HLA-DRA gene polymorphisms might play an important role in alcohol dependence (AD). We examined genetic associations of 29 single-nucleotide polymorphisms (SNPs) within the HLA-DRA gene with AD using two Caucasian samples - the Collaborative Study on the Genetics of Alcoholism (COGA) sample (660 AD cases and 400 controls) and the Study of Addiction: Genetics and Environment (SAGE) sample (623 cases and 1,016 controls). Logistic regression analysis using PLINK showed that 16 SNPs were associated with AD in the COGA sample and 13 SNPs were associated with AD in the SAGE sample (p < 0.05). The best novel signal was SNP rs2239803 associated with AD in both samples (p = 0.000817 for the COGA sample and p = 0.0026 for the SAGE sample, respectively) while one flanking SNP rs4935356 also showed strong association in both samples (p = 0.00219 and 0.0026 for the COGA and SAGE samples, respectively). Furthermore, these two SNPs revealed stronger associations in meta-analysis of these two samples (p = 8.97 × 10-6 and 2.02 × 10-5 for rs2239803 and rs4935356, respectively). In addition, the G-A haplotype from these two SNPs revealed a significant association with AD in both the COGA and SAGE samples (p = 0.0007 and 0.0019, respectively). These findings highlight the novel associations with HLA-DRA that may play an important role in the etiology of AD.

OBJECTIVES: We have previously reported a top-ranked risk gene [i.e., serine incorporator 2 gene (SERINC2)] for alcohol dependence in individuals of European descent by analyzing the common variants in a genome-wide association study. In the present study, we comprehensively examined the rare variants [minor allele frequency (MAF)<0.05] in the NKAIN1-SERINC2 region to confirm our previous finding. MATERIALS AND METHODS: A discovery sample (1409 European-American patients with alcohol dependence and 1518 European-American controls) and a replication sample (6438 European-Australian family participants with 1645 alcohol-dependent probands) were subjected to an association analysis. A total of 39 903 individuals from 19 other cohorts with 11 different neuropsychiatric and neurological disorders served as contrast groups. The entire NKAIN1-SERINC2 region was imputed in all cohorts using the same reference panels of genotypes that included rare variants from the whole-genome sequencing data. We stringently cleaned the phenotype and genotype data, and obtained a total of about 220 single-nucleotide polymorphisms in individuals of European descent and about 450 single-nucleotide polymorphisms in the individuals of African descent with 0

Alcohol addiction may increase the risk of obesity due to shared genetic components. The Copine V (CPNE5) gene is involved in Ca2+ binding and may play an important role in the development of the central nervous system. This study tested the genetic associations of 77 single-nucleotide polymorphisms (SNPs) within the CPNE5 gene with alcohol dependence (AD) and obesity using a Caucasian sample - The Study of Addiction - Genetics and Environment (SAGE) sample (1066 AD cases and 1278 non-AD controls, 422 obese cases and 1395 non-obese controls). The Marshfield sample (1442 obese cases and 2122 non-obese controls) was used for replication of obesity. Multiple logistic regression analysis was performed using the PLINK software. In the SAGE sample, we identified 10 SNPs associated with AD and 17 SNPs associated with obesity (p < 0.05). Interestingly, 6 SNPs (rs9986517, rs9470387, rs3213534, rs10456444, rs3752482, and rs9470386) were associated with both AD (OR = 0.77, 0.77, 0.83, 0.84, 0.79 and 1.14, respectively; p = 9.72 × 10-5, 1.1 × 10-4, 4.09 × 10-3, 5.26 × 10-3, 1.59 × 10-2, and 3.81 × 10-2, respectively) and obesity (OR = 0.77, 0.77, 0.78, 0.77, 0.68 and 1.18, respectively; p = 2.74 × 10-3, 2.69 × 10-3, 2.45 × 10-3, 1.01 × 10-3, 5.18 × 10-3 and 3.85 × 10-2, respectively). In the Marshfield sample, rs3752480 was associated with obesity (p = 0.0379). In addition, four SNPs (rs9986517, rs10456444, rs7763347 and rs4714010) showed associations with obesity in the meta-analysis using both samples (p = 0.00493, 0.0274, 0.00346, and 0.0141, respectively). These findings provide the first evidence of common genetic variants in the CPNE5 gene influencing both the AD and obesity; and will serve as a resource for replication in other populations.

