Rising health care costs in recent years have increased pressures on providers, insurers, and policymakers to monitor the costs, cost-effectiveness, and cost-benefit of all health care services, including alcohol-related services. Without solid information regarding the economic implications of alcohol-related services, health insurance companies, managed care organizations, and policymakers may be reluctant to fund these services. As reviewed in this article, economic analyses-such as cost, cost-effectiveness, and cost-benefit analyses, including cost-offset studies--have been applied to alcoholism treatment outcomes research to provide such information. Methodological issues discussed here that concern these approaches will shape the future direction of economic analyses in the alcohol field.

Family History of Alcoholism and earlier Age of Onset are found to predict Severity of alcoholism. Previous Indian studies in this regard have methodological issues related to the definition of alcoholism and reliability of information obtained.

No abstract available

The P300 event-related brain potential (ERP) was elicited with auditory and visual stimuli from members of 13 families who were at high risk (HR) for alcoholism (father diagnosed as alcoholic) and 13 families at low risk (LR) for alcoholism. Each family consisted of a father, mother, and at least two biological children. The intrafamily member correlations (father vs. child, mother vs. child, child vs. child) for P300 amplitude were obtained for 15 electrode sites. P300 amplitude from auditory stimuli was not correlated among HR family members, but was positively correlated among LR family members. P300 amplitude from visual stimuli was positively correlated among both HR and LR family members. When taken in conjunction with previous findings, the present results suggest that P300 amplitude from auditory stimuli may not be as reliable as ERPs from visual stimuli for the assessment of alcoholism heritability.

No abstract available

We have used a translational Convergent Functional Genomics (CFG) approach to discover genes involved in alcoholism, by gene-level integration of genome-wide association study (GWAS) data from a German alcohol dependence cohort with other genetic and gene expression data, from human and animal model studies, similar to our previous work in bipolar disorder and schizophrenia. A panel of all the nominally significant P-value SNPs in the top candidate genes discovered by CFG  (n=135 genes, 713 SNPs) was used to generate a genetic  risk prediction score (GRPS), which showed a trend towards significance (P=0.053) in separating  alcohol dependent individuals from controls in an independent German test cohort. We then validated and prioritized our top findings from this discovery work, and subsequently tested them in three independent cohorts, from two continents. A panel of all the nominally significant P-value single-nucleotide length polymorphisms (SNPs) in the top candidate genes discovered by CFG (n=135 genes, 713 SNPs) were used to generate a Genetic Risk Prediction Score (GRPS), which showed a trend towards significance (P=0.053) in separating alcohol-dependent individuals from controls in an independent German test cohort. In order to validate and prioritize the key genes that drive behavior without some of the pleiotropic environmental confounds present in humans, we used a stress-reactive animal model of alcoholism developed by our group, the D-box binding protein (DBP) knockout mouse, consistent with the surfeit of stress theory of addiction proposed by Koob and colleagues. A much smaller panel (n=11 genes, 66 SNPs) of the top CFG-discovered genes for alcoholism, cross-validated and prioritized by this stress-reactive animal model showed better predictive ability in the independent German test cohort (P=0.041). The top CFG scoring gene for alcoholism from the initial discovery step, synuclein alpha (SNCA) remained the top gene after the stress-reactive animal model cross-validation. We also tested this small panel of genes in two other independent test cohorts from the United States, one with alcohol dependence (P=0.00012) and one with alcohol abuse (a less severe form of alcoholism; P=0.0094). SNCA by itself was able to separate alcoholics from controls in the alcohol-dependent cohort (P=0.000013) and the alcohol abuse cohort (P=0.023). So did eight other genes from the panel of 11 genes taken individually, albeit to a lesser extent and/or less broadly across cohorts. SNCA, GRM3 and MBP survived strict Bonferroni correction for multiple comparisons. Taken together, these results suggest that our stress-reactive DBP animal model helped to validate and prioritize from the CFG-discovered genes some of the key behaviorally relevant genes for alcoholism. These genes fall into a series of biological pathways involved in signal transduction, transmission of nerve impulse (including myelination) and cocaine addiction. Overall, our work provides leads towards a better understanding of illness, diagnostics and therapeutics, including treatment with omega-3 fatty acids. We also examined the overlap between the top candidate genes for alcoholism from this work and the top candidate genes for bipolar disorder, schizophrenia, anxiety from previous CFG analyses conducted by us, as well as cross-tested genetic risk predictions. This revealed the significant genetic overlap with other major psychiatric disorder domains, providing a basis for comorbidity and dual diagnosis, and placing alcohol use in the broader context of modulating the mental landscape.

