Statistical Validation of Risk Alleles in Genetic Addiction Risk Severity (GARS) Test: Early Identification of Risk for Alcohol Use Disorder (AUD) in 74,566 Case-Control Subjects

Abstract

Since 1990, when our laboratory published the association of the DRD2 Taq A1 allele and severe alcoholism in JAMA, there has been an explosion of genetic candidate association studies, including GWAS. To develop an accurate test to help identify those at risk for at least Alcohol Use Disorder (AUD), Blum's group developed the Genetic Addiction Risk Severity (GARS) test, consisting of ten genes and eleven associated risk alleles. In order to statistically validate the selection of these risk alleles measured by GARS, we applied strict analysis to studies that investigated the association of each polymorphism with AUD or AUD-related conditions published from 1990 until 2021. This analysis calculated the Hardy-Weinberg Equilibrium of each polymorphism in cases and controls. If available, the Pearson's χ² test or Fisher's exact test was applied to comparisons of the gender, genotype, and allele distribution. The statistical analyses found the OR, 95% CI for OR, and a post-risk for 8% estimation of the population's alcoholism prevalence revealed a significant detection. The OR results showed significance for DRD2, DRD3, DRD4, DAT1, COMT, OPRM1, and 5HTT at 5%. While most of the research related to GARS is derived from our laboratory, we are encouraging more independent research to confirm our findings.

Keywords: Genetic Addiction Risk Severity (GARS); Reward Deficiency Syndrome (RDS); dopamine; neurotransmitters; odds ratios; opioids; statistical validation of GARS.

Figure 1

Illustrates the interaction of at least six major neurotransmitter pathways involved in the Brain Reward Cascade (BRC). In the hypothalamus, environmental stimulation causes the release of serotonin, which in turn, via 5HT-2a receptors, activates (the green, equal sign) the subsequent release of opioid peptides into the hypothalamus. Then, the opioid peptides have two distinct effects, possibly via two different opioid receptors. (A) Inhibits (the red hash sign) through the Mu-opioid receptor (possibly via enkephalin) and projects to the substania nigra to GABAA neurons. (B) Stimulates (the green, equal sign) cannabinoid neurons (e.g., anandamide and 2-archydonoglcerol) through beta–endorphin-linked delta receptors, which in turn inhibit GABAA neurons at the substania nigra. Cannabinoids, primarily 2-archydonoglcerol, when activated, can also indirectly disinhibit (the red hash sign) GABAA neurons in the substania nigra through activation of G1/0 coupled to CB1 receptors. Similarly, glutamate neurons located in the Dorsal Raphe Nuclei (DRN) can indirectly disinhibit GABAA neurons in the substania nigra by activating GLU M3 receptors (the red hash sign). GABAA neurons, when stimulated, will, in turn, powerfully (the red hash signs) inhibit Ventral Tegmental Area (VTA) glutaminergic drive via GABAB 3 neurons. Finally, glutamate neurons in the VTA will project to dopamine neurons through NMDA receptors (the green, equal sign) to preferentially release dopamine at the NAc, shown as a bullseye indicating well-being (Blum et al. with permission).

Figure 2

Schematic of statistical validation of risk alleles in genetic addiction risk severity (GARS) test: Early identification of risk for Alcohol Use Disorder (AUD) in 74,566 case-control subjects.