Nature vs Nurture: Is Alcohol Use Disorder in Our Genes?

Understanding the role of the ALDH gene in alcohol metabolism is crucial for comprehending the genetic predisposition to alcoholism. Variations in the ALDH gene directly affect the rate at which acetaldehyde is eliminated from the body after alcohol consumption. Slower metabolism of acetaldehyde can lead to increased levels of this toxic compound in the blood, resulting in adverse effects and potentially promoting the development of alcohol dependence. In conclusion, while genetic factors play a significant role in the predisposition to alcoholism, the emerging field of epigenetics highlights the importance of studying the epigenetic influence on this disease. Understanding how epigenetic modifications contribute to alcoholism can provide valuable insights into the development of targeted treatments and prevention strategies.

• Genes related to alcoholism can affect the way a person metabolizes alcohol, their response to its effects, and their risk of developing an addiction.
• The GWAS study (cohort 1) on which our discovery was based contained males as probands but contained males and females as controls.
• Other top candidate genes in the panel (MOBP, MBP and MOG) are involved in myelination (Table 3).
• Overview of COGA participants across data modalitiesa including the Semi‐Structured Assessment for the Genetics of Alcoholism (SSAGA), genome‐wide association study (GWAS) and electroencephalography (EEG) data.

Human subject cohorts

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. Alcohol use disorder (AUD) is a diagnosis once referred to as “alcoholism.” It’s a condition characterized by patterns of excessive alcohol misuse despite negative consequences and major distress in important areas of daily function. Alcohol use disorder (AUD) can have a hereditary component, but not everyone living with AUD has a family history of AUD. Recordings from Hackman’s pacemaker revealed that he could have died as early as February 17, more than a week before the couple’s bodies were discovered.

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. The sharing of data and biospecimens has been a cornerstone of the COGA project, and COGA Drug rehabilitation is a key contributor to large-scale GWAS consortia. Susceptibility loci for alcoholism include both alcohol-specific genes acting either at the pharmacokinetic or pharmacodynamic levels, as well as loci moderating neuronal pathways such as reward, behavioral control and stress resiliency, that are involved in several psychiatric diseases. In recent years, major progress in gene identification has occurred using intermediate phenotypes such as task-related brain activation that confer the advantage of increased power and the opportunity of exploring the neuronal mechanisms through which genetic variation is translated into behavior. Fundamental to the detection of gene effects is also the understanding of the interplay between genes as well as genes/environment interactions.

Environment Matters Too

Severe childhood stress and neglect increase vulnerability to alcoholism but also several alcoholism-related psychiatric diseases including ASPD, CD, anxiety and depression, with the risks of these common diseases being elevated several-fold in the stress-exposed 66,67. However, not all subjects exposed to environmental stressors develop alcoholism or other psychiatric diseases, indicating that people differ widely in stress resiliency. Gene × environment interaction (G × E) occurs when the effect of exposure to an environmental factor on a person’s health is conditional upon his or her genotype (for review see Caspi & Moffitt 68). The knowledge that differences in DNA sequence moderate individuals in their resiliency or vulnerability to environmental pathogens is well known for several complex diseases, including psychiatric diseases as well as cancer, diabetes and cardiovascular, infective and immune diseases, etc.

Epigenetics, the combination of genes and environment, plays a more significant role in alcohol use disorders. Although most of the genetic determinants of alcoholism remain to be discovered there are reasons for optimism. In recent years a technological revolution has occurred producing a shift from single-locus studies to genome-wide searches.

• The goal of this series of reviews is to describe the study design, highlight the multi‐modal data available in the Collaborative Study on the Genetics of Alcoholism (COGA), and document the insights that these data have produced in our understanding of the lifecourse of AUD.
• With the advent of microarrays that can measure hundreds of thousands tomillions of single nucleotide polymorphisms (SNPs) across the genome,genome-wide association studies (GWAS) have provided a relatively unbiased wayto identify specific genes that contribute to a phenotype.
• COGA’s brain function data (see, 3. Brain Function) have also been paired with the project’s functional genomics pipeline (see, 5. Functional Genomics) to provide mechanistic insights.
• This has been done through the examination of neuropsychological tests and noninvasively recorded brain electrical activity during resting state and cognitive tasks, and more recently, by deriving measures of neural synchrony and connectivity (3. Brain Function).
• 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.
• Hackman pressed further with his career in the 1960s, booking guest spots on top TV shows and on stage.
• Other existing pharmacological drugs that modulate alcohol candidate genes identified by us include, besides benzodiazepines, dopaminergic agents, glutamatergic agents, serotonergic agents, as well as statins (Supplementary Table S3).

Understanding the role of these genes can provide valuable insights into the underlying mechanisms of the disease and potential targets for treatment. Epigenetics, the study of changes in gene expression or cellular phenotype that do not involve alterations to the DNA sequence, has emerged as a promising field for understanding the underlying mechanisms of alcoholism. Epigenetic modifications can occur in response to various environmental factors, such as chronic exposure to alcohol, and can significantly impact gene expression.