Alcohol consumption, particularly heavier drinking, is an important risk factor for many health problems and, thus, is a major contributor to the global burden of disease. In fact, alcohol is a necessary underlying cause for more than 30 conditions and a contributing factor to many more. The most common disease categories that are entirely or partly caused by alcohol consumption include infectious diseases, cancer, diabetes, neuropsychiatric diseases (including alcohol use disorders), cardiovascular disease, liver and pancreas disease, and unintentional and intentional injury. Knowledge of these disease risks has helped in the development of low-risk drinking guidelines. In addition to these disease risks that affect the drinker, alcohol consumption also can affect the health of others and cause social harm both to the drinker and to others, adding to the overall cost associated with alcohol consumption. These findings underscore the need to develop effective prevention efforts to reduce the pain and suffering, and the associated costs, resulting from excessive alcohol use.

No abstract available

The feasibility of effectively analyzing high-density single nucleotide polymorphism (SNP) maps in whole genome scans of complex traits is not known. The purpose of this study was to compare variance components linkage results using different density marker maps in data from the Collaborative Study on the Genetics of Alcoholism (COGA). Marker maps having an average spacing of 10 cM (microsatellite), 0.78 cM (SNP1), and 0.31 cM (SNP2) were used to identify quantitative trait loci (QTLs) affecting maximum number of alcoholic drinks consumed in a 24-hour period (Inmaxalc).

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) was founded 40 years ago to help elucidate the biological underpinnings of alcohol dependence, including the potential contribution of genetic factors. Twin, adoption, and family studies conclusively demonstrated that genetic factors account for 50 to 60 percent of the variance in risk for developing alcoholism. Case-control studies and linkage analyses have helped identify DNA variants that contribute to increased risk, and the NIAAA-sponsored Collaborative Studies on Genetics of Alcoholism (COGA) has the expressed goal of identifying contributing genes using state-of-the-art genetic technologies. These efforts have ascertained several genes that may contribute to an increased risk of alcoholism, including certain variants encoding alcohol-metabolizing enzymes and neurotransmitter receptors. Genome-wide association studies allowing the analysis of millions of genetic markers located throughout the genome will enable discovery of further candidate genes. In addition to these human studies, genetic animal models of alcohol's effects and alcohol use have greatly advanced our understanding of the genetic basis of alcoholism, resulting in the identification of quantitative trait loci and allowing for targeted manipulation of candidate genes. Novel research approaches-for example, into epigenetic mechanisms of gene regulation-also are under way and undoubtedly will further clarify the genetic basis of alcoholism.

Alcoholism is a complex disease caused by a confluence of environmental and genetic factors influencing multiple brain pathways to produce a variety of behavioral sequelae, including addiction. Genetic factors contribute to over 50% of the risk for alcoholism and recent evidence points to a large number of genes with small effect sizes as the likely molecular basis for this disease. Recent progress in genomics (microarrays or RNA-Seq) and genetics has led to the identification of a large number of potential candidate genes influencing ethanol behaviors or alcoholism itself. To organize this complex information, investigators have begun to focus on the contribution of gene networks, rather than individual genes, for various ethanol-induced behaviors in animal models or behavioral endophenotypes comprising alcoholism. This chapter reviews some of the methods used for constructing gene networks from genomic data and some of the recent progress made in applying such approaches to the study of the neurobiology of ethanol. We show that rapid technology development in gathering genomic data, together with sophisticated experimental design and a growing collection of analysis tools are producing novel insights for understanding the molecular basis of alcoholism and that such approaches promise new opportunities for therapeutic development.

There is good evidence for impairment of spermatogenesis and reductions in sperm counts and testosterone levels in chronic alcoholics. The mechanisms for these effects have not yet been studied in detail. The consequences of chronic alcohol consumption on the structure and/or metabolism of testis cell macromolecules require to be intensively investigated. The present work reports the effects of chronic alcoholism on contents of free amino acids, levels of cytochrome P450 3A2 (CYP3A2) mRNA expression and DNA fragmentation, as well as on contents of different cholesterol fractions and protein thiol groups in rat testes. Wistar albino male rats were divided into two groups: I - control (intact animals), II - chronic alcoholism (15% ethanol self-administration during 150 days). Following 150 days of alcohol consumption, testicular free amino acid content was found to be significantly changed as compared with control. The most profound changes were registered for contents of lysine (-53%) and methionine (+133%). The intensity of DNA fragmentation in alcohol-treated rat testes was considerably increased, on the contrary CYP3A2 mRNA expression in testis cells was inhibited, testicular contents of total and etherified cholesterol increased by 25% and 45% respectively, and protein SH-groups decreased by 13%. Multidirectional changes of the activities of testicular dehydrogenases were detected. We thus obtained complex assessment of chronic alcoholism effects in male gonads, affecting especially amino acid, protein, ATP and NADPH metabolism. Our results demonstrated profound changes in testes on the level of proteome and genome. We suggest that the revealed metabolic disorders can have negative implication on cellular regulation of spermatogenesis under long-term ethanol exposure.