The DPYSL2 gene at 8p22-p21 is expressed widely in neuronal tissues and has been implicated in multiple psychiatric disorders such as Alzheimer's disease and schizophrenia. We therefore hypothesized that DPYSL2 gene polymorphisms may play a role in alcohol dependence (AD). We investigated the genetic associations of 57 single-nucleotide polymorphisms (SNPs) within the DPYSL2 gene with AD using two Caucasian samples - the Collaborative Study on the Genetics of Alcoholism (COGA) sample (660 AD cases and 400 controls), and the Study of Addiction: Genetics and Environment (SAGE) sample (623 cases and 1,016 controls). The SNP rs11995227 was most significantly associated with AD (p = 0.000122) in the COGA sample while one flanking SNP rs7832576 revealed the second most significant association with AD (p = 0.00163) in the COGA sample and association with AD (p = 0.0195) in the SAGE sample. Meta-analysis of two samples showed both rs119952227 and rs7832576 were associated with AD (p = 0.000363 and 0.000184, respectively). Furthermore, the C-A haplotype from rs11995227 and rs7832576 revealed significant association with AD (p = 0.0000899) in the COGA sample while the T-G haplotype revealed association with AD both in the COGA and SAGE samples (p = 0.00098 and 0.021, respectively). These findings suggest that genetic variants in DPYSL2 may play a role in susceptibility to AD.

Several genome-wide association (GWA) studies of alcohol dependence (AD) and alcohol-related phenotypes have been conducted; however, little is known about genetic variants influencing alcohol withdrawal symptoms (AWS). We conducted the first GWA study of AWS using 461 cases of AD with AWS and 408 controls in Caucasian population in the Collaborative Study on the Genetics of Alcoholism (COGA) sample. Logistic regression analysis of AWS as a binary trait, adjusted for age and sex, was performed using PLINK. We identified 51 SNPs associated with AWS with p<10 -4. The first best signal was rs770182 (p = 3.65 × 10 -6) at 5q21 near EFNA5 gene which was replicated in the Australian twin-family study of 273 families (p = 0.0172). Furthermore, three SNPs (rs10975990, rs10758821 and rs1407862) within KDM4C gene at 9p24.1 showed p<10 -4 (p = 7.15 × 10 -6, 2.79 × 10 -5 and 4.93 × 10 -5, respectively) in the COGA sample while one SNP rs12001158 within KDM4C with p = 1.97 × 10 -4 in the COGA sample was replicated in the family sample (p = 0.01). Haplotype analysis further supported the associations of single-marker analyses of KDM4C in the COGA sample. Moreover, two SNPs (rs2046593 and rs10497668) near FSIP2 at 2q32.1 with moderate associations with AWS in the COGA sample (p = 2.66 × 10 -4 and 9.48 × 10 -5, respectively) were replicated in the family sample (p = 0.0013 and 0.0162, respectively). In addition, several SNPs in GABRA1, GABRG1, and GABRG3 were associated with AWS (p<10 -2) in the COGA sample. In conclusion, we identified several loci associated with AWS. These findings offer the potential for new insights into the pathogenesis of AD and AWS.

