The collaborative study on the genetics of alcoholism: Genetics

This review describes the genetic approaches and results from the family-based Collaborative Study on the Genetics of Alcoholism (COGA). COGA was designed during the linkage era to identify genes affecting the risk for alcohol use disorder (AUD) and related problems, and was among the first AUD-focused studies to subsequently adopt a genome-wide association (GWAS) approach. COGA's family-based structure, multimodal assessment with gold-standard clinical and neurophysiological data, and the availability of prospective longitudinal phenotyping continues to provide insights into the etiology of AUD and related disorders. These include investigations of genetic risk and trajectories of substance use and use disorders, phenome-wide association studies of loci of interest, and investigations of pleiotropy, social genomics, genetic nurture, and within-family comparisons. COGA is one of the few AUD genetics projects that includes a substantial number of participants of African ancestry. The sharing of data and biospecimens has been a cornerstone of the COGA project, and COGA is a key contributor to large-scale GWAS consortia. COGA's wealth of publicly available genetic and extensive phenotyping data continues to provide a unique and adaptable resource for our understanding of the genetic etiology of AUD and related traits.     

The collaborative study on the genetics of alcoholism: Sample and clinical data

The collaborative study on the genetics of alcoholism (COGA) is a multi-site, multidisciplinary project with the goal of identifying how genes are involved in alcohol use disorder and related outcomes, and characterizing how genetic risk unfolds across development and in conjunction with the environment and brain function. COGA is a multi-generational family-based study in which probands were recruited through alcohol treatment centers, along with a set of community comparison families. Nearly 18,000 individuals from >2200 families have been assessed over a period of over 30 years with a rich phenotypic battery that includes semi-structured psychiatric interviews and questionnaire measures, along with DNA collection and electrophysiological data on a large subset. Participants range in age from 7 to 97, with many having longitudinal assessments, providing a valuable opportunity to study alcohol use and problems across the lifespan. Here we provide an overview of data collection methods for the COGA sample, and details about sample characteristics and comorbidity. We also review key research findings that have emerged from analyses of the COGA data. COGA data are available broadly to researchers, and we hope this overview will encourage further collaboration and use of these data to advance the field.     

Alcohol‐dependent molecular adaptations of the NMDA receptor system

Phenotypes such as motivation to consume alcohol, goal‐directed alcohol seeking and habit formation take part in mechanisms underlying heavy alcohol use. Learning and memory processes greatly contribute to the establishment and maintenance of these behavioral phenotypes. The N‐methyl‐d ‐aspartate receptor (NMDAR) is a driving force of synaptic plasticity, a key cellular hallmark of learning and memory. Here, we describe data in rodents and humans linking signaling molecules that center around the NMDARs, and behaviors associated with the development and/or maintenance of alcohol use disorder (AUD). Specifically, we show that enzymes that participate in the regulation of NMDAR function including Fyn kinase as well as signaling cascades downstream of NMDAR including calcium/calmodulin‐dependent protein kinase II (CamKII), the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) and the mammalian target of rapamycin complex 1 (mTORC1) play a major role in mechanisms underlying alcohol drinking behaviors. Finally, we emphasize the brain region specificity of alcohol's actions on the above‐mentioned signaling pathways and attempt to bridge the gap between the molecular signaling that drive learning and memory processes and alcohol‐dependent behavioral phenotypes. Finally, we present data to suggest that genes related to NMDAR signaling may be AUD risk factors.     

The role of α-synuclein in the pathophysiology of alcoholism

Alcoholism has complex etiology and there is evidence for both genetic and environmental factors in its pathophysiology. Chronic, long-term alcohol abuse and alcohol dependence are associated with neuronal loss with the prefrontal cortex being particularly susceptible to neurotoxic damage. This brain region is involved in the development and persistence of alcohol addiction and neurotoxic damage is likely to exacerbate the reinforcing effects of alcohol and may hinder treatment. Understanding the mechanism of alcohol’s neurotoxic effects on the brain and the genetic risk factors associated with alcohol abuse are the focus of current research. Because of its well-established role in neurodegenerative and neuropsychological disorders, and its emerging role in the pathophysiology of addiction, here we review the genetic and epigenetic factors involved in regulating α-synuclein expression and its potential role in the pathophysiology of chronic alcohol abuse. Elucidation of the mechanisms of α-synuclein regulation may prove beneficial in understanding the role of this key synaptic protein in disease and its potential for therapeutic modulation in the treatment of substance use disorders as well as other neurodegenerative diseases.     

