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Decades of work has led researchers to believe that risk for complex behavioral phenotypes, such as alcohol use disorders, is likely influenced by multiple genes of small effect acting in conjunction with each other and the environment. Currently, the field of psychiatric genetics is developing methodologies for the identification of genetic risk variants that predispose individuals to the development of complex behavioral disorders. Several challenges related to the complex and polygenic nature of these phenotypes, must be considered. This dissertation study attempts to address these important challenges in the context of alcohol use disorders and related phenotypes. A rich twin and family study literature has indicated that 40-70% of the variance in alcohol use disorders (AUDs) is influenced by genetics. Recent attempts to identify specific x genetic risk variants associated with AUDs have been met with limited success. Meanwhile, evidence of the moderating effects of the environment on AUDs has been mounting, providing a strong rationale for examining gene-environment interaction. In the following chapters several studies will be described that integrate established twin methodologies into gene identification projects in an effort to reduce heterogeneity (both phenotypic and genotypic), elucidate environmental constructs that moderate genetic influences, and to enhance statistical power to detect the subtle genetic influences on alcohol related phenotypes.

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.

The opioid receptors and their endogenous ligands have long been implicated in a variety of traits including addiction, impulsive behaviors and substance dependence. Using phenotypic measurements collected from the IASPSAD, data from a latent class analysis and data from a SNP array and additional genotyping assays, association and regression tests were performed to determine the effects of common SNPs encoded in the genes of the opioid receptors and ligands on various traits relating to alcohol dependence. Although only one SNP can be reported as significant for substance dependence within alcoholics, there were a few results approaching significance that may offer some insight into variation within alcoholism.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Candidate: Bc. Jana Mičulková Consultant: Doc. MUDr. Josef Herink, DrSc. Title of Thesis: The temporo-limbic dysfunction in alcohol dependent persons This thesis is concerned on the temporo-limbic dysfunction of persons dependent on alcohol. The theoretical part summarizes the information about the neuroanatomical correlates, alcohol dependence syndrome, epidemiology of alcohol addiction in the Czech republic and the relationship between alcohol and epilepsy. The practical part includes evaluation of questionnaires filled out by alcohol dependent persons. These questionnaires are concerned on recognizing epilepsy spectrum disorder. The results are compared with the results obtained from previous studies in the healthy population and are used to evaluate other aims of this thesis. Keywords: alcohol dependence, epilepsy, epilepsy spectrum disorder, limbic system, questionnaire investigation