Family, twin and adoption studies have clearly demonstrated that genetic factors are important in modulating the vulnerability to alcohol dependence. Several genome-wide association (GWA) studies of alcohol dependence have been conducted; however, few loci have been replicated. A meta-analysis was performed on two GWA studies of 1283 cases of alcohol dependence and 1416 controls in Caucasian populations. Through meta-analysis we identified 131 SNPs associated with alcohol dependence with p<10-4. The best novel signal was rs6701037 (p=1.86 × 10-7) at 1q24-q25 within KIAA0040 gene while the second best novel hit was rs1869324 (p=4.71 × 10-7) at 2q22.1 within THSD7B. The third novel locus was NRD1 at 1p32.2 (the top SNP was rs2842576 with p=7.90 × 10-6). We confirmed the association of PKNOX2 at 11q24.4 with alcohol dependence. The top hit of PKNOX2 (rs750338 with p=1.47 × 10-6) in the meta-analysis was replicated with the Australian Twin-Family Study of 778 families (p=1.39 × 10-2) Furthermore, several flanking SNPs of the top hits in the meta-analysis demonstrated borderline associations with alcohol dependence in the family sample (top SNPs were rs2269655, rs856613, and rs10496768 with p=4.58 × 10-3, 2.1 × 10-4, and 2.86 × 10-3 for KIAA0040, NRD1 and THSD7B, respectively). In addition, ALK, CASC4, and SEMA5A were strongly associated with alcohol dependence (p<2 × 10-5) in the meta-analysis. In conclusion, we identified three new loci (KIAA0040, THSD7B and NRD1) and confirmed the previous association of PKNOX2 with alcohol dependence. These findings offer the potential for new insights into the pathogenesis of alcohol dependence.

Sammanfattning: Titel: "När hon la en hand på min rygg kunde jag känna om hon var full eller inte" Hur vuxna relationer formas av en uppväxt med alkoholberoende förälder/föräldrar Författare: Ida Björkman och Linda Höglund Syftet med den här studien var att undersöka hur vuxna relationer formas utifrån en uppväxt präglad av alkoholberoende förälder/föräldrar. Frågeställningarna vi utgick från för att göra det var: Hur ser de vuxna relationerna ut hos ett urval av informanter som har upplevt en barndom med en eller två föräldrar som var alkoholberoende? och Hur kan de vuxna relationerna hos informanterna förstås utifrån deras uppväxt präglad av alkoholberoende förälder/föräldrar? Det här är en kvalitativ studie utförd genom narrativa intervjuer (n=10) med vuxna personer som vuxit upp med alkoholberoende förälder/föräldrar och den visade att det görs ett val att begränsa antalet relationer man omger sig med i vuxen ålder för att minimera risken att bli sårad. Rädslan för att bli sårad beror på upprepade tillfällen av bristande tillit under uppväxten. Det finns en rädsla att brista i det egna föräldraskapet på liknande sätt som de egna föräldrarna har gjort. Beslut att avstå helt från eget föräldraskap och en beslutsamhet att lyckas i det finns också. Det finns förståelse och förlåtelse kring att de egna föräldrarna har gjort så gott de kunde utifrån sina förutsättningar och det bottnar i ett omvänt vårdnadsbehov där man från uppväxt in i vuxen ålder känner sig ansvarig för sina föräldrars välmående. Studien är genomförd med fenomenologisk ansats och har inspirerats av den hermeneutiska meningstolkningen där system- och anknytningsteori har legat till grund för analysen. Slutsatsen i den här studien är att olika situationer och relationer genom livsloppet medför reflektioner där uppfattningen av den egna uppväxten successivt förändras och det görs olika typer av anpassningar för att hantera tidigare erfarenheter. Det framträder en medvetenhet hos informanterna att relationer idag är påverkade av uppväxten, dock strävar de själva med att förstå hur den påverkar. / Abstract: Titel: "When she put a hand on my back I could tell if she was drunk or not" How adult relationships form due to an upbringing with alcohol dependent parent/parents Authors: Ida Björkman and Linda Höglund The purpose of this study was to examine how adult relationships form due to an upbringing with alcohol dependent parent/parents. The questions we used to do this were: How do the adult relationships look like in a selection of informants who have experienced a childhood with one or two parents who were alcohol dependent? and How can the adult relationships of the informants be understood due to an upbringing with alcohol dependent parent/parents? This is a qualitative study conducted through narrative interviews (n = 10) with adults who grew up with alcohol dependent parent/parents and it showed that the informants choose to limit the number of relationships they surround themselves with to minimize the risk of being hurt. The fear of being hurt is due to repeated situations of lacking continuity in childhood. Present is a fear of becoming a parent with the same shortcomings as one’s own parents. This results in the decision to not become a parent at all, or on a contrary, a determination to succeed in one’s own parenthood. They have always felt more or less responsible for their parents wellbeing and this also leads to an understanding that the parents did the best they could. The study has been conducted with a phenomenological approach and was inspired by the hermeneutical circle in the interpretation of the data, in which system- and attachment theory has been the basis for the analysis. This study concludes that the own perception of one’s upbringing gradually changes due to different situations and relationships throughout the lifecycle and different types of adaptations are made to deal with past experiences. There is an awareness among the informants that relationships today are influenced by their upbringing, however, they themselves strive to understand how it affects.

