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Family-based and genome-wide association studies (GWAS) of alcohol dependence (AD) have reported numerous associated variants. The clinical validity of these variants for predicting AD compared to family history has not yet been reported. These studies aim to explore the aggregate impact of multiple genetic variants with small effect sizes on risk prediction in order to provide a clinical interpretation of genetic contributions to AD. Data simulations showed that given AD’s prevalence and heritability, a risk prediction model incorporating all genetic contributions would have an area under the receiver operating characteristic curve (AUC) approaching 0.80, which is often a target AUC for screening. Adding additional environmental factors could increase the AUC to 0.95. Using the Collaborative Study on the Genetics of Alcoholism (COGA) and the Study of Addiction: Genes and Environment (SAGE) GWAS samples, we used several different sources to capture genetic information associated with AD in discovery samples, and then tested genetic sum scores created based on this information for predictive accuracy in validation samples. Scores were assessed separately for single nucleotide polymorphisms (SNPs) associated in candidate gene studies and in GWAS analyses. Candidate gene sum scores did not exhibit significant predictive accuracy, but SNPs meeting less stringent p-value thresholds in GWAS analyses did, ranging from mean estimates of 0.549 for SNPs meeting p<0.01 to 0.565 for SNPs meeting p<0.50. Variants associated with subtypes of AD showed that there is similarly modest and significant predictive ability for an externalizing subtype. Scores created based on all individual SNP effects in aggregate across the entire genome accounted for 0.46%-0.57% of the variance in AD symptom count, and have AUCs of 0.527 to 0.549. Additional covariates and environmental factors that are correlated with AD increased the AUC to 0.865. Family history was a better classifier of case-control status than genetic sum scores, with an AUC of 0.686 in COGA and 0.614 in SAGE. This project suggests that SNPs from candidate gene studies and genome-wide association studies currently have limited clinical validity, but there is potential for enhanced predictive ability with better detection of genetic factors contributing to AD.

This thesis looks at risk factors for multiple sclerosis (MS), a chronic, degenerative autoimmune disease which is usually diagnosed between the ages of 20 and 50 years. It is estimated to affect over 100,000 people in the UK. The research setting was Orkney and Shetland, two archipelagos situated north of mainland Scotland, and both of which have very high MS prevalence as do other countries at high latitudes. I examine genetic and environmental risk factors in Orkney and Shetland using multiple methods over four studies. I also review the vitamin D and UV exposure literatures as these are risk factors pertinent to MS in Orkney and Shetland. After devoting three chapters to introducing the purpose of the thesis, MS, and Orkney and Shetland, in the fourth chapter, I aim to establish whether the birthplace of cases show any spatial, temporal, or spatiotemporal clustering. Evidence of these kinds of clustering may indicate that there are environmental risk factors present in some areas or that were present over particular periods, which raise risk of developing MS. Although I find statistically significant temporal, spatial, and spatiotemporal clustering in Orkney, and a spatial cluster in Shetland, for multiple reasons these results need to be interpreted with caution. I conclude that the clusters are very likely to be artefacts. Furthermore, there are multiple possible alternative explanations for such clusters that could not be explored by the available data. Chapter 5 examines the heritability of MS in Orkney and Shetland to estimate the proportion of phenotypic variance attributable to additive genetic effects. I also look at the birthplaces of ancestors of cases and controls to see if any locations contribute a greater amount of ancestral DNA to the gene pool of modern MS cases, which I term ‘genetic clustering’. In Orkney I obtained a heritability estimate of 0.36 (95% CI -0.26, 0.98); in Shetland this estimate was 0.20 (95% CI -1.88, 2.28). These modest estimates are consistent with the heritability literature. The genetic clustering analyses highlight two Orkney registration districts, Kirkwall and Westray, which earlier studies identified as areas of MS clustering. I also identify three Shetland registration districts, however these locations had not shown any evidence