Background: The organization of risk genes within signaling pathways may provide clues about the converging neurobiological effects of risk genes for alcohol dependence. Aims: Identify risk genes and risk gene pathways for alcohol dependence. Methods: We conducted a pathway-based genome-wide association study (GWAS) of alcohol dependence using a gene-set-rich analytic approach. Approximately one million genetic markers were tested in the discovery sample which included 1409 European-American (EA) alcohol dependent individuals and 1518 EA healthy comparison subjects. An additional 681 African-American (AA) cases and 508 AA healthy subjects served as the replication sample. Results: We identified several genome-wide replicable risk genes and risk pathways that were significantly associated with alcohol dependence. After applying the Bonferroni correction for multiple testing, the 'cellextracellular matrix interactions' pathway (p<2.0E-4 in EAs) and the PXN gene (which encodes paxillin) (p=3.9E-7 in EAs) within this pathway were the most promising risk factors for alcohol dependence. There were also two nominally replicable pathways enriched in alcohol dependence-related genes in both EAs (0.015≤p≤0.035) and AAs (0.025≤p≤0.050): the 'Na+/Cl- dependent neurotransmitter transporters' pathway and the 'other glycan degradation' pathway. Conclusions: These findings provide new evidence highlighting several genes and biological signaling processes that may be related to the risk for alcohol dependence.

The PDZ and LIM domain 5 (PDLIM5) gene may play a role in alcohol dependence (AD), bipolar disorder, and major depressive disorder; however, no study has identified shared genetic variants within PDLIM5 gene among AD, type 2 diabetes (T2D), and hypertension. This study investigated the association of 72 single nucleotide polymorphism (SNPs) with AD (1066 AD cases and 1278 controls) in the Study of Addiction - Genetics and Environment (SAGE) sample and 47 SNPs with T2D (878 cases and 2686 non-diabetic) and hypertension (825 cases and 2739 non-hypertensive) in the Marshfield sample. Multiple logistic regression models in PLINK software were used to examine the associations of genetic variants with AD, T2D, and hypertension and SNP x alcohol consumption interactions for T2D and hypertension. Twenty-five SNPs were associated with AD in the SAGE sample (p < 0.05); rs1048627 showed the strongest association with AD (p = 5.53 × 10−4). Of the 25 SNPs, 5 SNPs showed associations with both AD in the SAGE sample and T2D in the Marshfield sample (top SNP rs11097432 with p = 0.00107 for T2D and p = 0.0483 for AD) while 6 SNPs showed associations with both AD in the SAGE sample and hypertension in the Marshfield sample (top SNP rs12500426 with p = 0.0119 for hypertension and p = 1.51 × 10−3 for AD). SNP (rs6532496) showed significant interaction with alcohol consumption for hypertension. Our results showed that several genetic variants in PDLIM5 gene influence AD, T2D and hypertension. These findings offer the potential for new insights into the pathogenesis of AD, T2D, and hypertension.

The hermeneutic phenomenological study interprets the lived experience of female alcohol dependence. Literature reveals that past research into alcohol dependence has generally used male subjects that formed the standard for theories, and treatment, of alcohol dependence. Researchers realised that alcohol dependent women differ significantly from their male counterparts, leading to an increase in exploratory studies of female alcohol dependence. However, these studies only provided a description of the disorder. How female alcohol dependents experience their disorder and how it makes sense to them has been largely ignored. The philosophy of Martin Heidegger provided the framework for collection, analysis and interpretation of data. Analysis revealed four life-worlds: „The Disheartened One‟, „The Ambivalent Player, „The Contemplator‟ and „The Covert Chauvinist‟. A lived experience typology of female alcohol dependence was proposed, namely „The Condemned‟, „The Utopian‟ and „The Realist‟. Implications of the findings on treatment and recommendations for future research are discussed. / Psychology / M.A. (Psychology)

Alcohol dependence (AD) is a serious and common public health problem that contributes to great societal, medical, and legal costs. It has taken work from multiple disciplines, including developmental psychology, genetic epidemiology, and molecular genetics, to achieve our current understanding of environmental and genetic risk factors for AD as well as its variable developmental trajectories. Nevertheless, there is still much to be learned in order to improve treatment outcomes. One approach to augmenting our understanding of this disorder is through genetically informative study designs that either examine risk in aggregate or assess specific susceptibility variants. In this dissertation, we utilize both study designs and provide support for the idea that they are both important and useful approaches to continue to pursue.

