although these effect sizes are relatively small, it is important to note that PGS are not typically strong predictors on their own, but rather capture a small portion of the genetic variation that contributes to a trait or outcome. My findings suggest that PGS for ADHD and EA are associated with DD, indicating that DD has a complex genetic basis. However, these findings also raise questions about the impact of PGS on psychiatric research moving forward. To address these questions, I provide recommendations for future researchdirections.

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.

Introduction Research show that both educational attainment and genetic propensity to education (PGSEdu) can be associated with geographic mobility and that individuals living in more deprived areas tend to have poorer health while those living in more advantaged places tend to have better health. In this thesis, the aim was to study how polygenic scores for education and attained education influence and differ by geographic mobility, and how they influence the association between geographic mobility and mortality. Methods Data was retrieved from the Swedish Twin Registry with twins born 1926-1955 (n=14,211). Logistic regression models were performed to test if PGSEdu and attained education predicted geographic mobility. Cox regression models were then performed to test if geographic mobility, attained education or PGSEdu decreased the risk of mortality. Results The results show that both the PGSEdu and attained education predicted geographic mobility, in both independent and joint models, with higher education indicating a higher mobility. Geographic mobility decreased the risk of mortality in the independent model, but joint models showed that the association was completely explained by attained education.  Conclusions To conclude, both PGSEdu and attained education influenced geographic mobility. Moreover, attained education explained the relationship between geographic mobility and mortality.

Il y a consensus qu’approximativement la moitié des différences individuelles liées à l’agression physique sont héritées. Cependant, les premières manifestations comportementales et sociales de cette propension génétique demeurent inconnues. Cette étude vise à tester l’hypothèse selon laquelle, les scores polygéniques liés à l’agression (SPGAG) et au trouble du déficit de l’attention/hyperactivité (TDAH; SPGTDAH), tous deux ayant précédemment été associés à l’agression physique à l’âge scolaire, se manifesteraient d’abord par des comportements externalisés et des expériences adverses à la petite enfance. Les données génétiques de 718 participants (44,6 % garçons) de l’Étude longitudinale du développement des enfants du Québec (ELDEQ) ont été utilisées pour estimer les SPGs. L’agression physique à l’âge scolaire a été rapportée à six reprises entre 6 et 13 ans par des enseignants indépendants. Les mères ont rapporté les comportements externalisés (agression physique, hyperactivité, opposition) et les expériences adverses (difficultés avec les pairs, pratiques parentales hostiles et coercitives) à trois occasions entre l’âge de 3½ et 5 ans. Les résultats indiquent que ces deux SPGs prédisent l’agression physique à l’âge scolaire. Néanmoins, seules les difficultés avec les pairs expliquent l’association entre le SPGAG et l’agression physique. L’hyperactivité, l’opposition et les pratiques parentales hostiles et coercitives sous-tendent toutes, de façon séparée, l’association entre le SPGTDAH et l’agression physique à l’âge scolaire, bien que seule l’hyperactivité ait une contribution unique lorsque ces construits sont examinés simultanément. Ces résultats contribuent à décrire comment l’étiologie génétique liée à l’agression physique se manifeste à la petite enfance, identifiant ainsi des cibles précoces d’intervention. / There is now a consensus in the literature suggesting that approximately half of the individual differences related to physical aggression (PA) are inherited. However, the behavioral and social early manifestations of this genetic propensity remain unknown. This study aims to test the hypothesis that polygenic scores related to aggression (PGSAGG) and attention deficit hyperactivity disorder (ADHD; PGSADHD), both of which were previously shown to be associated with PA during school-age, would be first phenotypically expressed as externalized behaviors and adverse experiences in early childhood. The genetic data of 718 participants (44,6% boys) from the Quebec Longitudinal Study of Child Development (QLSCD) were used to estimate the SPGs. PA in school age was reported up to six times between 6 and 13 years old by independent teachers. Externalized behaviors (PA, hyperactivity, opposition) and adverse experiences (difficulties with peers, harsh and coercive parenting practices) were reported by mothers on three occasions between the ages of 3½ and 5 years old. Results indicate that both SPGs predicted PA in school age. However, only difficulties with peers explain the association between PGSAGG and PA. Hyperactivity, opposition, and harsh and coercive parenting practices in early childhood all separately partially mediated the association between PGSADHD and PA in school age, although only hyperactivity has a unique contribution when these constructs are examined simultaneously. These findings contribute to describing how PA measured genetic etiology ascertained by the PGS come to be first phenotypically expressed in early childhood, identifying early intervention targets for interventions.