Alcoholism and Genes: Nature vs Nurture

However, much is still not known about this disease and the role of genetics in the development, course, and outcome of alcoholism. While the first tranche of COGA GWAS data followed a case–control design,72, 73 all subsequent COGA analyses have used family‐based analytic approaches. The initial family‐based GWAS of COGA,74, 75 conducted in a second subset of the data, was analyzed using Genome‐Wide Association analyses with Family data (GWAF76).

PREVALENCE AND DIAGNOSTIC CRITERIA

Moreover, it has become apparent that variants in stress-related genes such as CRHR1, may only confer risk in individuals exposed to trauma, particularly in early life. Over the past decade there have been tremendous advances in large scale SNP genotyping technologies allowing for genome-wide associations studies (GWAS). As a result, it is now recognized that genetic risk for alcoholism is likely to be due to common variants in very many genes, each of small effect, although rare variants with large effects might also play a role. This has resulted in a paradigm shift away from gene centric studies towards analyses of gene interactions and gene networks within biologically relevant pathways. Understanding the genetic predisposition to alcoholism is crucial in order to develop effective prevention strategies and interventions. It is well established that genes play a significant role in the inheritance of alcoholism, with studies showing that children of alcoholics are more likely to develop the disease themselves compared to individuals without a family history of alcoholism.

Initial recruitment prioritized families with at least three first degree relatives meeting criteria for alcohol dependence (i.e., densely affected) although many families include more than three individuals with AUD, hence the higher than population prevalence of alcohol dependence and AUD (Table 1). As shown in Figure 2, the proportion of families where more than half of the members met criteria for AUD ranged from 51% to 57%. Both probands and family members were characterized with age‐appropriate assessments, including a standardized diagnostic instrument designed by COGA, the Semi‐Structured Assessment for the Genetics of Alcoholism (SSAGA),10, 11 administered by trained interviewers. Additional questionnaires (e.g., personality, family history and home environment) were also administered (see 2. Sample and Clinical Data for details).

• Variations in these genes can alter the way dopamine is released in the brain, affecting the pleasurable effects of alcohol and increasing the risk of addiction.
• Major determinants of complexity are likely to include genetic heterogeneity (see Glossary at the end of this paper), heterogeneity at the level of neurobiological vulnerability, polygenicity, phenocopies, gene × environment interaction and incomplete penetrance.
• Genetic predisposition to alcoholism refers to the increased likelihood of developing the disease due to inherited genetic factors.
• 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.
• The results of several studies suggest that there are likely to be independent, complex contributions to alcoholism vulnerability from both linked genes 52–54.
• In conclusion, gene therapy holds great potential for addressing the genetic factors that contribute to alcoholism.

In vertebrates, neuropeptide Y (NPY) signaling plays a role in alcohol intake and dependence 61, 62. Invertebrates have an ortholog to NPY, neuropeptide F (NPF), and signaling via NPF also influences ethanol-related behaviors 44, 63. Majority of genomic data for large alcohol consumption and AUD meta-analysis was either from UKBiobank or from Million Veterans Project. Several other cohorts from dbGAP also contributed to large sample size of alcohol consumption GWAS by Liu et al, 2019. Genome-wide data on 14,904 DSM-IV diagnosed AD individuals and 37,944 controls from 28 case/control and family-based studies were meta-analyzed for PGC’s AD GWAS.

Prevention Strategies Based on Genetic Factors

Genes alone cannot determine if someone will become an alcoholic, as environmental factors also play a significant role. While it is known that there is a strong genetic component to the disease, the specific inheritance patterns are still not fully understood. Future research could investigate the interactions between different genes and determine how they contribute to an individual’s risk of developing alcoholism. By equipping individuals with genetic predisposition with accurate, science-based information, they can better understand their condition and the steps they can take to minimize their risk of developing alcoholism.

For example, the amount of DNA methylation in promoter regions correlates with gene inactivation. Chromatin remodeling can be studied at the single locus level; however, methods such as the chromatin immunoprecipitation in combination with DNA sequencing (ChIP-seq) allow for high-resolution genome-wide analysis. Alcohol exposure has been shown to cause changes in chromatin structure in rat brain 124,125. Alpha synuclein (SNCA) is a gene that maps to a QTL for alcohol preference, and expression of alpha synuclein is increased in different brain areas in rats displaying alcohol preference 126. Recently, an increase in alpha synuclein promoter DNA methylation has been found in patients with alcoholism 127, and genetic variation within the human SNCA gene has been linked to alcohol craving 128.

Genetics Of Alcoholism

While environmental factors such as social and cultural influences play a significant role in the development of alcoholism, there is a growing body of evidence suggesting that genetic predisposition also contributes to the risk of developing this addiction. Alcoholism has long been considered a complex disease influenced by a combination of genetic and environmental factors. The role of genetics in alcoholism has been a topic of great interest and debate, with researchers exploring the extent to which genes contribute to an individual’s risk of developing the disease. While the inheritance of certain genes can increase the risk of developing alcoholism, recent research has shown that the epigenetic factors also play a significant role in the development of this disease. The inheritance pattern of alcoholism is complex, as it is influenced by multiple genes and environmental factors. However, research suggests that there is a strong genetic component to alcoholism, with estimates ranging from 40-60% of the risk being attributed to genetics.