Alcohol Dependence (AD) is a chronic substance use disorder with moderate heritability (60%). Linkage and genome-wide association studies (GWAS) have implicated a number of loci; however, the molecular mechanisms underlying AD are unclear. Advances in systems biology allow genome-wide expression data to be integrated with genetic data to detect expression quantitative trait loci (eQTL), polymorphisms that regulate gene expression levels, influence phenotypes and are significantly enriched among validated genetic signals for many commonly studied traits including AD. We integrated genome-wide mRNA and miRNA expression data with genotypic data from the nucleus accumbens (NAc), a major addiction-related brain region, of 36 subjects (18 AD cases, 18 matched controls). We applied weighted gene co-expression network analysis (WGCNA) to identify mRNA and miRNA gene co-expression modules significantly associated with AD. We identified six mRNA modules, two of which were downregulated in AD and were enriched for neuronal marker gene expression. The remaining four modules were upregulated in AD and enriched for astrocyte and microglial marker gene expressions. After performing gene set enrichment analysis (GSEA), we found that neuronal-specific modules enriched for oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling pathways and glial-specific modules enriched for immune related processes, cell adhesion molecules and cell signaling pathways. WGCNA was also applied to miRNA data and identified two downregulated and one upregulated modules in AD. We intersected computationally predicted miRNA:mRNA interactions with miRNA and mRNA expression correlations to identify 481 significant (FDR<0.10) miRNA:mRNA targeting pairs. Over half (54%) of the mRNAs were targeted cooperatively by more than one miRNA suggesting a potentially important cellular mechanism relevant to AD. After integrating our expression and genetic data we identified 591 significant mRNA and 68 significant miRNA cis-eQTLs (<1 megabase) (FDR<0.10). After querying against GWAS data from the Colaborative Study on Genetics of Alcohol and Study of Addiction: Gentics and Environment, eQTLs for neuronatin (NNAT; rs1780705), proteosome subunit type 5 (PSMB5; rs10137082), long non-coding RNA (PKI55; rs13392737), adaptor related protein complex 1 sigma one subunit (AP1S1; rs12079545) and translocation associate membrane protein 1 (TRAM1; rs13277972) were associated with AD or alcohol related phenotypes at p<10-4.

Contexte : Les troubles liés à l’usage des substances psychoactives constituent une priorité de santé publique dans le champ des pathologies chroniques. Les indicateurs de type Patient-Reported Outcomes (PRO) offrent des perspectives complémentaires aux indicateurs classiques pour la mesure de l’état de santé des patients et l’appréciation de la qualité des soins. Objectifs : Étudier les propriétés psychométriques de questionnaires de qualité de vie (QV) et les déterminants de la satisfaction précoce vis-à-vis des soins ambulatoires de patients dépendants aux substances de type alcool ou opiacés. Méthode : Les caractéristiques des patients et des médecins ont été recueillies à l’inclusion dans la cohorte SUBUSQOL. La satisfaction précoce a été mesurée quinze jours après la première consultation et ses déterminants ont été testés dans des modèles de régression linéaires multivariés. Les propriétés psychométriques du questionnaire spécifique Q-LES-Q-SF ont été étudiées au préalable sur un échantillon de patients. Résultats : La version française du Q-LES-Q-SF constitue un outil unidimensionnel robuste et fiable, les items du SF-12 et Q-LES-Q-SF présentent peu ou pas de fonctionnement différentiel selon l’âge, le sexe, le niveau d’éducation et le type d’addiction. Peu de variables recueillies sont associées à la satisfaction. Les patients dépendants à l’alcool se révèlent être plus satisfaits des modalités de contact et du délai de rendez-vous et ceux sans aucun antécédent de prise en charge pour leur dépendance plus satisfaits de leur consultation avec le médecin. Conclusion : Les questionnaires SF-12 et Q-LES-Q-SF peuvent être utilisés dans des populations de patients suivis en ambulatoire pour une dépendance aux substances psychoactives / Context: Of chronic diseases, substance use disorders are a public health priority. Patient-reported outcome indicators (PRO) offer additional insights into the classical indicators used to measure the patient’s health status and appreciation of their quality of care. Objectives: to study the psychometric properties of quality of life instruments and to study the determinants of early outpatient satisfaction with ambulatory care in alcohol- or opiate-dependent patients. Method: Patient and physician characteristics were collected in the SUBUSQOL cohort. Early satisfaction with care was measured fifteen days after the first consultation. The determinants of satisfaction were tested using multivariate linear models of regression. Prior data on the self-reported health status of a sample of alcohol- or opiate-dependent outpatients were used to investigate the psychometric properties of a specific questionnaire, the Q-LES-Q-SF. Results: Our results establish that the French version of the Q-LES-Q-SF is a unidimensional, valid and reliable instrument of self-reported health status assessment for use in care or medical research and that few items of the SF-12 and the Q-LES-Q-SF displayed differential functioning according to age, sex, educational level and type of substance use disorder. Our results show that few variables are associated with the level of patient satisfaction. Alcohol dependence was strongly associated with higher satisfaction with appointment making, and patients with no history of previous care for substance use disorders had a higher level of satisfaction with the doctor consultation. Conclusion: The use of the SF-12 and the Q-LES-Q-SF is recommended for outpatients suffering from substance use disorders