Alcoholism has a strong genetic component. Twin studies have demonstrated the heritability of a large proportion of phenotypic variance of alcoholism ranging from 50-80%. The search for genetic variants associated with this complex behavior has epitomized sequence-based studies for nearly a decade. The limited success of genome-wide association studies (GWAS), possibly precipitated by the polygenic nature of complex traits and behaviors, however, has demonstrated the need for novel, multivariate models capable of quantitatively capturing interactions between a host of genetic variants and their association with non-genetic factors. In this regard, capturing the network of SNP by SNP or SNP by environment interactions has recently gained much interest.

Alcohol use disorders (AUD) are commonly occurring, heritable and polygenic disorders with etiological origins in the brain and the environment. To outline the causes and consequences of alcohol-related milestones, including AUD, and their related psychiatric comorbidities, the Collaborative Study on the Genetics of Alcoholism (COGA) was launched in 1989 with a gene-brain-behavior framework. COGA is a family based, diverse (~25% self-identified African American, ~52% female) sample, including data on 17,878 individuals, ages 7-97 years, in 2246 families of which a proportion are densely affected for AUD. All participants responded to questionnaires (e.g., personality) and the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) which gathers information on psychiatric diagnoses, conditions and related behaviors (e.g., parental monitoring). In addition, 9871 individuals have brain function data from electroencephalogram (EEG) recordings while 12,009 individuals have been genotyped on genome-wide association study (GWAS) arrays. A series of functional genomics studies examine the specific cellular and molecular mechanisms underlying AUD. This overview provides the framework for the development of COGA as a scientific resource in the past three decades, with individual reviews providing in-depth descriptions of data on and discoveries from behavioral and clinical, brain function, genetic and functional genomics data. The value of COGA also resides in its data sharing policies, its efforts to communicate scientific findings to the broader community via a project website and its potential to nurture early career investigators and to generate independent research that has broadened the impact of gene-brain-behavior research into AUD.

Chronic alcoholism can damage the cytoskeleton and aggravate neurological deficits. However, the effect of chronic alcoholism on hippocampal neurons remains unclear. In this study, a model of chronic alcoholism was established in rats that were fed with 6% alcohol for 42 days. Endogenous hydrogen sulfide content and cystathionine-beta-synthase activity in the hippocampus of rats with chronic alcoholism were significantly increased, while F-actin expression was decreased. Hippocampal neurons in rats with chronic alcoholism appeared to have a fuzzy nuclear membrane, mitochondrial edema, and ruptured mitochondrial crista. These findings suggest that chronic alcoholism can cause learning and memory decline in rats, which may be associated with the hydrogen sulfide/cystathionine-beta-synthase system, mitochondrial damage and reduced expression of F-actin.

Men and women may use alcohol to regulate emotions differently, with corresponding differences in neural responses. We explored how the viewing of different types of emotionally salient stimuli impacted brain activity observed through functional magnetic resonance imaging (fMRI) from 42 long-term abstinent alcoholic (25 women) and 46 nonalcoholic (24 women) participants. Analyses revealed blunted brain responsivity in alcoholic compared to nonalcoholic groups, as well as gender differences in those activation patterns. Brain activation in alcoholic men (ALCM) was significantly lower than in nonalcoholic men (NCM) in regions including rostral middle and superior frontal cortex, precentral gyrus, and inferior parietal cortex, whereas activation was higher in alcoholic women (ALCW) than in nonalcoholic women (NCW) in superior frontal and supramarginal cortical regions. The reduced brain reactivity of ALCM, and increases for ALCW, highlighted divergent brain regions and gender effects, suggesting possible differences in the underlying basis for development of alcohol use disorders.

