A Critical Review of Methods and Results in the Search for Genetic Contributors to Alcohol Sensitivity.
paper
Primary
Public
- Authors
- Schuckit, Marc A
- Year
- 2018
- Journal
- Alcoholism, clinical and experimental research
- PMID
- 29623680
- DOI
- 10.1111/acer.13628
- PMCID
- PMC5916326
Attributes of alcohol sensitivity are present before alcohol use disorders (AUDs) develop, they predict those adverse alcohol outcomes, are familial in nature, and many are heritable. Whether measured by alcohol challenges or retrospective reports of numbers of drinks required for effects, alcohol sensitivity reflects multiple phenotypes, including low levels of alcohol response and alcohol-related stimulation. Identification of genes that contribute to alcohol sensitivity could help identify individuals carrying risks for AUDs through their alcohol responses for whom early intervention might mitigate their vulnerability. Such genes could also improve understanding of biological underpinnings of AUDs, which could lead to new treatment approaches. However, the existing literature points to a wide range of genetic mechanisms that might contribute to alcohol responses, and few such genetic findings have been widely replicated. This critical review describes the potential impact of the diverse methods used to study sensitivity on the diversity of genetic findings that have been reported, places the genetic variants mentioned in the literature into broader categories rather than isolated results, and offers suggestions regarding how to advance the field by interpreting findings in light of the methods used to select research subjects and to measure alcohol sensitivity. To date, the most promising results have been for GABA, glutamate, opioid, dopamine, serotonin, and cholinergic system genes. The more gene variants that can be identified as contributors to sensitivity the better future gene screening platforms or polygenic scores are likely to be.
Description of Potential Pathways Across Studies Working to Identify Genes Related to Alcohol Sensitivity
| # | Section | Preview |
|---|---|---|
| 20 | The search for gene variants related to alcohol sensitivity (See Table 1) — Gene variations related to stress responses | The stress response system is of interest for drug reactions (Koob and Kreek, 2007), but has rarely… |
| 21 | The search for gene variants related to alcohol sensitivity (See Table 1) — GABA-related genes | Alcohol has prominent effects on GABA-A receptors (e.g., Korpi et al., 1993; Ray and Hutchinson,… |
| 22 | The search for gene variants related to alcohol sensitivity (See Table 1) — GABA-related genes | The potential relevance to alcohol responses of GABRA1 (chromosome 5q34) variants comes from animal… |
| 23 | The search for gene variants related to alcohol sensitivity (See Table 1) — GABA-related genes | Several animal studies implicated GABRA6 (chromosome 5q34) regarding lower LRs for cerebellar and… |
| 24 | The search for gene variants related to alcohol sensitivity (See Table 1) — GABA-related genes | GABRG1 (chromosome 4p12) variants in rs1391166 and rs1497571 are potentially related to low… |
| 25 | The search for gene variants related to alcohol sensitivity (See Table 1) — GABA-related genes | Finally, regarding GABA, a GWAS and meta-analysis using SREs highlighted possible sensitivity… |
| 26 | The search for gene variants related to alcohol sensitivity (See Table 1) — Glutamate and NMDA receptors | Glutamate receptors, including NMDA, are important for alcohol intoxication, sensitivity, and… |
| 27 | The search for gene variants related to alcohol sensitivity (See Table 1) — Glutamate and NMDA receptors | for T137346C regarding higher maximum drinks (a possible marker for a low sensitivity per drink)… |
| 28 | The search for gene variants related to alcohol sensitivity (See Table 1) — Opioid receptors and dopamine | Alcohol affects release of beta endorphin and impacts on ventral tegmentum and nucleus accumbens… |
| 29 | The search for gene variants related to alcohol sensitivity (See Table 1) — Opioid receptors and dopamine | A nonsynonymous SNP rs1799971 of OPRM1 (chromosome6q25.2) relates to IV alcohol subjective effects… |
| 30 | The search for gene variants related to alcohol sensitivity (See Table 1) — Opioid receptors and dopamine | Kappa opioid receptor, OPRK1 (chromosome 8q11.23), its’ endogenous ligand, dynorphin, and the… |
| 31 | The search for gene variants related to alcohol sensitivity (See Table 1) — Opioid receptors and dopamine | The dopamine transporter (DAT) gene (chromosome 5q15.3) has a common variable number of tandem… |
| 32 | The search for gene variants related to alcohol sensitivity (See Table 1) — 5-HT (serotonin) systems | Low synaptic 5-HT in humans and animals is associated increased drinking; medications that increase… |
| 33 | The search for gene variants related to alcohol sensitivity (See Table 1) — Cholinergic systems | Alcohol- and nicotine-related disorders often co-occur (e.g., Hopfer et al., 2001), the presence of… |
| 34 | The search for gene variants related to alcohol sensitivity (See Table 1) — Potassium and calcium channel related genes | Animal homologs of human KCNMA1 (chromosome 10q22.3) might relate to the intensity of alcohol… |
| 35 | The search for gene variants related to alcohol sensitivity (See Table 1) — NPY | This inhibitory neuropeptide affects appetitive behaviors and emotion (Foroud et al., 2000; Hayes et… |
| 36 | The search for gene variants related to alcohol sensitivity (See Table 1) — Additional genes of potential interest | Protein Arginine Methyltransferase 3, PRMT3 (chromosome 11p15.1) variant rs74761974 (A-allele)… |
| 37 | The search for gene variants related to alcohol sensitivity (See Table 1) — Additional genes of potential interest | Zinc-finger gene ZNF699 (chromosome 19p13.2) is related to Drosophila gene “hang”, which is… |
| 38 | The search for gene variants related to alcohol sensitivity (See Table 1) — Additional genes of potential interest | Homologes of human anaplastic lymphoma kinase (ALK) (also known as ALK tyrosine kinase; chromosome… |
| 39 | The search for gene variants related to alcohol sensitivity (See Table 1) — Additional genes of potential interest | Glypican 5 (GPC5) (chromosome 13q31.3) modulates cellular signaling in the caudate nucleus, putamen… |
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| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| The 10-year stability of three subscale scores of the Self-Report of the Effects of Alcohol measure and their relationship to changes in drinking quantities over the same period. | Schuckit MA et al. | — | 2026 | → |
| Association Between GABRG2 and Self-Rating of the Effects of Alcohol in a French Young Adult Sample. | Moe JS et al. | — | 2025 | → |
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