The NIAAA funds approximately 90 percent of the ongoing research in the United States on the causes, consequences, treatment, and prevention of alcohol abuse and alcohol-related problems. In 2017, the NIAAA issued a new five-year strategic plan, and in 2020, the organization noted its fiftieth anniversary with a science symposium. The design of COGA as a large, multi‐modal, family‐based study that was enriched for AUD liability also brings forth certain caveats.
BEHAVIORAL AND CLINICAL DATA
- Fourth, estimates of SNP heritability and genetic correlation for estradiol had low precision, partly related to the older age of the GWAS cohort.
- Genetic correlations (rg) of alcohol consumption (39) with the steroid sex hormones and their binding proteins are presented in Table 1, and genetic correlations with alcohol dependence (40) are presented in Table 2.
- 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).
- Strengths of this study include the use of previously published, publicly available GWAS with large sample sizes, rigorous application of LDSC regression to assess SNP heritability and genetic correlation, and a distinction between the traits of alcohol consumption and alcohol dependence.
This may be due, in part, to a lack of information about prenatal alcohol exposure or difficulty in distinguishing FASD from other developmental disorders that might have similar cognitive or behavioral symptoms. Prenatal alcohol exposure and central nervous system (CNS) involvement are factors common to the disorders encompassing FASD. Evidence of CNS involvement can be structural (e.g., small brain size, alterations in specific brain regions) or functional (e.g., cognitive and behavioral deficits, motor and coordination problems). For fetal alcohol syndrome—which is also characterized by growth deficiencies, distinct facial features, and other physical factors in addition to CNS involvement—confirmation of prenatal alcohol exposure is not required. In addition to its effects on the brain, alcohol also affects the peripheral nervous system, which comprises the nerves outside the brain and spinal cord.
Dual addictions and dependencies
For example, the COGA prospective study gathered longitudinal assessments of adolescent and young adult offspring from the families. More recently, recognizing the numerous changes including marriage, divorce, childbirth and career transitions that can significantly impact the course of alcohol use, AUD and remission, COGA has focused on longitudinal data collection of those in mid‐life (30–40s). In addition, because heavy drinking can exacerbate age‐related physical and neurocognitive problems, interact with medications, and cause falls and accidents, especially in older adults, a longitudinal follow‐up of COGA participants aged 50 and older is in progress. Of note, assessments, interviewer training and data cleaning are standardized across all sites, with some variations in assessment driven by individual institutional IRB criteria. Taken together, these waves of longitudinal follow‐up provide a perspective of AUD risk and resilience across the lifespan. The accompanying review (3. Brain Function) covers the available brain function data and resulting findings in detail.
Molecular Biology Databases
As genetic information is used to better understand human health and health inequities, expansive and inclusive data collection is essential. NIDA and other Institutes at NIH supported a recently released report on responsible use and interpretation of population-level genomic data, by the National Academies of Sciences, Engineering, and Medicine. Learn up-to-date facts and statistics on alcohol consumption and its impact in the United States and globally.
Genetic Influences on the Development of Alcoholism
These longitudinal data have been instrumental in COGA’s ability to chart the etiology and course of alcohol use and AUD across the lifecourse. For instance, our early family data documented the increased co‐aggregation of multiple SUDs in AUD probands and their first degree relatives, relative to comparison families, providing initial support for familial clustering of and potential genetic influences on the comorbidity across AUD and SUDs (e.g., References 21, 22). We have since conducted several studies that have disentangled family history into elements of genetic liability, nurture and density of risk (e.g., References 23, 24, 25). Our data on adolescent offspring of individuals with AUD documented the role of behavioral precursors, such as externalizing problems, and social environments, such as peers and parents, in trajectories that separated persisting drinking problems from developmentally‐delimited heavy alcohol use (e.g., References 26, 27, 28).
Direct Sequencing of Rare Variants
That is, a predisposition to metabolize the substance in such a way that the pleasurable effects are more prominent than adverse effects such as nausea and headaches increases a person’s risk of developing an alcohol use disorder. Alcoholism has a substantial heritability yet the detection of specific genetic influences has largely proved elusive. 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.
Genetic studies of alcohol dependence in the context of the addiction cycle
- Our functional genomics efforts continue to accelerate the pace at which genetic discoveries can be placed in a biological context.
- 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.
- Although testosterone and estradiol are mainly synthesized within the gonads, their regulatory influence extends far beyond the primary and secondary sex organs.
- 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.
- NIAAA also added a clinician’s portal to the Alcohol Treatment Navigator website, helping clinicians to feel more confident making patient referrals for AUD.
Research has suggested that it’s a combination of the above risk factors as well as genetics that could determine whether or not you develop alcohol use disorder. The gene variations that result in things like nausea, headaches, and skin flushing with alcohol consumption may genetics of alcohol use disorder national institute on alcohol abuse and alcoholism niaaa 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. “Substance use disorders and mental disorders often co-occur, and we know that the most effective treatments help people address both issues at the same time.
The sex chromosomes present unique features compared to the autosomes, including sex-dependent diploid or haploid dosages of X, recombination only within the pseudo-autosomal region of Y, and the developmental mosaic of X-inactivation in females (62), which lead to several analytical challenges that are beginning to be addressed (63). However, many analytical methods avoid these challenges by ignoring the sex chromosomes, including currently available methods to estimate SNP heritability and genetic correlation, such as LDSC (46, 47). The genetic etiologies of testosterone, estradiol, and SHBG all differ quantitatively between females and males even when only considering the autosomes (27–30), but prior GWAS have demonstrated additional genome-wide-significant associations with variants on the X chromosome (27, 30). Furthermore, for the alcohol use traits, the recent meta-analysis GWAS on alcohol consumption and alcohol use disorder excluded the sex chromosomes (33, 39, 40).
Recently, genome-wide association studies have become one of the major tools for identifying genes for alcohol use disorders by examining correlations between millions of common single-nucleotide polymorphisms with diagnosis status. Genome-wide association studies are just beginning to uncover novel biology; however, the functional significance of results remains a matter of extensive debate and uncertainty. In this review, we present a select group of genome-wide association studies of alcohol dependence, as one example of a way to generate functional hypotheses, within the addiction cycle framework. This analysis may provide novel directions for validating the functional significance of alcohol dependence candidate genes. Overall, we found that most of the prior published associations (18) between alcohol-use traits and sex-hormone levels did not correspond to genetic correlations with consistent directionality.
To outline the causes and consequences of alcohol‐related milestones, including AUD, and their related psychiatric comorbidities, the Collaborative Study on the Genetics of Alcoholism (COGA) was launched in 1989 with a gene‐brain‐behavior framework. 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).
Specifically, the GWAS (30) for total testosterone did not adjust for aspects of female physiology such as phase of the menstrual cycle, menopause, or use of oral contraception and other hormonal therapies, whereas the GWAS for bioavailable testosterone (30) and for estradiol (27) adjusted for some of these covariates. Furthermore, the GWAS of testosterone and estradiol were not stratified by menopause status in females, which correspond to major differences in the concentrations of these steroid sex hormones. Whereas previous studies have performed GWAS of testosterone and estradiol separately in premenopause and postmenopause females (29, 58), to our knowledge the summary statistics are not publicly available.