P300 event-related potential amplitude as an endophenotype of alcoholism — Evidence from the collaborative study on the genetics of alcoholism

There is substantial information supporting the role of genetic factors in the susceptibility for alcohol dependence. However, the identification of specific genes that contribute to this predisposition has proven elusive, although several theoretically relevant candidates, e.g. DRD2 or 5-HT(1B), have been considered. The difficulty in identifying specific genes may be related to the clinical heterogeneity of the disorder resulting in a poorly defined phenotype for genetic analysis. An alternative approach to the use of a diagnostic phenotype for identifying alcoholism susceptibility genes may lie in the examination of the neurobiological correlates of the disorder, the so-called endophenotypes. One possible endophenotype of alcohol dependence may be related to the P300 waveform of the event-related brain potential (ERP). Using data obtained from the Collaborative Study on the Genetics of Alcoholism (COGA), a multi-site family-based study, the utility of P300 amplitude as an endophentype was examined. Differences in P300 amplitude were found between alcoholics and nonalcoholics, between unaffected relatives of alcoholics and relatives of controls, as well as between unaffected offspring of alcoholic fathers and offspring of controls. A genetic analysis indicated that attributes of the P(3) ERP waveform are heritable, and a quantitative trait locus analysis found linkage to several chromosomal regions. These data provide significant support for P300 as an endophenotype for alcohol dependence.     

A review on EEG-based methods for screening and diagnosing alcohol use disorder

The screening test for alcohol use disorder (AUD) patients has been of subjective nature and could be misleading in particular cases such as a misreporting the actual quantity of alcohol intake. Although the neuroimaging modality such as electroencephalography (EEG) has shown promising research results in achieving objectivity during the screening and diagnosis of AUD patients. However, the translation of these findings for clinical applications has been largely understudied and hence less clear. This study advocates the use of EEG as a diagnostic and screening tool for AUD patients that may help the clinicians during clinical decision making. In this context, a comprehensive review on EEG-based methods is provided including related electrophysiological techniques reported in the literature. More specifically, the EEG abnormalities associated with the conditions of AUD patients are summarized. The aim is to explore the potentials of objective techniques involving quantities/features derived from resting EEG, event-related potentials or event-related oscillations data.     

Description of the data from the Collaborative Study on the Genetics of Alcoholism (COGA) and single-nucleotide polymorphism genotyping for Genetic Analysis Workshop 14

The data provided to the Genetic Analysis Workshop 14 (GAW 14) was the result of a collaboration among several different groups, catalyzed by Elizabeth Pugh from The Center for Inherited Disease Research (CIDR) and the organizers of GAW 14, Jean MacCluer and Laura Almasy. The DNA, phenotypic characterization, and microsatellite genomic survey were provided by the Collaborative Study on the Genetics of Alcoholism (COGA), a nine-site national collaboration funded by the National Institute of Alcohol and Alcoholism (NIAAA) and the National Institute of Drug Abuse (NIDA) with the overarching goal of identifying and characterizing genes that affect the susceptibility to develop alcohol dependence and related phenotypes. CIDR, Affymetrix, and Illumina provided single-nucleotide polymorphism genotyping of a large subset of the COGA subjects. This article briefly describes the dataset that was provided.     

Collaborative study on the genetics of alcoholism: The strength of collaboration,team science,and longitudinal data

This issue contains a series of articles describing the various resources, studies, results, and future directions for the collaborative study on the genetics of alcoholism (COGA). The collaborative and integrative approach initiated by this group ~30 years ago serves as an excellent example of the strength of team science. Individually, various aspects of COGA would be limited in their impact toward improved understanding of alcohol use disorder. Collectively, their wholistic approach which spans deep longitudinal phenotypic assessments in families to include the application of large-scale omics technologies and cell-culture based molecular studies has demonstrated the power of working together.     

Effect of alcohol consumption on peripheral blood Alu methylation in Korean men

Alcohol use disorders (AUD) are defined as alcohol abuse and alcohol dependence, which create a substantial public health problem worldwide. To date, no therapeutic can effectively solve these problems. They are complex diseases characterized by both genetic and environmental factors. DNA methylation can act as a downstream effector of environmental signals and account for multi-factorial nature of the disease. Global DNA methylation of peripheral blood cells has recently been proposed as a potential biomarker for disease risk. Alu elements host one-quarter of CpG dinucelotides in the genome to function as proxies for global DNA methylation. In this study, we evaluated the Alu methylation in the peripheral blood DNA of healthy volunteers and AUD patients using the pyrosequencing technology. The Alu methylation level is significantly higher in AUD compared to healthy controls (23.4?±?1.6 versus 22.1?±?1.0, t?=?7.83, p?<?0.0001). Moreover, significant correlation was found between Alu methylation and alcohol use disorders identification test score (r?=?0.250, p?<?0.0001), alcohol problem (r?=?0.294, p?<?0.0001), and life position (r?=?–0.205, p?=?0.0005). Overall, these novel findings indicate that alcohol-related increase in Alu methylation might play a complex role in the etiology and pathogenesis of AUD. Further studies are required to elucidate the mechanisms underlying this relationship.     