Die These fasst die ersten Untersuchungen zum Pawlowsch`-Instrumentellen Transfer in alkoholabhängigen (AA) Patienten zusammen. Es ist bekannt, dass kontextuelle Umgebungsreize Verhalten beeinflussen. Tier- und Humanstudien haben gezeigt, dass positive Pawlowsche Reize instrumentelles Antwortverhalten verstärken und negative Pawlowsche Reize dieses reduzieren (PIT-Effekt). Bei Abhängigkeit wird angenommen, dass dieser Mechanismus relevant für Rückfall ist, da z.B. drogenassoziierte Reize bei Patienten im Vergleich zu Kontrollen erhöhtes Verlagen und funktionelle Aktivität in Belohnungsarealen auslösen. In Tier- und Humanstudien wurden stärkere PIT-Effekte vor allem mit funktioneller Aktivierung im Nucleus Accumbens (NAcc) beobachtet. Weiterhin zeigten sich bei Probanden mit stärkerem PIT-Effekt und bei AA Patienten erhöhte Impulsivitätswerte. Die PIT-Aufgabe besteht aus 3 Hauptteilen: i) Instrumentelle Konditionierung, ii) Pawlowsche Konditionierung, iii) Transfer mit Pawlowschen oder alkoholassoziierten Kontextstimuli. Impulsives Auswahlverhalten wurde durch die delay discounting Aufgabe erhoben. Es zeigten sich signifikant stärkere PIT-Effekte mit Pawlowschen Kontextreizen in AA Patienten im Vergleich zu Kontrollen mit funktioneller Aktivierung im NAcc, die zur Rückfallvorhersage beitrug. Der Transfer mit alkoholassoziierten Kontextreizen bewirkte eine signifikante Reduktion des instrumentellen Antwortverhaltens mit neuronalem Korrelat im NAcc nur bei abstinenten Patienten. Impulsives Auswahlverhalten und PIT hingen nur bei Patienten positiv zusammen. Die Studien lassen darauf schließen, dass PIT ein für Rückfall wichtiger Mechanismus ist mit funktionellem Korrelat im NAcc, der sich für motivationale Prozesse als auch als Salienzsignal relevant gezeigt hat. Die Subgruppe von hoch impulsiven Patienten ist im Besonderen durch Kontextreize im instrumentellen Antwortverhalten beeinflussbar, daher sollte ihr besondere Aufmerksamkeit bei Interventionen zukommen. / This thesis summarizes the first Pavlovian-to-instrumental transfer (PIT) studies in alcohol-dependent (AD) patients. Contextual stimuli are known to influence our behavior. Animal and human studies showed that positive Pavlovian stimuli enhance and negative Pavlovian stimuli reduce instrumental behavior (PIT effect). This mechanism might be relevant for relapse risk, as drug-associated stimuli have shown to enhance e.g. craving and functional activation in reward-related brain areas in patients compared to controls. In animal and human studies enhanced PIT effects were associated with activation particularly in the nucleus accumbens (NAcc). Moreover, control subjects with stronger PIT effects and AD patients were more impulsive on different facets of impulsivity. The PIT task consists of three main parts: i) instrumental conditioning, ii) Pavlovian conditioning, iii) transfer with Pavlovian background stimuli and instrumental task in the foreground (nondrug-related PIT: Pavlovian contextual cues; drug-related PIT: alcohol-related contextual cues). Choice impulsivity was measured by delay discounting task. We observed significantly enhanced nondrug-related PIT effects in AD patients compared to controls with a functional activation in the NAcc being predictive for relapse. Regarding drug-related PIT effects, we observed significantly reduced instrumental behavior during alcohol-related backgrounds with neural correlates in the NAcc in abstainers only. Choice impulsivity was positively related to PIT in AD patients only. Our data suggest that PIT is a mechanism contributing to relapse in AD patients with functional correlations within the NAcc, which based on our data is involved in motivation and attribution of salience. The subgroup of high impulsive patients is particularly susceptible for PIT effects, thus should be main target for intervention programs.