of clustering in earlier studies. Again, I advise caution in interpreting results, particularly as all the error bars across registration districts overlap. Chapter 6 presents a scoping review to map the literature and identify evidence of an association between vitamin D and UV exposure with MS. In methodically searching the literature, I identify a large and heterogeneous evidence base comprising multiple observational, intervention, and genetic studies. Overall, many studies support an association between vitamin D deficiency and MS. There is also evidence for an association between UV exposure and MS, although UV exposure is considerably less explored than vitamin D. I finally identify gaps in the literature and make suggestions for future research. In Chapter 7 I aim to compare vitamin D levels in Orkney and mainland Scotland, and establish the determinants of vitamin D status in Orkney. I firstly compare mean vitamin D and prevalence of deficiency in cross-sectional data from studies in Orkney and mainland Scotland. I secondly use multivariable regression to identify factors associated with vitamin D levels in Orkney. I find that mean (standard deviation) vitamin D is significantly higher in Orkney compared to mainland Scotland (35.3 (18.0) and 31.7 (21.2), respectively), and prevalence of severe deficiency is lower in Orkney (6.6% to 16.2% p = 1.1 x 10-15). Factors associated with higher vitamin D in Orkney include older age, farming occupations and foreign holidays. I conclude that although mean vitamin D levels are higher in Orkney compared to mainland Scotland, there is substantial variation within the Orkney population which may influence MS risk. Chapter 8 examines the correlates and determinants of UVB exposure in Shetland. I firstly construct correlation matrices to visualise how 1) personal characteristics such as sex, occupation, and skin type, 2) physical activity, and 3) body weight and fat, correlate with UVB exposure. I then use multivariable regression to identify factors associated with UVB exposure in Shetland. I run two multivariable models. The first includes the full sample size where activity data were measured by questionnaires. The second includes both questionnaire physical activity data and step-count data from pedometers, however as only a subset of participants had been supplied with pedometers, this analysis comprises a smaller sample size. I find that the amount of skin exposed was most strongly correlated with UVB exposure. Step count and activity minutes were also moderately positively correlated, and indoor occupations moderately negatively correlated, with UVB exposure. The regression analysis using the full sample with questionnaire activity data found that factors associated with greater UVB exposure were age and ambient UVB, while working indoors was significantly associated with lower UVB exposure. The model including the pedometer data found that found that age, total steps, and the amount of ambient UVB were significantly associated with greater UVB exposure. I conclude that atmospheric conditions, working outdoors and older age are important factors in UVB exposure in Shetland. It remains to be seen how UVB exposure translates to vitamin D levels in Shetland. I found evidence for environmental and genetic risk factors for MS in Orkney and Shetland. The two environmental risk factors, vitamin D deficiency and reduced UV exposure, are more likely to affect the younger population who are still within their lifetime risk of developing MS.

Submitted by Irene Nascimento (irene.kessia@ufpe.br) on 2016-10-18T19:17:10Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertacao -Gilderlanio Santana de Araujo.pdf: 9533988 bytes, checksum: 951b1cf090729a87ebf3a8741ff00ad4 (MD5) / Made available in DSpace on 2016-10-18T19:17:10Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertacao -Gilderlanio Santana de Araujo.pdf: 9533988 bytes, checksum: 951b1cf090729a87ebf3a8741ff00ad4 (MD5) Previous issue date: 2013-03-07 / FACEPE / O desenvolvimento de técnicas de genotipagem de baixo custo (SNP arrays) e as anotações de milhares de polimorfismos de nucleotídeo único (SNPs) em bancos de dados públicos têm originado um crescente número de estudos de associação em escala genômica (do inglês, Genome-Wide Associations Studies - GWAS). Nesses estudos, um enorme número de SNPs (centenas de milhares) são avaliados com métodos estatísticos univariados de forma a encontrar SNPs associados a um determinado fenótipo. Testes univariados são incapazes de capturar relações de alta ordem entre os SNPs, algo comum em doenças genéticas complexas e são afetados pela alta correlação entre SNPs na mesma