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

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13398号 / 論医博第2222号 / 新制||医||1051(附属図書館) / (主査)教授 妹尾 浩, 教授 中山 健夫, 教授 西浦 博 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

<p>This dissertation evaluated the complex inter-relatedness between co-occurring childhood maltreatment exposures, physical intimate partner violence (perpetration and victimization), substance use frequency, and molecular genetics for substance use, utilizing appropriate developmental models and theoretical approaches. Three studies were proposed within this dissertation. Data for the three studies come from a national longitudinal panel study: The National Longitudinal Study of Adolescent to Adult Health (Add Health; Harris, 2013). Across studies, latent profile analysis was used to evaluate co-occurring childhood maltreatment exposures based on type and severity of exposures, which resulted in three homogenous sub-groups. The first sub-group was composed of individuals that had high levels of physical abuse exposure and moderate levels of childhood neglect and emotional abuse exposures (high physical abuse sub-group). The second sub-group (high sexual abuse sub-group) included individuals with high severity of sexual abuse exposure and moderate severity of all other childhood maltreatment types (i.e., physical abuse, emotional abuse, and neglect). This second sub-group was, therefore, the most vulnerable in terms of their childhood maltreatment exposure. A final normative sub-group was also found that included a majority of individuals with low severity of childhood maltreatment exposure across types. Additionally, across all three studies, a probabilistic multifaceted genetic risk score (i.e., polygenic risk score) was created to evaluate substance use related genetic risk. The first study evaluated the role of co-occurring childhood maltreatment exposure on substance use development from adolescence to young adulthood while evaluating substance use related genetic moderation. Generalized estimating equations were used to test the proposed model in study 1. Findings suggest that the high physical abuse sub-group was more susceptible to genetic risk and had increases in substance use frequency only at high levels of genetic risk. In contrast, for the high sexual abuse sub-group, childhood maltreatment and environmental exposures were more ubiquitous for substance use development from adolescence to young adulthood. To elaborate, the high sexual abuse sub-group demonstrated increases in substance use from adolescence to young adulthood irrespective of genetic risk. In study 2, substance use frequency in young adulthood was tested as a mechanism between childhood maltreatment sub-groups and subsequent physical intimate partner violence perpetration in adulthood. Once again, genetic moderation for the direct association between childhood maltreatment sub-groups and substance use frequency in young adulthood was tested within the larger mediation model. In study 3, physical partner violence victimization in young adulthood was tested as a mediator of the association between childhood maltreatment sub-groups and substance use frequency in adulthood. In study 3, in addition to the above-mentioned genetic risk score, an additional substance use related dopamine polygenic risk score was also tested. Specifically, in study 3, genetic moderation by both genetic risk scores was tested on 1) the direct pathway from childhood maltreatment sub-groups to substance use frequency in adulthood, and 2) the direct pathway from physical intimate partner violence victimization in young adulthood to substance use frequency in adulthood. In both studies 2 and 3, product of co-efficient method was used to estimate mediation hypothesis, and moderated-mediation models were used to test for genetic moderation within the mediation model. Research aims for studies 2 and 3 were largely not supported. However, supplementary models indicate that substance use frequency may not be a causal mechanism but may be a contextual factor exacerbating the association between childhood maltreatment exposures and physical intimate partner violence perpetration. Implications for findings are discussed in detail. </p>

La stéatose hépatique non-alcoolique (NAFLD) est une altération hépatique fréquente dans le diabète de type 2 (DT2) et est associée à diverses complications telles que la mortalité. L’établissement d’outils de prédiction non-invasifs de NAFLD est primordial. Mon projet de maîtrise avait pour objectif d’établir des marqueurs génétiques de NAFLD dans le DT2 via deux stratégies : 1) une sélection non-ciblée des marqueurs génétiques (SNPs) via la méthode LASSO et 2) une sélection ciblée de SNPs rapportés comme liés à la maladie ou à des altérations associées. Une population de 4098 patients avec DT2 d’origine caucasienne (ADVANCE) a été utilisée. Des données statistiques sommaires d’études pangénomiques ont été exploitées pour sélectionner, via LASSO, les marqueurs génétiques (SNPs) à inclure dans le score de risque polygénique (PRS). J’ai également développé un modèle de 3210 SNPs ajusté par des covariables capable de prédire les taux élevés de ALT (AUC=0,69) et la mortalité non-cardiovasculaire (AUC=0,66). Le criblage du locus candidat PNPLA3-SAMM50 a mis en avant une diversité des associations génétiques aux différentes altérations métaboliques comme les taux de ALT (substitut du diagnostic de NAFLD) (rs2294915, P = 1,83x10-7), à la mortalité non-cardiovasculaire (rs2294917, P = 3,9x10-4) et à l’efficacité de la thérapie intensive antidiabétique chez certains patients de la population (porteurs GG de rs16991236, P=0,007). Mes travaux ont permis de mieux comprendre le fond génétique de NAFLD dans le DT2 et laissent envisager l’établissement d’outils de diagnostic et de suivi de la maladie plus adéquats. / Non-alcoholic fatty liver disease (NAFLD) is a liver disorder more frequent in type 2 diabetes (T2D) and is associated with complications such as mortality. For this reason, establishing non-invasive tools for predicting NAFLD is crucial. My master’s project aimed to establish genetic markers for NAFLD in T2D using two strategies: 1) a non-targeted selection of genetic markers (SNPs) by the LASSO method and 2) a targeted selection of SNPs reported as associated with the disease or its related abnormalities. A population involving 4098 patients with T2D and Caucasian ancestry was used. Summary statistics data of pangenomic studies were exploited for the selection of SNPs to be involved in the polygenic risk score (PRS). I also designed a model of 3210 SNPs adjusted by covariates and able to predict the high rates of ALT (AUC=0.69) and non-cardiovascular death (AUC=0.66). Mapping of the candidate locus PNPLA3-SAMM50 allowed the observation of diversity in terms of genetic association with the metabolic abnormalities such as ALT (surrogate of NAFLD) (rs2294915, P = 1.83x10-7), non-cardiovascular death (rs2294917, P = 3.9x10-4) and the efficiency of the intensive antidiabetic therapy within a subgroup in the population (individuals with GG of rs16991236, P = 0.007). My studies allowed for a better understanding of the genetic background of NAFLD in T2D and open perspectives for establishing more adequate tools for diagnosis and follow-up of the disease.

Obesity prevalence continues to increase worldwide, yet few safe and effective treatment options are available suggesting there needs to be a greater emphasis on preventing rather than treating obesity. This research investigated the association of obesity predisposing SNPs and a gene score with nutrient consumption patterns including total energy intake and macronutrient distribution in a European ancestry population as well as discussing an evolutionary perspective on eating disorders using current epidemiological evidence to identify genes which may be involved. The association of two of the 14 obesity predisposing SNPs and the gene score with BMI was confirmed in the EpiDREAM population. Novel associations between two SNPs located in or near BDNF (rs6265 and rs1401635) were found with total fat, MUFA, and PUFA intake. Rs1401635 was also associated with total energy and trans fat intake. Novel associations of rs6235 (PCSK1) and the gene score were found with total energy intake. The novel associations found indicate that food related behaviours are one of the mechanisms of action through which obesity predisposing SNPs cause obesity and therefore warrant further investigation. The lack of association among all genes and the modest association of the gene score show that mechanisms other than food consumption are important. The investigation of the evolutionary history of eating disorders revealed that the adapted to flee famine hypothesis is a plausible theory explaining anorexia nervosa while the thrifty genotype hypothesis provides a possible explanation for bulimia nervosa and binge eating disorder. These evolutionary theories can be applied to identify new candidate genes as well as phenotypic traits to investigate to better understand the genetic architecture of eating disorders. Understanding genes associated with disordered eating patterns may highlight future areas for obesity prevention. / Thesis / Master of Science (MSc) / A large percentage of the risk of developing obesity or an eating disorder (anorexia nervosa, bulimia nervosa, and binge eating disorder) is determined by genetics. For obesity, many genes have been identified as influencing risk, but the mechanisms through which the genes work are largely unknown. For eating disorders, gene identification efforts have been mostly unsuccessful and no mechanisms of action have been determined. In the first component of this thesis we found an association between previously identified obesity risk genes and food intake, specifically the total number of calories consumed per day and the percentage of calories from total fat and fat subtypes. These results support that food related behaviours are possible mechanisms of action which need to be further investigated. In the second half of the thesis we viewed eating disorder behaviours from an evolutionary perspective. We concluded that there are theories that possibly explain eating disorder behaviours including being able to live off of small quantities of food as well as binging. These evolutionary theories can be applied to identify new genes to study in the context of eating disorders as well as different definitions of eating disorders.

