The genetic basis of alcoholism: multiple phenotypes, many genes, complex networks.
paper
Cited
Public
- Authors
- Morozova, Tatiana V; Goldman, David; Mackay, Trudy F C; Anholt, Robert R H
- Year
- 2012
- Journal
- Genome biology
- PMID
- 22348705
- DOI
- 10.1186/gb-2012-13-2-239
- PMCID
- PMC3334563
Alcoholism is a significant public health problem. A picture of the genetic architecture underlying alcohol-related phenotypes is emerging from genome-wide association studies and work on genetically tractable model organisms.
Alcohol metabolism. 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 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'.
The malic enzyme metabolic switch. Malic enzyme mediates the conversion of malate to pyruvate, which is accompanied by the production of NADPH. NADPH is a necessary cofactor for the biosynthesis of fatty acids along with acetyl-CoA, generated by the metabolism of ethanol. The diagram highlights auxiliary pathways for the biosynthesis of fatty acids. Pyruvate carboxylase and malic enzyme mediate a cyclic metabolic pathway, which via the mitochondrial citrate and pyruvate transporters results in the transport of acetyl-CoA across the mitochondrial membrane and generation of cytosolic NADPH. An alternative metabolic pathway is the direct conversion of pyruvate into acetyl-CoA via the pyruvate dehydrogenase complex. This metabolic switch channels excess metabolic energy into the synthesis of fatty acids and contributes to the development of fatty liver syndrome during excessive alcohol consumption. Modified from [94].
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| Name | Type |
|---|---|
| acetaldehyde | drug |
| acetic acid | drug |
| acetylcholine | drug |
| acetyl-CoA | drug |
| ACN9 | gene |
| acute withdrawal | phenotype |
| ADCY1 | gene |
| ADCY3 | gene |
| ADD1 local | gene |
| ADH | gene |
| ADH1B | gene |
| ADH1B His48Arg local | variant |
| ADH4 | gene |
| age at first drink | phenotype |
| aggression | phenotype |
| alcohol | phenotype |
| alcohol abuse | phenotype |
| alcohol dependence | phenotype |
| alcohol-induced fatty liver syndrome local | phenotype |
| alcohol-induced flushing | phenotype |
| Alcohol-induced withdrawal seizures local | phenotype |
| alcohol intoxication | phenotype |
| alcoholism | phenotype |
| Alcohol-non-preferring rat strains local | cohort |
| alcohol preference | phenotype |
| Alcohol preference drinking local | phenotype |
| Alcohol-preferring mice local | cohort |
| Alcohol-preferring rat strains local | cohort |
| alcohol-related phenotypes | phenotype |
| Alcohol-related problem behavior local | phenotype |
| alcohol sensitivity | phenotype |
| alcohol tolerance | phenotype |
| Alcohol Use | phenotype |
| alcohol withdrawal | phenotype |
| ALDH1A1 | gene |
| ALDH2 | gene |
| ALDH2 Lys487 | variant |
| ALDH2 missense variant local | variant |
| amino acids | drug |
| amnesiac local | gene |
| antisocial alcoholism | phenotype |
| apoptosis | phenotype |
| arouser local | gene |
| Asian | cohort |
| Australian population | cohort |
| Australian twin-family samples local | cohort |
| Australian Twin Registry | cohort |
| AUTS2 | gene |
| Beadex local | gene |
| behavioral disorders | phenotype |
| behavioral responses to ethanol local | phenotype |
| brain | anatomy |
| breast cancer | phenotype |
| C12orf51 | gene |
| Caenorhabditis elegans | cohort |
| CCDC63 | gene |
| CCK2R local | gene |
| CDH13 | gene |
| cheapdate local | variant |
| chemical synapse local | anatomy |
| CHRM2 | gene |
| CHRNA5 | gene |
| chronic alcoholism | phenotype |
| chronic tolerance | phenotype |
| cocktail drinking local | phenotype |
| Collaborative Study on the Genetics of Alcoholism (COGA) | cohort |
| common variants | cohort |
| Co-morbid alcohol/nicotine dependence local | phenotype |
| COMT | gene |
| CRYAB | gene |
| CUX2 | gene |
| CYP2E1 | gene |
| DDX6 local | gene |
| depression | phenotype |
| development | phenotype |
| dopamine | drug |
| Drosophila melanogaster | cohort |
| DSCAML1 | gene |
| EDNRB local | gene |
| epidermal growth factor | drug |
| epilepsy | phenotype |
| ethanol consumption | phenotype |
| ethanol-induced behaviors | phenotype |
| ethanol-related behaviors | phenotype |
| European ancestry population-based samples local | cohort |
| fasciclin II local | gene |
| fatty acids | drug |
| fatty liver | phenotype |
| fetal alcohol syndrome | phenotype |
| fibrosis | phenotype |
| Focal gene local | gene |
| Framingham Offspring cohort local | cohort |