Bakgrund: Patienter med alkoholberoende är vanligt förekommande inom sjukvården. Forskning visar att vårdpersonalen uttrycker bristande kunskap i mötet med dessa patienter. Livsvärlden är den värld människan dagligen möter och lever i. Ett livsvärldsperspektiv innebär att vara öppen och se den andra människan där hon befinner sig. Alkoholberoende lever med känslor av skuld och skam, dessa känslor skapar ett lidande hos patienten, vilket kan förvärras av vårdpersonal. Syfte: Att beskriva människans upplevelser av att leva med alkoholberoende. Metod: Studien har en kvalitativ ansats. En kvalitativ innehållsanalys har genomförts utifrån tre självbiografier som underlag. Resultat: Upplevelsen av att leva med alkoholberoende kan ses som en rörelse mellan flykt och kamp. Flykten består i att fly från svåra känslor eller situationer, vilket leder till känslor av skuld och skam. I rörelsen infinner sig en kamplust som uttrycks i att kämpa för sitt människovärde. Insikt om problemet är ett steg i kampen för ett nyktert liv. Kampen för att bli nykter innebär självkontroll och att sluta fly. Slutsats: I rörelsen visas att den alkoholberoende människan aldrig står still, utan är i ständig rörelse mellan flykt och kamp. Förståelse för denna rörelse och förståelse för att etiketter och fördömanden från omgivningen skymmer människan är viktigt för att undvika att människan blir betraktad som ett hjälplöst objekt. Klinisk betydelse: Studiens resultat kan bidra till ökad förståelse hos vårdpersonal om hur människor med alkoholberoende lever och att de ska bli sedda och bekräftade som de personer de är. / Background: Patients with alcohol dependence are common in healthcare. Research shows that caregivers express a lack of knowledge during contact with those patients. The Life-world is the world that people encounters daily and lives in. A Life-world perspective means being open and see the other person as she is. An alcohol dependent person lives with feelings of guilt and shame and those feelings create suffering for the patient, which may be exacerbated by health professionals. Purpose: To describe the human experience of living with alcohol dependence. Method: The study was a qualitative method approach. A qualitative content analysis was carried out on three autobiographies. Results: The experience of living with alcohol addiction can be seen as a movement between escape and struggle. The escape is to run from difficult emotions or situations, which leads to feelings of living with guilt and shame. The motion raises a fighting spirit that is expressed in the fight for their human dignity. Insight into the problem is a step in the struggle for a sober life. The struggle to get sober means self-control and to stop the escape. Conclusion: The motion is that the alcohol dependent never stands still, but is in a constant movement between escape and struggle. An understanding of this movement and the understanding of that labels and condemnations from the surrounding obscure the human being, is important to avoid that the human being is seen as a helpless object. Clinical significance: The study results can be used to give health professionals a better understanding of people living with alcohol dependence and that these people are seen and acknowledged as whole people.