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.

Introduction : La fibrillation auriculaire (FA) est l’arythmie la plus répandue au monde avec une prévalence estimée autour de 1-2% pour la population générale. Il s’agit d’une maladie complexe de causes multifactorielles, telles que la génétique, l’environnement et les habitudes de vie. Il est aussi important de prendre en compte que les risques de FA augmentent drastiquement avec l’âge. La fibrillation auriculaire post-opératoire (POAF) est la complication la plus commune à la suite d’une chirurgie cardiaque. Elle est associée avec une prolongation de la durée d’hospitalisation et à une augmentation du risque d’accident vasculaire cérébral (AVC) et de la mortalité. Il devient donc une priorité d’identifier les individus à risque de POAF et d’AVC causés par la FA, surtout en considérant l’existence d’interventions simples qui peuvent atténuer ces risques, comme certaines thérapies pharmacologiques. Hypothèse : L’hypothèse de ce projet est qu’un score polygénique (PGS) aurait un impact sur l’identification des individus à plus haut risque de FA à la suite d’une chirurgie cardiaque, mais aussi sur l’identification des individus à risque de récidive de FA lors d’un premier épisode de FA après une chirurgie. Objectifs : Ce projet se divise en 2 objectifs principaux. Dans un premier temps, nous cherchons à évaluer la capacité prédictive d’un PGS déjà validé (mais jamais utilisé pour la POAF) pour la POAF après une chirurgie cardiaque dans une population québécoise. Dans un second temps, nous cherchons à évaluer la capacité prédictive du même PGS au niveau de la récidive à distance de la FA chez le sous-groupe de personnes qui ont eu un épisode de POAF. Méthodes : Nous avons inclus 2340 participants de la Biobanque hospitalière de l’Institut de Cardiologie de Montréal (ICM) qui ont subi une chirurgie cardiaque entre 2005 et 2020 et qui n’avaient pas de FA diagnostiquée avant la chirurgie. La POAF a été définie comme une FA survenant jusqu’à 30 jours après la chirurgie. Le génotypage de la cohorte a été effectué à l’aide d’une puce de génotypage pangénomique, suivi d’une imputation avec l’aide du panel de référence TOPMed. Le PGS déjà validé et corrigé pour les principales composantes génétiques (PGS-AF) a été calculé à l’aide des poids d’un PGS publié (identifiant du PGS catalog : PGS000016). L’association entre le PGS-AF et la POAF a été évaluée par une régression logistique avec et sans la correction pour les facteurs de risque cliniques connus de la FA, y compris le score de risque clinique CHARGE-AF. Pour valider la valeur prédictive du PGS-AF indépendamment des prédicteurs cliniques, un indice de reclassement net (NRI) a été calculé. L’association entre le PGS-AF et le CHARGE-AF au niveau de la récidive de FA à distance, à plus de 30 jours après la chirurgie, au sein du sous-groupe de patients atteints de POAF a été évaluée avec un modèle de régression de Cox. Résultats : Sur les 2340 participants inclus dans l’étude rétrospective (80% d’hommes; âgés de 66 ans [59-71] au moment de la chirurgie cardiaque), 871 (37%) ont développé de la POAF. La POAF était plus fréquente après une chirurgie valvulaire que les autres chirurgies cardiaques (43% contre 32%, P<0,001) et avec une augmentation dans le score de risque clinique CHARGE-AF (P<0,001). Le PGS-AF était significativement associé à la POAF (P<0,001; augmentation du risque de POAF de 46% par augmentation de 1 écart-type du PGS-AF; statistique C = 0,61). L’incidence de la POAF était significativement plus élevée chez les patients avec PGS-AF au-dessus du 95e percentile (62%) comparativement aux patients avec PGS-AF en dessous du 95% percentile (36%; ratio de cote 2.3, intervalle de confiance 95% 1.6-3.4; P<0,001). Dans un modèle combinant le PGS-AF avec des prédicteurs cliniques (CHARGE-AF et chirurgie valvulaire), l’association du PGS-AF avec la POAF reste significative (P<0,001). De plus, par rapport à la prédiction clinique uniquement, l’ajout du PGS-AF entraine une amélioration significative du modèle (statistique C de 0,68 contre 0,65; test du rapport de vraisemblance P<0,001; NRI = 35%). Parmi les patients atteints de POAF, 235 (27%) ont développé de la FA au cours d’un suivi médian de 4,4 ans. Le PGS-AF et le CHARGE-AF étaient à la fois associés de manière significative et indépendante à la récidive de FA à distance (P<0,05), où chaque