Alkoholabhängigkeit (AA) zeichnet sich durch einen starken Drang nach Alkoholkonsum trotz schwerwiegender negativer Folgen aus. Eine gängige Theorie aus der Suchtforschung besagt, dass AA mit einer Verlagerung von zielgerichteter zu habitueller Kontrolle einhergeht, durch welche Handlungen automatisiert ausgeführt werden und weitgehend unabhängig von ihren Folgen sind. Evidenzen hierfür stammen weitgehend aus experimentellen Untersuchungen an Tieren. Das Fachgebiet des maschinellen Lernens hat zudem neue Experimente hervorgebracht, welche die Anwendung von Algorithmen erlauben, um die Verlagerung von zielgerichtetem zu habituellen Verhalten zu untersuchen. Diese Paradigmen fanden bisher keine Anwendung in der Untersuchung von alkoholabhängigen Patienten. Daher widmet sich diese Dissertation der Untersuchung von habituellem und zielgerichtetem Verhalten bei AA aus unterschiedlichen Perspektiven. Hierfür adaptierten wir zunächst ein Paradigma aus der Tierliteratur, durch welches habituelles Verhalten als reizgesteuerte Kontrolle quantifiziert wird. Anschließend nutzten wir eine Aufgabe, die aus dem maschinellen Lernen stammt und die Untersuchung von habitueller und zielgerichteter Kontrolle ermöglicht. Drittens untersuchten wir den Zusammenhang des Verhaltens über beiden Paradigmen hinweg. Zuletzt untersuchten wir, ob habitueller und zielgerichteter Kontrolle mit dem Alkoholkonsum in jungen sozialen Trinkern assoziiert ist. Die Ergebnisse liefern weitere Hinweise auf eine Verlagerung von zielgerichteter zu habitueller Kontrolle bei AA. Das Verhalten in beiden Paradigmen war miteinander assoziiert, was darauf rückschließen lässt, dass ähnliche kognitive Mechanismen involviert sind. Soziale Trinker zeigten keine Verlagerung von zielgerichteter zu habituellem Verhalten, was darauf hin weist, dass jenes Ungleichgewicht erst im Verlauf der AA entsteht und kein Korrelat von Alkoholkonsum per se darstellt. / Alcohol dependence (AD) manifests as a strong drive to consume alcohol despite serious adverse consequences. A popular theory in addiction research thus suggests that AD is characterized by a shift from goal-directed to habitual control, where actions are automatic and disentangled from outcomes. Evidence for this has mainly been drawn from experimental investigations in animals. The field of machine learning has additionally advanced new experiments that allow the application of reinforcement learning algorithms to investigate a shift towards habits. Again, these tasks have yet not been applied to human AD. To fill this gap, this thesis investigates habitual at the expense of goal-directed control from distinct theoretical fields in AD patients. We adapted a paradigm from the animal literature, which quantifies habits as cue-induced control over behavior. Then, we applied an experimental procedure inspired from machine learning that allows to investigate the balance between habitual and goal-directed control. Third, we examined the relationship between behavior across these paradigms. Last, we investigated whether the imbalance between habitual and goal-directed control was associated with alcohol consumption in young social drinkers. Our results add further evidence that AD is associated with a shift from goal-directed to habitual control, e.g. increased cue-induced control / reductions in goal-directed decision-making. Behavior across both paradigms were associated with each other, suggesting the involvement of similar mechanisms. As non-pathological alcohol intake was not associated with an imbalance between goal-directed and habitual control, this imbalance might arise over the course of AD rather than being a trait marker of alcohol intake.

Bakgrund: Alkoholberoende är en sjukdom som är individuell men beror på genetiska och biologiska faktorer. Alkohol är skadligt för kroppen och medför en större risk för somatiska sjukdomar. För att se hela personen behöver sjuksköterskan vårda med livsvärlden som grund. Hälsa är ett komplext begrepp som innefattar det fysiska, psykiska och sociala välmåendet. Sjuksköterskan har en viktig roll i att motivera och tillgodose personens informationsbehov. Syfte: Att beskriva personers upplevelse av att leva med ett alkoholberoende. Metod: Studien baseras på en kvalitativ analys av narrativer. Resultat: I resultatet framkom tre teman och sju subteman. (1) Att överleva vardagen; en verklighetsflykt, alkoholen kommer först, känslor av svek och ensamhet. (2) Att hitta förklaringar och försvar; döljer och förnekar, ursäkter och lögner. (3) Att behöva hjälp för att kunna leva; en tro om att klara sig själv, stöd som förutsättning. Konklusion: Vad som motiverar den unika personen till att söka hjälp är individuellt och något som sjuksköterskan behöver beakta. Stöd är viktigt för alkoholberoende personer och då krävs en god relation mellan vårdare och patient. Sjuksköterskan behöver ha kunskap om hur en alkoholberoende person upplever sin livsvärld för att skapa förutsättningar för att kunna motivera personen till förändring. / Background: Alcohol dependence is a disease, which is individual but depends on genetic and biological factors. Alcohol is harmful to the body and causes greater risk of somatic diseases. To see the whole person, the nurse needs to care for the lifeworld as a basis. Health is a complex concept, which includes the physical, mental and social well-being. The nurse has an important role in motivating and meeting the person's information needs. Aim: To describe persons experiences of living with alcohol dependence. Method: The study is based on a qualitative analysis of the narratives. Result: The result showed three themes and seven sub-themes. (1) To survive the everyday life; an escape of reality, the alcohol comes first, feelings of betrayal and loneliness. (2) Finding explanations and defenses; hides and denies, excuses and lies. (3) The need of help to live; the belief in self-reliance, support as a prerequisite. Conclusion: What motivates the unique person to seek help is individual and something that needs to be taken into account. Support is important for alcohol dependent persons and a good relationship between the nurse and the patient is required. The nurse needs knowledge of how an alcohol-dependent person experiences the lifeworld to create the conditions for being able to motivate the person to change.