Introduction : La dépendance à l'alcool est un problème majeur et mondial de santé publique. Pour tenter d'en comprendre les déterminants individuels, plusieurs études se sont centrées sur l'examen de la personnalité, des styles défensifs, des stratégies de coping et de la symptomatologie anxio-dépressive au sein de populations alcoolo-dépendantes. En revanche, à notre connaissance, aucune recherche n'a étudié l'ensemble de ces facteurs simultanément. En conséquence, dans le cadre d'une approche intégrative, le but de cette thèse a été d'évaluer ces variables et d'étudier leurs relations afin d'apporter des éléments de compréhension à l'installation et au maintien de la dépendance à l'alcool. Méthode : Au cours de cette étude multicentrique (5 centres de recrutement) et transversale, 122 patients consultants pour une problématique alcoolique et 185 témoins ont répondu à un questionnaire sociodémographique et centré sur la consommation de substances, au Big Five Inventory (BFI) pour évaluer la personnalité, au Defense Style Questionnaire - 40 (DSQ-40) pour relever les styles défensifs, au Brief Cope pour estimer les stratégies de coping et à l'Hospital Anxiety and Depression Scale (HADS) pour mesurer la symptomatologie anxio-dépressive. Dans un premier temps, des analyses statistiques descriptives, comparatives et de corrélations ont été réalisées. Dans un second temps, des tests de régressions linéaires et logistiques, d'analyse en composantes principales et une analyse discriminante ont permis d'approfondir les résultats en lien avec l'objectif de la thèse (logiciel SPSS). Résultats : Les personnes alcoolo-dépendantes obtiennent des scores significativement différents pour la personnalité (névrosisme élevé, extraversion et conscience basses), pour les styles défensifs (style mature bas, styles névrotique et immature élevés), pour les stratégies de coping (stratégies centrées sur le problème basses, stratégies centrées sur les émotions et évitantes élevées) et pour la symptomatologie anxio-dépressive (symptômes anxieux et dépressifs importants) que les sujets du groupe contrôle. Les relations entre ces variables montrent le rôle des dimensions de personnalité dans l'utilisation de style défensif et/ou de stratégies de coping pouvant conduire à l'installation et au maintien d'une alcoolo-dépendance. En effet, le névrosisme entraîne l'utilisation d'un fonctionnement défensif inadapté. L'extraversion, la conscience et plus particulièrement l'ouverture à l'expérience sont associées à une activité défensive efficace. L'agréabilité, quant à elle, affiche des liens plus complexes avec l'organisation défensive. La présence de liens cohérents entre les styles défensifs et les stratégies de coping confirme l'intérêt de considérer le fonctionnement défensif de manière intégrative et globale. L'analyse discriminante, réalisée sur les facteurs principaux, permet de prédire l'appartenance au groupe « Alcool » pour 3 sujets sur 4. Les analyses de régressions linéaires multiples, exécutées selon un regroupement théorique, montrent que le style immature et les stratégies de coping évitantes prédisent le maintien d'une alcoolo-dépendance. L'ensemble des analyses, étayées par l'apport de différents modèles théoriques, permet de proposer un modèle théorico-clinique de l'installation et du maintien d'une dépendance à l'alcool. Des analyses comparatives complémentaires, exécutées sur les facteurs principaux, indiquent des scores significativement différents selon le genre chez les personnes alcoolo-dépendantes. Conclusion : Cette recherche montre la présence d'une association de déterminants individuels favorisant l'installation d'une alcoolo-dépendance en termes de personnalité, de style défensif, de stratégies de coping et de symptomatologie anxio-dépressive. Cette étude souligne l'intérêt d'appréhender le fonctionnement défensif globalement et permet de proposer un modèle théorico-clinique de l'alcoolo-dépendance et de son maintien. / Introduction: Alcohol dependence is a major and global public health problem. To try to understand the individual determinants, several studies have focused on the examination of personality, defense styles, coping strategies, anxiety and depressive symptoms in alcohol-dependent populations. However, to our knowledge, no research has studied all these factors simultaneously. Accordingly, as part of an integrative approach, the aim of this thesis was to evaluate these variables and study their relationships to bring elements of understanding the installation and the maintenance of alcohol dependence. Method: In this multicenter (5 recruitment centers) and cross-sectional study, 122 consultants patients with alcohol dependence and 185 controls answered a sociodemographic and focused on the substance questionnaire, the Big Five Inventory (BFI) to assess personality, the