augmentation d’écart-type du PGS-AF augmente le risque de récidive de FA de 19%. Discussion et conclusion : Un score de risque polygénique précédemment validé pour la fibrillation auriculaire (PGS-AF) est significativement associé à la FA survenant comme une complication de la chirurgie cardiaque, indépendamment des prédicteurs de risque cliniques. Bien que la capacité discriminative soit modeste globalement, le PGS-AF permet d’identifier 5% de la population de patients avec risque de POAF 2,3 fois plus élevé, une magnitude d’effet de pertinence clinique. Le PGS-AF est également associé à la récidive à distance de la FA et, s’il est validé, pourrait aider à identifier les patients plus susceptibles de bénéficier d’une anticoagulation à long terme pour prévenir les AVC. Plus globalement, ces données impliquent le risque polygénique pour expliquer la variance de scénarios cliniques complexes tels que les complications chirurgicales. / Introduction: Atrial fibrillation (AF) is the most common arrhythmia in the world with an estimated prevalence of around 1-2% of the general population. It is a complex disease with multifactorial causes, such as genetics, environment, and lifestyle. It is also important to consider that the risk of AF increases drastically with age. Postoperative atrial fibrillation (POAF) is the most common complication following cardiac surgery. It is associated with a prolonged hospital stay length and an increased risk of cerebrovascular accident (CVA) and mortality. It therefore becomes a priority to identify individuals at higher risk of POAF and stroke caused by AF, especially considering the existence of simple interventions that can mitigate these risks, such as certain pharmacological therapies. Hypothesis: The project hypothesis is that a polygenic score (PGS) would have an impact on the identification of individuals at higher risk of AF following cardiac surgery, but also on the identification of individuals at higher risk of recurrence of AF within the subgroup of patients who had a first episode of AF after surgery. Aims: This project is divided into 2 main objectives. First, we seek to assess the predictive ability of an already validated PGS (but never used before for POAF) for POAF after cardiac surgery in a Quebec population. In a second step, we seek to assess the predictive capacity of the same PGS for distant recurrence of AF within the subgroup of people who have had an episode of POAF. Methods: We included 2,340 participants from the Montreal Heart Institute (MHI) hospital Biobank who underwent heart surgery from 2005 to 2020 and did not have an AF diagnosis before surgery. POAF was defined as AF occurring in up to 30 days after surgery. Cohort genotyping was performed using a genome-wide genotyping array, followed by imputation using the TOPMed reference panel. The PGS already validated and corrected for the main genetic components (PGS-AF) was calculated using weights of a published PGS (PGS catalog ID: PGS000016). The association between PGS-AF and POAF was assessed by logistic regression with and without correction for known AF clinical risk factors, including the CHARGE-AF clinical score. To validate the predictive ability of PGS-AF independently of clinical predictors, a net reclassification index (NRI) was calculated. The association between PGS-AF and CHARGE-AF in remote AF recurrence, more than 30 days after cardiac surgery, within the subgroup of patients with POAF was assessed using a Cox Proportional Hazards Model. Results: Of the 2,340 participants included in the retrospective study (80% males; aged 66 years old [59-71] at the time of cardiac surgery), 871 (37%) developed POAF. POAF was more common after valve surgery than other cardiac surgeries (43% vs 32%, P<0.001) and with an increase in the CHARGE-AF clinical risk score (P<0.001). PGS-AF was significantly associated with POAF (P<0.001; POAF risk increased by 46% per each standard deviation increase in PGS-AF; C-statistic = 0.61). The incidence of POAF was significantly higher in patients with PGS-AF above the 95th percentile (62%) compared to patients with PGS-AF below the 95% percentile (36%; odds ratio 2.3, range 95% confidence interval 1.6-3.4; P<0.001). In a model combining PGS-AF with clinical predictors (CHARGE-AF and valve surgery), the association of PGS-AF with POAF remains significant (P<0.001). Moreover, compared to the clinical