Externalizing disorders such as attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), and oppositional defiant disorder (ODD) have a high prevalence rate in both children of alcoholics and in those with prenatal alcohol exposure (PAE). These disorders are also predictors of alcohol dependence (alcdep), heritable, and share an underlying genetic liability with alcdep. Furthermore, a mother who drinks while pregnant is likely to be alcohol dependent (AD), and vice-versa. This study incorporated these factors into one model, including as well as a measure of broad genetic risk for ADHD and alcdep to test for the contributions of these effects simultaneously. An independent sample was used to confirm the results for PAE and broad genetic risk. The hypothesis is that PAE will increase the risk to ADHD but not to CD or ODD.

Background Among adolescents and young adults with DSM-IV alcohol use disorders (AUDs), there are inter-individual differences in the speed of transition from initial alcohol use (AU) to AUD. AUDs are highly co-morbid with other mental disorders. The factors associated with rapid transition from first AU to AUD remain unknown and the role of mental disorders in rapid transitions is unclear. Given this background we examined (1) whether prior anxiety, mood, externalizing and non-alcohol substance use disorders are related to the risk and speed of transition from first AU to DSM-IV alcohol abuse (AA) and alcohol dependence (AD) and (2) whether early age of onset of prior mental disorders (PMDs) is a promoter of rapid transition. Method A total of 3021 community subjects (97.7% lifetime AU) aged 14–24 years at baseline were followed up prospectively for up to 10 years. AU and mental disorders were assessed with the DSM-IV/M-CIDI. Results Among subjects with lifetime AU, several PMDs, such as specific phobia, bipolar disorder and nicotine dependence, were associated with an increased risk of AUD independent of externalizing disorders. Associations of PMDs with the speed of transition to AUDs were mostly weak and inconsistent. Only social phobia and externalizing disorders were associated with faster transitions to AD even after adjustment for other PMDs. Earlier age of onset of PMD was not associated with rapid transition. Conclusions Mental disorders are associated with the risk of AUD. With the possible exception of social phobia and externalizing disorders, they do not promote rapid transition, even if they occur particularly early. Future research needs to identify factors relevant to rapid transition to AUD.

The aim of the present study was to examine the effects of the cinematherapy technique on the treatment of alcohol dependent patients. In terms of change, selfefficacy, decisional balance and motivation levels of participants were examined. 94 alcoholic patients from a state hospital, and 14 members of Alcoholics Anonymous&rsquo / Istanbul groups participated in the study. Participants were either inpatients in the dependence treatment center, or alcohol dependent patients who had been clean and sober for various periods of time. The cinematherapy technique was applied as an adjunct to alcohol dependence treatment. It included the presentation of a movie with an alcohol dependence theme followed by an elaboration session. Participants in the experimental group received two sessions of cinematherapy. On the other hand, control group A participants watched one movie unrelated with alcohol dependence. It was followed by an elaboration session with a non-alcoholic theme. Control group B participants watched two movies unrelated with alcohol dependence. Any elaboration session was not made with control group B participants. Decisional balance, self-efficacy, treatment motivation and stages of change were used as the main outcome measures in the pre-treatment and posttreatment assessments. Since the experimental and control groups sample sizes were small, non-parametric tests were used in data analysis. According to results, cons of alcohol and self-efficacy increased for the overall sample after cinematherapy sessions. In addition, the cinematherapy group showed higher identification than the control groups. Stages of change differences were gained for pros of alcohol use and self-efficacy in line with literature.