The hermeneutic phenomenological study interprets the lived experience of female alcohol dependence. Literature reveals that past research into alcohol dependence has generally used male subjects that formed the standard for theories, and treatment, of alcohol dependence. Researchers realised that alcohol dependent women differ significantly from their male counterparts, leading to an increase in exploratory studies of female alcohol dependence. However, these studies only provided a description of the disorder. How female alcohol dependents experience their disorder and how it makes sense to them has been largely ignored. The philosophy of Martin Heidegger provided the framework for collection, analysis and interpretation of data. Analysis revealed four life-worlds: „The Disheartened One‟, „The Ambivalent Player, „The Contemplator‟ and „The Covert Chauvinist‟. A lived experience typology of female alcohol dependence was proposed, namely „The Condemned‟, „The Utopian‟ and „The Realist‟. Implications of the findings on treatment and recommendations for future research are discussed. / Psychology / M.A. (Psychology)

Cette thèse aborde les processus nationaux d'Evaluation des Technologies de la Santé (HTA) en Europe, en Australie et au Canada, avec comme point de référence le processus proposé par le National Institute for Health and Care Excellence (NICE) en Angleterre. Une attention particulière est portée sur la façon dont les décisions sont prises dans la gestion des soins de santé, sur quelles considérations ces décisions sont fondées, et sur la valeur des différents éléments d'évidence disponibles pour correctement évaluer les implications d'une mise en oeuvre d'un point de vue pratique. Cette thèse analyse le développement de recommandations dans la gestion des soins de santé afin de permettre l'accès aux traitements les plus efficaces d'un point de vue clinique et économique. Ces recommandations sont réalisées à partir des meilleures évidences disponibles et d'un consensus entre cliniciens, scientifiques, économistes de la santé, gestionnaires des services de soin et patients. La pertinence d'une évaluation en continu des différentes étapes de la gestion d'un problème de santé est également abordée durant cette thèse. L'objectif serait de permettre la production optimale de bénéfices de santé publique en reliant l'évaluation des différents stades d'une maladie. Ainsi, on obtiendrait une appréciation générale qui prendrait en considération que certaines recommandations de soin peuvent appeler à plus de flexibilité ou de contraintes selon les différents stades d'une maladie. Appliquée à la gestion de la dépendance à l'alcool, les abus d'alcool et conséquences attribuables, cette thèse contextualise et analyse le développement optimal d'évidences d'efficacité, d'efficience et d'économie de la santé, le choix de méthodologies appropriées et la manière d'interpréter et d'analyser leurs résultats pour la production optimale de bénéfices de santé publique / The current thesis discusses national processes of Health Technology Assessment (HTA) in Europe, Australia and Canada, with a central reference to the one proposed by the National Institute for Health and Care Excellence (NICE) in England. This is with a focus on the manner decisions about healthcare technologies are taken, based on which considerations and evidence, and with which weight the evidence elements are interlinked with regard to public health implications. The thesis analyses the development of recommendations of care to allow access to the most clinicallyand cost-effective treatments available, based on the best and most up-to-date evidence, and on the consensus from collaboration between clinicians, scientists, health economists, health service managers, as well as patients. Additionally, is discussed the value of covering all components of a disease evolution in assessing in continuum the different steps of disease management. This aims to allow the optimal generation of public health benefits in interlinking appraisals across different stages of disease for a generalist assessment of care, considering that recommendations in some aspects of care can call for more flexibility or constraints in other aspects. With an application to the management of alcohol use disorders, alcohol dependence and attributable harmful consequences, the thesis contextualizes and analyses decisions in the development of health economics and outcomes research evidence, the choice of methodology and directions taken, and their interpretation for optimal generation of public health benefits

Background: Alcohol consumption is one of the most important factors for disease and disability in Europe. In clinical trials, nalmefene has resulted in a significant reduction in the number of heavy-drinking days (HDDs) per month and total alcohol consumption (TAC) among alcohol-dependent patients versus placebo. Methods: A microsimulation model was developed to estimate alcohol-attributable diseases and injuries in patients with alcohol dependence and to explore the clinical relevance of reducing alcohol consumption. Results: For all diseases and injuries considered, the number of events (inpatient episodes) increased with the number of HDDs and TAC per year. The model predicted that a reduction of 20 HDDs per year would result in 941 fewer alcohol-attributable events per 100,000 patients, while a reduction in intake of 3,000 g/year of pure alcohol (ethanol) would result in 1,325 fewer events per 100,000 patients. Conclusion: The potential gains of reducing consumption in alcohol-dependent patients were considerable.