predictors only, the addition of PGS-AF leads to a significant improvement in the model (C-statistic of 0.68 vs 0.65; likelihood ratio test P<0.001; NRI = 35%). Among patients with POAF, 235 (27%) developed AF during a median follow-up of 4.4 years. PGS-AF and CHARGE-AF were both significantly and independently associated with distant recurrence of AF (P<0.05 for both), where each standard deviation increase in PGS-AF increases the risk of distant AF recurrence by 19%. Discussion and conclusion: A previously validated polygenic risk score for atrial fibrillation (PGS-AF) is significantly associated with AF occurring as a complication of cardiac surgery, independently of clinical risk predictors. Although the discriminative ability is modest overall, the PGS-AF identifies 5% of the patient population with a 2.3 times higher risk of POAF, an effect size of clinical relevance. PGS-AF is also associated with distant recurrence of AF and, if validated, could help identify patients who could most likely benefit from long-term anticoagulation to prevent stroke. More broadly, these data implicate polygenic risk to explain the variance of complex clinical scenarios such as surgical complications.

Introduction: There are no economic evaluations to determine the value of PRSs. The objective of this study was to determine if the addition of a PRS to traditional risk factors to guide statin therapy is a cost-effective intervention for the prevention of primary MI cases in the Ontario healthcare payer perspective. Methods: A PRS cost-effectiveness model was constructed to produce various statin prescription strategies in conjunction with the FRS. Upper PRS thresholds (between 25% to 70%) were set such that individuals falling into them would be eligible for statins while those in lower PRS thresholds (between 1% to 25%) were deemed protected and removed from consideration. The model determined number of incident MIs saved or not saved by statins, costs, quality of life, and the effect of statins on preventing MIs over a 10-year time horizon, discounted at 1.5% annually. One-way sensitivity analysis and a PSA were performed by varying all model parameters. Non-related participants of white British descent from 96,736 participants in the UK Biobank at intermediate risk for cardiovascular disease, determined using the Canadian Cardiovascular Society dyslipidemia guidelines of 2016, were used for the study. Results: The optimal clinical and economic strategy was one whereby the top 70% PRS individuals are eligible for statins, with the lower 5% PRS excluded. A base-case analysis at a PRS cost of $70 produced an ICER of $747,184.10/QALY, ranging from $525,678.90/QALY to $930,144.40/QALY in a one-way sensitivity analysis. In the PSA, the intervention has approximately a 50% probability of being cost-effective at $750,000/QALY. At a genotyping cost of $0, statin strategies guided by PRS dominated standard care when at least 12% of the lower PRS individuals were withheld from statins. When the predictive performance of the PRS is increased, the ICER drops drastically depending on the cost of genotyping and statin strategy. Conclusion: The cost-effectiveness model considers MI cases exclusively and a short, 10-year time horizon which likely overestimate the ICER. However, this study elucidates that the PRS has the potential to be extremely cost-effective in the future. / Thesis / Master of Science (MSc) / Approximately 1 in 3 Canadians live with at least one genetically linked chronic disease. Together, these diseases constitute a large economic burden on the healthcare system and well-being of individuals. Recent advancements in genetics allow risk prediction of developing complex, but common chronic diseases such as cardiovascular disease. Termed as polygenic risk scores, they have the potential to carry beneficial clinical outcomes such as an improved quality of life. However, the economics is not yet understood. This study determined that when targeting heart attacks, approximately $750,000 is required to gain an additional life-year for an adult. Although this may seem high, the result is closer to an upper-limit estimate than the true cost since polygenic risk scores have more benefits than solely for heart attacks. In the future, when accounting for their entire potential, the cost per life-year is likely to be lower, and perhaps even a money-returning investment.