região genômica. Métodos de aprendizado de máquina, como o Random Forest (RF), têm sido aplicados em dados de GWAS para realizar a previsão de riscos de doenças e capturar os SNPs associados às mesmas. Apesar de RF ser um método com reconhecido desempenho em dados de alta dimensionalidade e na captura de relações não-lineares, o uso de todos os SNPs presentes em um estudo GWAS é computacionalmente inviável. Neste estudo propomos o uso de redes biológicas para a seleção inicial de SNPs candidatos a serem usados pela RF. A partir de um conjunto inicial de genes já relacionados à doença na literatura, usamos ferramentas de redes de interação gene-gene, para encontrar novos genes que possam estar associados a doença. Logo, é possível extrair um número reduzido de SNPs tornando a aplicação do método RF viável. Os experimentos realizados nesse estudo concentram-se em investigar quais polimorfismos podem influenciar na suscetibilidade à doença de Alzheimer (DA) e ao comprometimento cognitivo leve (MCI). O resultado final das análises é a delineação de uma metodologia para o uso de RF, para a análise de dados de GWAS, assim como a caracterização de potenciais fatores de riscos da DA. / The development of low cost genotyping techniques (SNP arrays) and annotations of thousands of single nucleotide polymorphisms (SNPs) in public databases has led to an increasing number of Genome-Wide Associations Studies (GWAS). In these studies, a large number of SNPs (hundreds of thousands) are evaluated with univariate statistical methods in order to find SNPs associated with a particular phenotype. Univariate tests are unable to capture high-order relationships among SNPs, which are common in complex genetic diseases, and are affected by the high correlation between SNPs at the same genomic region. Machine learning methods, such as the Random Forest (RF), have been applied to GWAS data to perform the prediction of the risk of diseases and capture a set of SNPs associated with them. Although, RF is a method with recognized performance in high dimensional data and capacity to capture non-linear relationships, the use of all SNPs present in GWAS data is computationally intractable. In this study we propose the use of biological networks for the initial selection of candidate SNPs to be used by RF. From an initial set of genes already related to a disease based on the literature, we use tools for construct gene-gene interaction networks, to find novel genes that might be associated with disease. Therefore, it is possible to extract a small number of SNPs making the method RF feasible. The experiments conducted in this study focus on investigating which polymorphisms may influence the susceptibility of Alzheimer’s disease (AD) and mild cognitive impairment (MCI). This work presents a delineation of a methodology on using RF for analysis of GWAS data, and characterization of potential risk factors for AD.

Genetic test results have important implications for close family members. Indeterminate negative results are the most common outcome of BRCA1/2 mutation testing. Little is known about family members' understanding of indeterminate negative BRCA1/2 test results. The purpose of this qualitative descriptive study was to investigate how daughters and sisters received and understood genetic test results as shared by their mothers or sisters. Participants included 81 women aged 40-74 with mothers or sisters previously diagnosed with breast cancer and who received indeterminate negative BRCA1/2 test results. Participants had never been diagnosed with breast cancer nor received their own genetic testing or counseling. This IRB approved study utilized semi-structured interviews administered via telephone. The research team developed descriptive codes, and NVIVO software was used during qualitative analysis. Participants reported low amounts of information shared with them. Most women described test results as negative and incorrectly interpreted the test to mean there was no genetic component to the pattern of cancer in their families. Only 7 of 81 women accurately described test results consistent with the meaning of an indeterminate negative result — meaning a genetic cause for cancer in their family could still exist. Our findings demonstrate that indeterminate negative genetic test results are not well understood by family members. Lack of understanding may lead to an inability to effectively communicate results to primary care providers and missed opportunities for prevention, screening and further genetic testing. We recommend providing family members letters they can share with their own primary care providers whenever genetic testing is performed.