| Functional tolerance | phenotype |
| GABA | phenotype |
| Gabbr1 | gene |
| GABRA2 | gene |
| GAD1 | gene |
| genetically amenable model organisms local | cohort |
| genetic variants | cohort |
| German males local | cohort |
| glutamate | drug |
| GRM8 | gene |
| hangover local | gene |
| Hemorrhagic stroke | phenotype |
| High-dose sensitivity local | phenotype |
| Homer1 | gene |
| Htr1b | gene |
| human genome | cohort |
| Human GWASs local | cohort |
| humans | cohort |
| hyperactivity | phenotype |
| hypertension | phenotype |
| immobility | phenotype |
| inflammation | phenotype |
| Kcnj9 | gene |
| Kcnma1 | gene |
| ketone bodies | drug |
| KIAA1409 local | gene |
| Korean male drinkers local | cohort |
| Krebs cycle local | drug |
| liver cancer | phenotype |
| Liver cirrhosis | phenotype |
| Lmo3 | gene |
| loss of postural control local | phenotype |
| Loss of postural control local | phenotype |
| MAOA | gene |
| MARK1 local | gene |
| MC4R | gene |
| Me1 | gene |
| ME1 intronic SNPs local | variant |
| Men local | gene |
| mice | cohort |
| model organisms | cohort |
| motivational effects | phenotype |
| Motor vehicle accidents | phenotype |
| mouse genome | cohort |
| Mouth cancer local | phenotype |
| Mpdz | gene |
| MYL2 | gene |
| neurons | phenotype |
| neuropsychiatric disorders | phenotype |
| NFKB1 | gene |
| nicotine dependence | phenotype |
| NKAIN2 | gene |
| NPF local | drug |
| NPF local | gene |
| NPF receptor local | gene |
| NPY | gene |
| NPY2R | gene |
| nucleus accumbens | anatomy |
| OAS3 | gene |
| opioid | drug |
| OPRK1 | cohort |
| OPRM1 | cohort |
| Oropharyngeal cancer | phenotype |
| Pdyn | gene |
| PECR | gene |
| pentobarbital | drug |
| PkaR2 local | gene |
| prefrontal cortex | anatomy |
| PRKACA | gene |
| PRKCA | gene |
| Progression to alcoholism local | phenotype |
| PTPRE local | gene |
| rapid tolerance | phenotype |
| rare variant | cohort |
| rats | cohort |
| Recombinant inbred rat strains local | cohort |
| Relapse-like behavior | phenotype |
| reproductive cycle local | phenotype |
| resilience | phenotype |
| RNA interference local | drug |
| RPH3A local | gene |
| rs6943555 | variant |
| rutabaga local | gene |
| SAGE | cohort |
| sedation time local | phenotype |
| sedatives | drug |
| serotonin | drug |
| severity of alcohol dependence | phenotype |
| SLC6A4 | gene |
| slowpoke local | gene |
| SNP | cohort |
| SNP in DDX6 local | variant |
| SNP in DSCAML1 local | variant |
| SNP in KIAA1409 local | variant |
| SNP in MARK1 local | variant |
| SNP in PECR local | variant |
| steroids local | drug |
| TACR3 | gene |
| TIPARP local | gene |
| tolerance | phenotype |
| TUBB6 local | gene |
| upper gastrointestinal cancer | phenotype |
| USA | cohort |
| USH2A local | gene |
| ventral tegmental area | anatomy |
| violent behavior | phenotype |
| voluntary ethanol consumption | phenotype |
| vulnerability | phenotype |
| whole brain | anatomy |
| withdrawal | phenotype |
| Withdrawal from ethanol local | phenotype |
| Withdrawal from pentobarbital local | phenotype |
| Withdrawal from zolpidem local | phenotype |
| zolpidem | drug |
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In this knowledge base
External
| Title | Authors | Journal | Year | Link |
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| Change in brain molecular landscapes following electrical stimulation of the nucleus accumbens. | Cai C et al. | — | 2026 | → |
| Cosubstrates in azo dye decolorization: From conventional anaerobic systems to microbial fuel cells. | Nguyen TH et al. | — | 2025 | → |
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| Neuropharmacology of Alcohol Addiction with Special Emphasis on Proteomic Approaches for Identification of Novel Therapeutic Targets. | Ray SK et al. | — | 2023 | → |
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| A genetic screen for Drosophila social isolation mutants and analysis of sex pistol. | Eddison M | — | 2021 | → |
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| The genetics of alcohol dependence: Twin and SNP-based heritability, and genome-wide association study based on AUDIT scores. | Mbarek H et al. | — | 2015 | → |
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| Identification of a QTL in Mus musculus for alcohol preference, withdrawal, and Ap3m2 expression using integrative functional genomics and precision genetics. | Bubier JA et al. | — | 2014 | → |
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