The Collaborative Study on the Genetics of Alcoholism: Overview PMC

COGA is the most comprehensive research project ever to be conducted on the inherited aspects of alcohol use disorder (AUD).COGA has the goal of identifying genes that influence an individual’s risk of developing alcohol problems, and understanding how that risk unfolds across the lifespan. These discoveries are used to develop more tailored and effective https://ecosoberhouse.com/ strategies to prevent and to treat alcohol problems. Independent genetic signals from the cross-ancestry meta-analysis were searched in OpenTargets.org37 for druggability and medication target status based on their nearest genes. Among them, OPRM1 implicated naltrexone and GABRA4 may implicate acamprosate, both current treatments for AUD.

• Substance use disorder (SUD) is a treatable mental disorder that affects a person’s brain and behavior, leading to their inability to control their use of substances like legal or illegal drugs, alcohol, or medications.
• Conversely, the strongest evidence in the replication sample for a region containing genes affecting the risk for alcoholism was on chromosome 3, which had shown no evidence of being linked with alcoholism in the initial sample.
• All data generated or analyzed during this study are included in this published article.
• The literature review served as the foundation for the manuscript including assisting with the formulation of the research question.
• Many factors are involved in the development of AUD, but having a relative, or relatives, living with AUD may account for almost one-half of your individual risk.

The ‘Educated Guess’ Approach – Candidate Genes on Arrays

However, a crucial disclaimer is that these markers don’t guarantee one will become a heavy drinker. The National Institute on Drug Abuse highlights a potential overlap between genes related to alcoholism and opioid misuse. This suggests that while a family history of alcoholism can increase susceptibility, it doesn’t dictate destiny.

• The evaluation consists of 11 yes or no questions that are intended to be used as an informational tool to assess the severity and probability of a substance use disorder.
• It can be challenging to make an accurate diagnosis because some symptoms are the same for both disorders, so the provider should use comprehensive assessment tools to reduce the chance of a missed diagnosis and provide the right treatment.
• Here we developed a methodology to non-invasively quantify acetaldehyde metabolism after alcohol consumption and identified two variants in ALDH2 besides rs671 that cause acetaldehyde accumulation after an alcohol challenge.
• Polygenic risk can also be challenging to communicate, and can lead to unrealistic expectations of what genomic medicine can do for the treatment and prevention of AUD.
• These efforts ultimately are expected to lead to the identification of genes that affect the risk for alcoholism and related phenotypes.

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

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. We report here the largest multi-ancestry GWAS for PAU so far, comprising over 1 million individuals and including 165,952 AUD/AD cases.

• The gene variations that result in things like nausea, headaches, and skin flushing with alcohol consumption may be more common in those of Asian or Jewish descent.
• According to the DSM-5-TR, the more relatives you have living with AUD and the closer they are to you in relation, the higher your individual genetic risk becomes.
• In wild-type ALDH2, R101 of one subunit forms a hydrogen bond with S517 of the opposite ALDH2 subunit via a conserved water molecule, while R114 forms an H-bond with E227 of the same subunit (Fig. 4C and D).
• Regarding alcohol dependence, heritability was as high as 56%, and the aggregate additive SNP effects estimated by GCTA on the parent sample accounted for 16% of the variance (Vrieze et al., 2013).
• We identified 85 independent risk variants in participants of EUR ancestry and 110 in the within-ancestry and cross-ancestry meta-analyses.

Genetics and alcoholism

• Data suggests that individuals hailing from families with an annual household income surpassing $75,000 face a higher susceptibility to becoming an alcoholic in comparison to their counterparts from economically modest backgrounds.
• Furthermore, AUD frequently co-occurs with other psychiatric disorders, including mood and anxiety disorders (Regier et al., 1990), post-traumatic stress disorder (Sampson et al., 2015), and other substance use disorders (Kessler et al., 1997).
• Some of these genes have been identified, including twogenes of alcohol metabolism, ADH1B and ALDH2,that have the strongest known affects on risk for alcoholism.
• This study is a basic experimental study involving humans with the manipulation or task used (consuming alcohol) expressly used for measurement and is not an intervention.
• These data highlight the heterogeneity of AUD and overlap with other psychiatric disorder that often also have strong genetic heritability estimates.