Whole-genome variance components linkage analysis using single-nucleotide polymorphisms versus microsatellites on quantitative traits of derived phenotypes from factor analysis of electroencephalogram waves

Alcohol dependence is a serious public health problem. We studied data from families participating in the Collaborative Study on the Genetics of Alcoholism (COGA) and made available to participants in the Genetic Analysis Workshop 14 (GAW14) in order to search for genes predisposing to alcohol dependence. Using factor analysis, we identified four factors (F1, F2, F3, F4) related to the electroencephalogram traits. We conducted variance components linkage analysis with each of the factors. Our results using the Affymetrix single-nucleotide polymorphism dataset showed significant evidence for a novel linkage of F3 (factor comprised of the three midline channel EEG measures from the target case of the Visual Oddball experiment ttdt2, 3, 4) to chromosome 18 (LOD = 3.45). This finding was confirmed by analyses of the microsatellite data (LOD = 2.73) and Illumina SNP data (LOD = 3.30). We also demonstrated that, in a sample like the COGA data, a dense single-nucleotide polymorphism map provides better linkage signals than low-resolution microsatellite map with quantitative traits.     

Effects of population structure on genetic association studies

Population-based case-control association is a promising approach for unravelling the genetic basis of complex diseases. One potential problem of this approach is the presence of population structure in the samples. Using the Collaborative Study on the Genetics of Alcoholism (COGA) single-nucleotide polymorphism (SNP) datasets, we addressed three questions: How can the degree of population structure be quantified, and how does the population structure affect association studies? How accurate and efficient is the genomic control method in correcting for population structure? The amount of population structure in the COGA SNP data was found to inflate the p-value in association tests. Genomic control was found to be effective only when the appropriate number of markers was used in the control group in order to correctly calibrate the test. The approach presented in this paper could be used to select the appropriate number of markers for use in the genomic control method of correcting population structure.     

Neurobiology of comorbid post‐traumatic stress disorder and alcohol‐use disorder

Post‐traumatic stress disorder (PTSD) and alcohol‐use disorder (AUD) are highly comorbid in humans. Although we have some understanding of the structural and functional brain changes that define each of these disorders, and how those changes contribute to the behavioral symptoms that define them, little is known about the neurobiology of comorbid PTSD and AUD, which may be due in part to a scarcity of adequate animal models for examining this research question. The goal of this review is to summarize the current state‐of‐the‐science on comorbid PTSD and AUD. We summarize epidemiological data documenting the prevalence of this comorbidity, review what is known about the potential neurobiological basis for the frequent co‐occurrence of PTSD and AUD and discuss successes and failures of past and current treatment strategies. We also review animal models that aim to examine comorbid PTSD and AUD, highlighting where the models parallel the human condition, and we discuss the strengths and weaknesses of each model. We conclude by discussing key gaps in our knowledge and strategies for addressing them: in particular, we (1) highlight the need for better animal models of the comorbid condition and better clinical trial design, (2) emphasize the need for examination of subpopulation effects and individual differences and (3) urge cross‐talk between basic and clinical researchers that is reflected in collaborative work with forward and reverse translational impact.     

Neurogranin Regulates Alcohol Sensitivity through AKT Pathway in the Nucleus Accumbens

Dysfunction of glutamate neurotransmission in the nucleus accumbens (NAc) has been implicated in the pathophysiology of alcohol use disorders (AUD). Neurogranin (Ng) is exclusively expressed in the brain and mediates N‐methyl‐d ‐aspartate receptor (NMDAR) hypo‐function by regulating the intracellular calcium‐calmodulin (Ca²⁺‐CaM) pathway. Ng null mice (Ng^–/– mice) demonstrate increased alcohol drinking compared to wild‐type mice, while also showing less tolerance to the effect of alcohol. To identify the molecular mechanism related to alcohol seeking, both in vivo microdialysis and label‐free quantification proteomics comparing Ng genotype and effects of alcohol treatment on the NAc are utilized. There is significant difference in glutamate and gamma‐aminobutyric acid (GABA) neurotransmission between genotypes; however, alcohol administration normalizes both glutamate and GABA levels in the NAc. Using label‐free proteomics, 427 protein expression changes are identified against alcohol treatment in the NAc among 4347 total proteins detected. Bioinformatics analyses reveal significant molecular differences in Ng null mice in response to acute alcohol treatment. Ingenuity pathway analysis found that the AKT network is altered significantly between genotypes, which may increase the sensitivity of alcohol in Ng null mice. The pharmacoproteomics results presented here illustrate a possible molecular basis of the alcohol sensitivity through Ng signaling in the NAc.     