Alcohol Use Disorder is a complex genetic disorder, involving genetic, neural, and environmental factors, and their interactions. The Collaborative Study on the Genetics of Alcoholism (COGA) has been investigating these factors and identified putative alcohol use disorder risk genes through genome-wide association studies. In this review, we describe advances made by COGA in elucidating the functional changes induced by alcohol use disorder risk genes using multimodal approaches with human cell lines and brain tissue. These studies involve investigating gene regulation in lymphoblastoid cells from COGA participants and in post-mortem brain tissues. High throughput reporter assays are being used to identify single nucleotide polymorphisms in which alternate alleles differ in driving gene expression. Specific single nucleotide polymorphisms (both coding or noncoding) have been modeled using induced pluripotent stem cells derived from COGA participants to evaluate the effects of genetic variants on transcriptomics, neuronal excitability, synaptic physiology, and the response to ethanol in human neurons from individuals with and without alcohol use disorder. We provide a perspective on future studies, such as using polygenic risk scores and populations of induced pluripotent stem cell-derived neurons to identify signaling pathways related with responses to alcohol. Starting with genes or loci associated with alcohol use disorder, COGA has demonstrated that integration of multimodal data within COGA participants and functional studies can reveal mechanisms linking genomic variants with alcohol use disorder, and potential targets for future treatments.

The impact of maternal nutrition on neurodevelopment and neonatal neuroprotection is a research topic with increasing interest. Maternal diet can also have deleterious effects on fetal brain development. Fetal exposure to alcohol is responsible for poor neonatal global development, and may increase brain vulnerability to hypoxic-ischemic encephalopathy, one of the major causes of acute mortality and chronic neurological disability in newborns. Despite frequent prevention campaigns, about 10% of women in the general population drinks alcohol during pregnancy and breastfeeding. This study was inspired by this alarming fact. Its aim was to evaluate the beneficial effects of maternal supplementation with two polyphenols during pregnancy and breastfeeding, on hypoxic-ischemic neonate rat brain damages, sensorimotor and cognitive impairments, in a context of moderate maternal alcoholism. Both stilbenoid polyphenols, trans-resveratrol (RSV - 0.15 mg/kg/day), and its hydroxylated analog, trans-piceatannol (PIC - 0.15 mg/kg/day), were administered in the drinking water, containing or not alcohol (0.5 g/kg/day). In a 7-day post-natal rat model of hypoxia-ischemia (HI), our data showed that moderate maternal alcoholism does not increase brain lesion volumes measured by MRI but leads to higher motor impairments. RSV supplementation could not reverse the deleterious effects of HI coupled with maternal alcoholism. However, PIC supplementation led to a recovery of all sensorimotor and cognitive functions. This neuroprotection was obtained with a dose of PIC corresponding to the consumption of a single passion fruit per day for a pregnant woman.

Alcohol affects gene expression in several brain regions. The amygdala is a key structure in the brain's emotional system and in recent years the crucial importance of the amygdala in drug-seeking and relapse has been increasingly recognized. In this study gene expression screening was used to identify genes involved in alcoholism in the human basolateral amygdala of male patients. The results show that alcoholism affects a broad range of genes and many systems including genes involved in synaptic transmission, neurotransmitter transport, structural plasticity, metabolism, energy production, transcription and RNA processing and the circadian cycle. In particular, genes involved in the glutamate system were affected in the alcoholic patients. In the amygdala the glutamate system is involved in the acquisition, consolidation, expression and extinction of associative learning, which is a vital part of addiction, and in alcohol abusers it is associated with withdrawal anxiety and neurodegeneration. Downregulation of the excitatory amino acid transporters GLAST, GLT-1 and the AMPA glutamate receptor 2 (GluR2) revealed by the microarray were confirmed by Western blots. The decreased expression of GLAST, GLT-1 and GluR2 in the alcoholic patients may increase glutamate tone and activity in the basolateral amygdala and this may contribute to neurodegeneration as well as the expression of associative memories and anxiety which underlie continued drug-seeking and chronic relapse.

Genomic imprinting, which is also known as the parent-of-origin effect, is a mechanism that only expresses one copy of a gene pair depending upon the parental origin. Although many chromosomal regions in the human genome are likely to be imprinted, imprinting is not accounted for in the usual linkage analysis. In this study, using a variance-components approach with a quantitative phenotype ttth-FP1, we found significant evidence of imprinting at two loci, D7S1790 and D1S1631, on chromosome 1 and chromosome 7, respectively. Our results suggest that allowing for the possibility of imprinting can increase the power to detect linkage for localizing genes for alcoholism.