En cette ère de «nouvelle santé publique», les professionnels sont exhortés à détourner leur attention de l’individu afin de pouvoir mettre l’accent sur les déterminants sociaux de la santé. Un phénomène contraire s’opère dans le domaine des sciences biomédicales, où un mouvement vers la santé personnalisée permet d’envisager des soins préventifs et curatifs adaptés à chaque individu, en fonction de son profil de risque génétique. Bien qu’elles n’aient que partiellement fait leur entrée dans notre système de santé, ces avancées scientifiques risquent de changer significativement le visage de la prévention, et dans cette foulée, de susciter des débats de société importants. L'étude proposée vise à contribuer à une réflexion sur l'avenir d'une des fonctions essentielles de la santé publique en tentant de mieux comprendre comment le public perçoit la prévention basée sur le risque génétique. Ce projet de recherche qualitative consiste en l'analyse secondaire des échanges ayant eu lieu lors de quatre ateliers délibératifs auxquels ont participé des membres du public d'horizons divers, et durant lesquels ceux-ci ont débattu de la désirabilité d'une technologie préventive fictive, le «rectificateur cardiaque». La théorie de la structuration d'Anthony Giddens est utilisée comme cadre conceptuel guidant l’analyse des échanges. Celle-ci permet d’émettre les trois constats suivants: a- le « rectificateur cardiaque » est loin d’être interprété par tous les participants comme étant une intervention préventive; b- son utilisation est perçue comme étant légitime ou non dépendamment principalement des groupes de personnes qu’elle viserait; c- l’intervention proposée ne se pense pas hors contexte. / In this era of «new public health», professionals are urged to shift their attention away from individuals and to pay greater attention to the social determinants of health. In the field of biomedical sciences, a movement in the opposite direction towards personalised health might allow for preventive and curative care tailored to each individual, according to their genetic risk profile. While scientific advances in the field of genomics have only begun to pave their way into our healthcare system, they carry the potential to change the face of prevention and give rise to important societal debates. This study’s aim is to contribute to a reflection on the future of one of the essential functions of public health by exploring public perceptions of prevention based on genetic risk. This qualitative research project consists of a secondary analysis of the content of exchanges which occurred between members of the public in the context of four deliberative workshops, during which they debated on the desirability of a fictive preventive technology, the «cardiac rectifier». Anthony Giddens’ theory of structuration is used as a conceptual framework to guide the analysis of the exchanges, which led to the following findings: a- the «cardiac rectifier» is far from being interpreted as a preventive intervention by every participant; b- its use is perceived as being legitimate or not on the basis of which group of individuals it would target; c- the proposed intervention cannot be thought of out of context.

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

Familial risk and environmental stress promote the development of alcohol dependence. We investigated whether a positive family history of alcoholism affects the neuroendocrine response to a standardized laboratory stress test in healthy subjects without alcohol use disorders. Twenty-four high-risk subjects with a paternal history of alcoholism (PHA) and 16 family history negative (FHN) controls were evaluated. Psychosocial stress was induced by having subjects deliver a 5-min speech and mental arithmetics in front of an audience on separate days, after drinking either placebo or ethanol (0.6 g/kg) in a randomized sequence. Adrenocorticotropin (ACTH) was measured in 10 plasma samples covering up to 75 min after the stress test. Plasma arginine vasopressin (AVP) was determined before the stressor, at the time of maximum ACTH secretion, and at 75 min after stress onset. The stress test induced a phasic increase in ACTH secretion. At the time of maximum ACTH, AVP was significantly increased in relation to baseline. Compared to placebo, alcohol administration significantly attenuated maximum ACTH concentration in PHA but not FHN subjects, and decreased AVP measured in the same samples in PHA but not FHN subjects. We conclude that activation of the hypothalamic–pituitary–adrenal system by psychosocial stress is accompanied by an increase in peripheral plasma AVP levels. Secretion of both ACTH and AVP suggest that alcohol attenuates the stress response selectively in PHA but not FHN subjects. This might imply some short-term positive alcohol effect in sons of alcoholics, but also constitute a mechanism by which their risk to develop alcohol use disorders is increased.