She went on to say that the resulting nausea eclipses any pleasurable effects of alcohol — think of a bad hangover that sets in almost immediately. GWAS investigating alcohol sensitivity using the Self-Rating of the Effects of Alcohol (SRE) as an AUD endophenotype have struggled to make similar progress. We describe the advances that these studies have made in terms of further demonstrating the heritability of alcohol sensitivity along with limitations in terms of identifying genome-wide significant loci and what we see as the primary challenges facing such studies. We conclude with suggestions for future research and what could be achieved with larger samples. Genetic disorders are diagnosable conditions directly caused by genetic mutations that are inherited or occur later in life from environmental exposure.
Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders
Furthermore, aggregating across multiple SUDs suggests that problematic and disordered substance use has a unique genetic architecture that, while shared across SUDs, does not overlap fully with nondependent substance use per se16. While these studies have been useful in giving us a preliminary sense of varying genetic architecture underlying alcohol use and AUD via pairwise genetic associations among constructs, the techniques used do not allow researchers to examine associations while accounting for other factors/constructs. Since the genetic architectures of alcohol use and AUD are correlated but distinct, approaches estimating variance that is common to and unique from these two phenotypes may be useful.
The Impact of Genes on Enzyme Activity:
Ethanol is converted to acetaldehyde by alcohol dehydrogenase (ADH) and subsequently to acetate by aldehyde dehydrogenase (ALDH). Acetate is conjugated to coenzyme A and the resulting acetyl-CoA can be metabolized in the Krebs cycle, or utilized how to build alcohol tolerance for the synthesis of fatty acids. In addition, a small fraction of ethanol is metabolized by cytochrome P450 2E1 (CYP2E1) and in the brain by catalase. The diagram presents only those members of the ADH and ALDH families referred to in the text. Accumulation of acetaldehyde is responsible for the physiological malaise commonly known as ‘hangover’.
- Additionally, genes can also influence an individual’s sensitivity to the effects of alcohol.
- Individuals with the alcohol-protecting alleles had generally better health, including less chronic fatigue and needing less daily assistance with daily tasks.
- Earlier nomenclature numbered the amino acids according to their position in the final, mature protein.
Alcohol metabolism
The link between genotype and phenotype is likely also confounded by multidimensional gene-gene interactions, the magnitudes of which depend on allele frequencies (Mackay 2014). In addition, the genetic architectures that underlie different phenotypic manifestations of alcohol drinking behavior appear to be distinct. Nevertheless, different studies reveal different aspects of the genetic underpinnings of the physiological and behavioral effects of ethanol, while underscoring the underlying genomic complexity of the genotype-phenotype relationship. Combining and integrating information from experimentally tractable model systems with human genetic studies provides a powerful strategy to disentangle the genomic elements that contribute to alcohol-related phenotypes.
The first thing we did was we asked whether a common factor model in which all alcohol-related and life satisfaction indicators loading on the same factor (Model A) would fit the data well. If Model A fits best, it would mean that these items are part of one underlying latent factor (versus more than one). Next, we tested whether either a two-factor model with all alcohol items loading on one factor and life satisfaction loading on a second factor (Model B) or a correlated three-factor model allowing for separate life satisfaction, alcohol use, and AUD-related factors (Model C) would provide better fit. If these models fit best it would mean that (Model B) the genetic influences on all alcohol indicators and life satisfaction are distinct, or that (Model C) the genetic influences on the alcohol use indicators are distinct from the AUD indicators and the life satisfaction indicators.