Health Topics: Genetics and Alcohol Use Disorder National Institute on Alcohol Abuse and Alcoholism NIAAA

This article does not contain any studies with human or animal subjects performed by any of the authors. Just as risk factors increase your chance of experiencing a condition, protective factors lower your risk. Other factors, such as friend groups and level of financial security, may be subject to change. While genetics can play a significant role in your overall AUD risk assessment, it isn’t the only factor that can elevate your chances of developing AUD. 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.

Extended Data Fig. 2 Manhattan and QQ plots for PAU sex-stratified meta-analyses in EUR.

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.

Supplementary Data 21

• COGA ascertained probands in treatment for alcohol dependence, and a smaller number of comparison individuals from the same communities, and then recruited their families.
• Most alcohol-dependent cases were mild, with 70% of those meeting AD criteria reporting only three or four dependence symptoms and ≤5% reporting seven dependence symptoms.
• It was supported by the National Institute on Drug Abuse (NIDA), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute of Mental Health (NIMH), the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute on Aging.
• This is probably due in part to the accuracy with which height is measured and its relative stability once adulthood is reached, and rare variants, in particular those in regions of low LD, that are a major source of the still-missing heritability.

The most significant pathway is reactome ethanol oxidation for both traits in both EAs and AAs. Multiple GO biological processes are enriched for AUDIT-C (Supplementary Data 13, Supplementary Fig. 17) and AUD (Supplementary Data 14, Supplementary Fig. 18), including ethanol and alcohol metabolism. Enrichments for chemical and genetic perturbation gene sets and for the GWAS catalog for both traits are shown in Supplementary Data 15–18 and Supplementary Figs. In addition to these findings, recent analyses demonstrate strong evidence for a locus that affects brain wave oscillations as measured by electroencephalography (Porjesz et al. 2002). Thus, a gene or genes that affect brain rhythms lies in a region of chromosome 4 that contains a cluster of genes encoding proteins (i.e., receptors) which interact with the brain chemical gamma-aminobutyric acid (GABA). COGA is the most comprehensive genetics of alcoholism 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.

Health Challenges

However, our analyses were limited by our reliance on the AUDIT-C, which includes only the first 3 of the 10 AUDIT items. We also obtained cumulative AUD diagnoses, which are also more informative than assessments obtained at a single time point. Because the diagnosis of AUD is based on features other than alcohol consumption per se2,5, use of  the AUD diagnosis from the EHR augmented the information provided by the AUDIT-C phenotype.

Supplementary Data 26

• The initiative will facilitate identification of therapeutic targets and development of prevention strategies for AUD, supported by data generation, curation and bioinformatic analyses.
• This study, conducted by researchers at Scripps Research, presents critical evidence that AUD could act as a risk factor for AD, impacting both inflammation and cellular signalling pathways in the brain.
• 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.
• In 2021, more than 46 million people in the United States aged 12 or older had at least one substance use disorder, and only 6.3% had received treatment.
• Other relevant cell types for AUDIT-C, but not for AUD, included cardiovascular, adrenal or pancreas, liver, and musculoskeletal.
• However, the COGA project was designed with these difficulties in mind and incorporated strategies to meet the challenges.

The genomic pattern linked to general addiction risk also predicted higher risk of mental and physical illness, including psychiatric disorders, suicidal behavior, respiratory disease, heart disease, and chronic pain conditions. In children aged 9 or 10 years without any experience of substance use, these genes correlated with parental substance use and externalizing behavior. 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. 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.

These discoveries are used to develop more tailored and effective 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. Additionally, DRD2, CACNA1C, DPYD, PDE4B, KLB, BRD3, NCAM1, FTO and MAPT were identified as druggable genes. To compare within- and cross-ancestry fine mapping, we performed within-ancestry fine mapping for the above 92 regions using the same SNP sets and EUR-only LD information (Fig. 2b,c).