A particularly attractive feature of studying rare variation in COGA is its family design, which aids the identification of both private and disorder‐generalized mutations. Similarly, our ability to measure the brain’s activity during resting state and during various cognitive tasks with exquisite temporal accuracy, allows us to develop and implement EEG protocols that uniquely address questions regarding the course of AUD. While the recent use of GWAS to identify the underlying genetic components of AUD has been promising, there are several limitations of GWAS that must be considered.

As alcohol flushing is not exclusive to those of East Asian descent, we questioned whether additional ALDH2 genetic variants can drive facial flushing and inefficient acetaldehyde metabolism using human testing and biochemical assays. The gene variations that result in things like nausea, headaches, and skin flushing with alcohol consumption may be more common in those of Asian or Jewish descent. These groups typically have a lower risk of developing alcohol use disorder compared to other populations.

There are gene variations that could predispose a person to mental illnesses like depression and schizophrenia. While heredity and genetics are closely linked, they can mean different things from a medical perspective. STAT’s coverage of chronic health issues is supported by a grant from Bloomberg Philanthropies. Rates of marijuana and other illicit drug use, including stimulants and opioids, were also roughly the same as the year before. Fentanyl misuse ticked downward from 0.4% of the population to 0.3% — a small change that nonetheless represents roughly 160,000 fewer people misusing the powerful synthetic opioid. Information about NIMH, research results, summaries of scientific meetings, and mental health resources.

Perhaps the largest challenge is the way in which the AUD diagnosis is operationalized. The DSM-5 [1] currently requires the endorsement of any 2 of 11 criteria to reach the diagnostic threshold for AUD at the mild severity level. This necessarily introduces high levels Genetics of Alcoholism of heterogeneity into the AUD phenotype, even at the moderate level (4+ symptoms), and given that the genetic influences underlying AUD may not be shared equally across all symptoms [31], likely reduces the statistical power of GWAS focusing on the AUD diagnosis.

MVP dataset

Sequencing is rapidly becoming the key tool for characterization of the genetic basis of human diseases [84]. Clearly very large sample sizes are required to detect large panels of rare variants and there are significant bioinformatic requirements to deal with vast quantities of data. One such successful study performed exon-focused sequencing of impulsive individuals derived from a Finnish population isolate and identified a stop codon in HTR2B (1% frequency) that was unique to Finns. The stop codon carriers performed violently impulsive acts, but only whilst intoxicated with alcohol [85]. Another study investigating the heritability of assorted substance dependencies, including alcohol, tobacco, cannabis, and illicit drugs, used GCTA estimates to conclude that common SNPs contribute to at least 20% of the variance in substance dependence vulnerability (Palmer et al., 2015). Because the GWAS findings on substance dependence broadly have been limited, Palmer et al. (2015) demonstrated the efficacy of GCTA in identifying the heritability of substance use disorders via aggregate effects of genetic variants.

They may increase the overall risk by increasing drinking, orreduce risk by reducing drinking. Some alleles that reduce heavy drinking can,nevertheless, increase risk for disease in the subset of individuals who drinkheavily despite having them. The genes with the clearest contribution to the risk for alcoholism andalcohol consumption are alcohol dehydrogenase 1B (ADH1B) andaldehyde dehydrogenase 2 (ALDH2; mitochondrial aldehydedehydrogenase), two genes central to the metabolism of alcohol (Figure 1)20. Alcohol is metabolized primarily in the liver, although thereis some metabolism in the upper GI tract and stomach. The first step in ethanolmetabolism is oxidation to acetaldehyde, catalyzed primarily by ADHs; there are 7closely related ADHs clustered on chromosome 4 (reviewed in20). The second step is metabolism of theacetaldehyde to acetate by ALDHs; again, there are many aldehyde dehydrogenases,among which ALDH2 has the largest impact on alcohol consumption20.