Defense Style Questionnaire - 40 (DSQ-40) to raise the defense styles, the Brief Cope to assess coping strategies and the Hospital Anxiety and Depression Scale (HADS) to measure anxiety and depressive symptoms. Initially, descriptive, comparative statistics and correlations were performed. Secondly, linear and logistic regression tests, principal component analysis and discriminant analysis have deepened the results related to the goal of this thesis (SPSS). Results: The alcohol-dependent obtain significantly different scores for personality (high neuroticism, low extraversion and conscientiousness), for defense styles (low mature style, high neurotic and immature styles), for coping strategies (low problem-focused strategies, high emotion-focused and avoidant strategies) and for anxiety and depressive symptoms (significant anxiety and depressive symptoms) than control subjects. The relationship found between these variables show the role of personality dimensions in adapting defense style and/or effective coping strategies to deal or not with stress. Neuroticism involves the use of an unsuitable defensive operation may lead to the alcohol dependence installation. The extraversion, conscientiousness, and particularly openness to experience are associated with effective defense activity. The agreeableness, meanwhile, appears more complex connections with the defensive organization. The presence of coherent links between defense styles and coping strategies confirms the interest in considering the defensive operation of integrative and comprehensive manner. The discriminant analysis performed on the main factors predicts group membership "Alcohol" subjects for 3 to 4. Analyses of multiple linear regressions, performed according to a theoretical regrouping show that immature style and avoidant coping strategies predict the maintenance of alcohol dependence. All analysis, supported by the contribution of different theoretical models allows proposing a theoretical-clinical model of the installation and maintenance of alcohol dependence. Further analyses comparing the main factors indicate significantly different scores by gender among alcohol-dependent people. Conclusion: This research shows the presence of a combination of individual determinants favoring the emergence of alcohol dependence in terms of personality, defense style, coping strategies and anxiety-depressive symptomatology. This study emphasizes the importance of understanding the overall defensive functioning and allows proposing a theoretical-clinical model of alcohol dependence and its maintenance.

Underage drinking has featured prominently in both scholarly and conventional literature in recent decades as a major health and socio-economic concern in the United States. As new evidence emerges associating underage drinking with a host of negative outcomes for both the youth who drinks and society in general, a closer examination of the long-term effects of underage drinking is critical. This exploratory study was designed to examine predictor variables and their ramifications (1) using logistic regression to identify a model for underage drinking history (UDHISTORY) as a predictor of concomitant alcohol dependence and poor educational attainment (CADAPEA) among individuals aged 25 and above, and (2) obtain a better understanding of how demographic variables (age, gender, race/ethnicity) influence the prediction. The nature and strength of the effect(s) of these demographic variables on the prediction were also investigated. The 2010 National Survey on Drug Use and Health data set ICPSR 32722-0001 which is previously unexploited for this purpose is utilized in this study. The data analysis tool, SDA on SAMHSA's website and IBM SPSS were used for correlation analysis and logistic regression to test the hypothesis that currently legal age drinkers 25 years and older with UDHISTORY are more likely to experience CADAPEA than their counterparts without UDHISTORY. When considered alone, UDHISTORY was a strong and statistically significant predictor of CADAPEA. The identified bivariate logistic regression model was statistically significant, &chi2 (1, n = 60) = 13.39, Adjusted Wald F1, 60 = 13.39, p = 0.001 < .05, accounting for 1.26% (Cox and Snell R square), 1.3% (Log Likelihood Pseudo R square), to 7.9% (Nagelkerke R square) of the variance in CADAPEA. However, adding demographic variables to the model made UDHISTORY a much stronger and more statistically significant predictor. The identified final multivariable logistic regression model was statistically significant, &chi2 (6, n = 55) = 170.43, Adjusted Wald F6, 55 = 26.04, p = 0.00 < .001, accounting for 1.8% (Cox and Snell R square), 7.2% (Log Likelihood Pseudo R square) to 7.9% (Nagelkerke R square) of the variance in CADAPEA. The model also correctly classified 99.1% of cases.