Variants located upstream of CHRNB4 on chromosome 15q25.1 are associated with age at onset of daily smoking and habitual smoking

Several genome-wide association and candidate gene studies have linked chromosome 15q24-q25.1 (a region including the CHRNA5-CHRNA3-CHRNB4 gene cluster) with alcohol dependence, nicotine dependence and smoking-related illnesses such as lung cancer and chronic obstructive pulmonary disease. To further examine the impact of these genes on the development of substance use disorders, we tested whether variants within and flanking the CHRNA5-CHRNA3-CHRNB4 gene cluster affect the transition to daily smoking (individuals who smoked cigarettes 4 or more days per week) in a cross sectional sample of adolescents and young adults from the COGA (Collaborative Study of the Genetics of Alcoholism) families. Subjects were recruited from families affected with alcoholism (either as a first or second degree relative) and the comparison families. Participants completed the SSAGA interview, a comprehensive assessment of alcohol and other substance use and related behaviors. Using the Quantitative trait disequilibrium test (QTDT) significant association was detected between age at onset of daily smoking and variants located upstream of CHRNB4. Multivariate analysis using a Cox proportional hazards model further revealed that these variants significantly predict the age at onset of habitual smoking among daily smokers. These variants were not in high linkage disequilibrium (0.28相似文献   

Metabolic Consequences of Chronic Alcohol Abuse in Non-Smokers: A Pilot Study

An alcohol use disorder (AUD) is associated with an increased susceptibility to respiratory infection and injury and, upon hospitalization, higher mortality rates. Studies in model systems show effects of alcohol on mitochondrial function, lipid metabolism and antioxidant systems. The present study applied high-resolution metabolomics to test for these changes in bronchoalveolar lavage fluid (BALF) of subjects with an AUD. Smokers were excluded to avoid confounding effects and compliance was verified by cotinine measurements. Statistically significant metabolic features, differentially expressed by control and AUD subjects, were identified by statistical and bioinformatic methods. The results show that fatty acid and acylcarnitine concentrations were increased in AUD subjects, consistent with perturbed mitochondrial and lipid metabolism. Decreased concentrations of methyl-donor compounds suggest altered one-carbon metabolism and oxidative stress. An accumulation of peptides suggests proteolytic activity, which could reflect altered epithelial barrier function. Two metabolites of possible microbial origin suggest subclinical bacterial infection. Furthermore, increased diacetylspermine suggests additional metabolic perturbations, which could contribute to dysregulated alveolar macrophage function and vulnerability to infection. Together, the results show an extended metabolic consequence of AUD in the bronchoalveolar space.     

Feasibility of an alcohol intervention programme for TB patients with alcohol use disorder (AUD)--a qualitative study from Chennai, South India

Background

The negative influences of alcohol on TB management with regard to delays in seeking care as well as non compliance for treatment has been well documented. This study is part of a larger study on the prevalence of AUD (Alcohol Use Disorder) among TB patients which revealed that almost a quarter of TB patients who consumed alcohol could be classified as those who had AUD. However there is dearth of any effective alcohol intervention programme for TB patients with Alcohol Use Disorder (AUD).

Methodology

This qualitative study using the ecological system model was done to gain insights into the perceived effect of alcohol use on TB treatment and perceived necessity of an intervention programme for TB patients with AUD. We used purposive sampling to select 44 men from 73 TB patients with an AUDIT score >8. Focus group discussions (FGDs) and interviews were conducted with TB patients with AUD, their family members and health providers.

Results

TB patients with AUD report excessive alcohol intake as one of the reasons for their vulnerability for TB. Peer pressure has been reported by many as the main reason for alcohol consumption. The influences of alcohol use on TB treatment has been elaborated especially with regard to the fears around the adverse effects of alcohol on TB drugs and the fear of being reprimanded by health providers. The need for alcohol intervention programs was expressed by the TB patients, their families and health providers. Suggestions for the intervention programmes included individual and group sessions, involvement of family members, audiovisual aids and the importance of sensitization by health staff.

Conclusions

The findings call for urgent need based interventions which need to be pilot tested with a randomized control trial to bring out a model intervention programme for TB patients with AUD.     

Segmental duplications: an 'expanding' role in genomic instability and disease

The knowledge that specific genetic diseases are caused by recurrent chromosomal aberrations has indicated that genomic instability might be directly related to the structure of the regions involved. The sequencing of the human genome has directed significant attention towards understanding the molecular basis of such recombination 'hot spots'. Segmental duplications have emerged as a significant factor in the aetiology of disorders that are caused by abnormal gene dosage. These observations bring us closer to understanding the mechanisms and consequences of genomic rearrangement.