From its inception, COGA has generated and utilized extensive arrays of genotypic and phenotypic data from families densely affected by AUD and from comparison families to identify genes and understand their role in susceptibility to (or protection from) developing AUD and related phenotypes. New genetic variants have been identified, refined endophenotypes have been characterized, and functional information has begun to emerge on known genetic variants that influence risk for and protection from AUD. Another approach that has been proposed is to use stratified False Discovery Rate methods to uncover new loci likely to replicate in independent samples. One recent study has demonstrated enrichment of polygenic effects, particularly for SNPs tagging regulatory and coding genic elements 78. For example, a study in 33,332 patients and 27,888 controls used a combination of polygenic risk score analyses and pathway analyses to support a role for calcium channel signaling genes across five psychiatric disorders 79. These data continue to serve, not only as a platform for characterization of loci discovered in our own GWAS of behavioral and brain data but also for emerging signals from larger scale meta‐analytic GWAS of AUD.
Am I at Risk of Becoming Addicted to Alcohol?
- In 2020, a research team including Gelernter, Polimanti, and Hang Zhou, an assistant professor of psychiatry at Yale, was able to greatly expand upon previous findings regarding alcoholism through a genome-wide association study published in Nature Neuroscience.
- From the outset, COGA utilized a single linking variable (record identifier, but without personal identifying information) that was unique to each family, and a sub‐variable for individuals within each family indicative of their relationship to the proband.
- Theories suggest that for certain people drinking has a different and stronger impact that can lead to alcohol use disorder.
- Alcohol exacerbates insulin resistance, mitochondrial dysfunction, and oxidative stress, disrupting lipid metabolism and promoting inflammation.
- This array was designed for Caucasian and African ancestry, hence the limited number of alcohol metabolism genes.
Although alcoholism is often comorbid with other psychiatric disorders the heritability is largely disease specific 1. In the study of complex disorders, it has become apparent that quitelarge sample sizes are critical if robust association results are to beidentified which replicate across studies. Meta-analyses, whichcombine results across a number of studies in order to attain the criticalsample sizes needed, are being developed. Another neurotransmitter highlighted in the development of alcoholism by the study of endophenotypes is acetylcholine, which, like GABA, affects neurons widely distributed through the central nervous system. Neurons that respond to acetylcholine–described as cholinergic neurons–also have an important role in modulating the overall balance between excitation and inhibition in the brain. Our measures of brain responses in COGA subjects uncovered a connection to the chromosomal region containing the CHRM2 gene, which encodes a particular type of cholinergic receptor known as the M2 muscarinic acetylcholine receptor (CHRM2).
Nature vs. Nurture: Is Alcohol Use Disorder in Our Genes?
Our science aims to identify pathways to enduring remission and processes that can be modified to minimize the deleterious impact of AUD across the lifespan. Through our collaborative gene‐brain‐behavior paradigm, we aspire to address both the causes and consequences of heavy alcohol use and AUD, which still contributes annually to 3 million preventable deaths globally. Individual reviews in this issue provide detailed illustrations of the ways in which COGA data have contributed towards advancing our understanding of the etiology, course and consequences of AUD, and pathways from onset to remission and relapse. COGA’s intergenerational design has, in addition to identifying genetic risk factors, contributed to our understanding of the role of social genetic mechanisms50, 52, 64, 65, 66 in the interplay between genetic liability and the socio‐environmental milieu (e.g., References 40, 48, 67, 68).
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COGA researchers have also analyzed candidate genes—genes suspected to play a role in the development of alcoholism based on other studies. Some of these candidate genes encode components of various brain chemical systems that allow communication among nerve cells. Two of these genes are the dopamine D2 receptor gene (DRD2) and a serotonin transporter gene (HTT). However, the analyses found no evidence that DRD2 affected the risk for alcoholism (Edenberg et al. 1998a) or that HTT was linked to either alcoholism in general or to a more severe form of alcoholism (Edenberg et al. 1998b).
Heavy drinking and alcoholism marked by distinct sets of genes
The researchers believe that even larger studies may help to differentiate the genetics behind alcohol addiction. Alcohol use disorder, more commonly known as alcoholism, is characterized by an inability to control ones drinking because of a physical or emotional dependence of alcohol. is alcoholism a genetic disease With current review, we aim to present the recent advances in genetic and molecular studies of AUDs. Recent successes in genetic studies of AUDs will definetely motivate researchers and lead to better therapeutic interventions for this complex disorder.
- This finding led to the discovery of the association of GABRA2 with AUD, a robust, widely replicated finding that will be discussed below.
- Individual reviews in this issue provide detailed illustrations of the ways in which COGA data have contributed towards advancing our understanding of the etiology, course and consequences of AUD, and pathways from onset to remission and relapse.
- For instance, a growing body of research has revealed that some variants of genes that encode cell-surface docking sites for the protein GABA (gamma-aminobutyric acid), which carries signals between certain nerve cells, increase vulnerability to alcoholism.
- Another phenotype that may reflect a protective influence against alcoholism is the maximum number of drinks a person has consumed in a 24-hour period (MAXDRINKS).
Alcohol is widely consumed, but excessive use creates serious physical,psychological and social problems and contributes to many diseases. Alcoholism(alcohol dependence, alcohol use disorders) is a maladaptive pattern ofexcessive drinking leading to serious problems. Abundant evidence indicates thatalcoholism is a complex genetic disease, with variations in a large number ofgenes affecting risk. 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. Studies arerevealing other genes in which variants impact risk for alcoholism or relatedtraits, including GABRA2, CHRM2,KCNJ6, and AUTS2. As larger samples areassembled and more variants analyzed, a much fuller picture of the many genesand pathways that impact risk will be discovered.
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This strategy will allow the investigators to increase the reliability of the data and to refine the phenotypes, which in turn will enhance the power of the genetic analyses. They data-mined the analyses of DNA from saliva samples submitted by consenting 23andMe research participants, as well as the responses to the surveys of health and behavior available from the 23andMe database, and found a constellation of associations, not necessarily connected with alcohol. Individuals with the alcohol-protecting alleles had generally better health, including less chronic fatigue and needing less daily assistance with daily tasks.
This finding suggested to researchers that the risk variants promoted certain brain pathways that contribute to the development of behavior patterns and disorders. COGA’s asset is its family‐based longitudinal design that supports an intensive clinical, behavioral, genetic, genomic and brain function data collection. As the project enters its late third decade of scientific exploration, we approach our contributions to the study of AUD with optimism.
Figure 1: Relationship among recently published genome-wide association studies related to AUDs.
You may have a higher genetic predisposition, but the underlying causes of AUD are multifaceted and complex. The Diagnostic and Statistical Manual of Mental Disorders, 5th edition, text revision (DSM-5-TR), a clinical diagnostic guidebook, indicates that AUD often runs in families at a rate of 3–4 times higher compared with the general population. 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.