Obesity, eating and drinking


Genes and alcoholism

1/6/04. By Caroline Cross

Understanding how genes affect vulnerability to alcoholism is key to reducing the disease's death toll. Researchers are beginning to find the genes that drive us to drink, as Caroline Cross reports.

Many of us drink alcohol because it helps us relax. And if we have a few too many, we suffer nothing more than a sore head and perhaps a dented ego. But for some, drinking alcohol becomes an addiction that can prove fatal. Three out of every hundred people die from alcohol-related causes and both our genes and environment play a part.

"Identifying genes, in which variations influence risk for alcoholism and related traits, will greatly increase our understanding of this devastating disease, and we hope will provide clues that lead to more effective therapies," says Howard Edenberg, Professor of Medical and Molecular Genetics at the Indiana School of Medicine, USA.

Alcohol dependence is a complex disease that affects more than 76 million people worldwide. Dr David Ball, a Senior Lecturer and honorary Consultant Psychiatrist at the Institute of Psychiatry in London, treats people who have been drinking 30 or more units of alcohol a day for many weeks. Most of them will complete their detoxification programme, he says, but using currently available treatments, only two out of ten will still be sober a year later. So, understanding what causes ongoing vulnerability is vital.

When you stop drinking, you metabolise about 1 unit of alcohol per hour. So for someone physically dependent on alcohol, after 24 hours, most of the alcohol is out of the system. "But, unfortunately, the brain can't readjust that quickly to not having alcohol in the system, and that's why you get withdrawal symptoms," explains Dr Ball.

Scientists have known for more than 30 years that alcoholism can run in families. Adopted children born to alcoholic parents are four times more likely to become alcoholic than those born to non-alcoholic parents, even when their adoptive parents don't drink. And by studying the inheritance of alcoholic traits in identical and non-identical twins, scientists have found genetic risk factors for many features of the disease, including the age when people begin to drink heavily and how much they will drink.

But proving a genetic link and distilling out the genes involved is not easy. Alcoholism is a complex disease that is influenced by many different factors.

"Rather than there being one gene that makes somebody alcohol dependent, there are probably multiple genes interacting, with each other and environmental factors," says Dr Ball.

Mary-Anne Enoch, a research physician at the National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA, is studying genetic and environmental risk factors in different population groups. "One of the strengths of our lab is that we have many large, very different, well-characterised datasets that include thousands of DNA samples," she says.

Dr Enoch has found that some members of a native American tribe who are exposed to environmental stresses such as poverty, trauma and deprivation, express a genotype - COMT Met158Met - that protects against alcoholism. And yet the same genotype, when expressed in European men is associated with late-onset alcoholism and increased alcohol consumption. Dr Enoch has shown that the Met158Met genotype is associated with increased anxiety and reserve. She speculates that Europeans who have this type of personality may drink to relieve anxiety but, in native Americans, a more cautious temperament may protect against such drinking excesses.

Alcoholism is often associated with other disorders such as nicotine addiction, depression and anti-social personality disorders and there may be a cocktail of susceptibility genes common to all of them.

"What is becoming clear is that the biology of alcohol addiction has many similarities to cocaine addiction. It is not substance specific," explains Dr Anne Lingford-Hughes, a Senior Lecturer in Biological Psychiatry and Addiction at Bristol University.

Variations in genes encoding a range of brain messenger proteins - neurotransmitters - may contribute to susceptibility to alcoholism and other addictions and personality disorders. Proteins in the dopamine and serotonin neurotransmission pathways, involved in pleasure seeking and reward, are probably involved. A team at the National Institute on Alcohol Abuse and alcoholism has recently identified a variant of a serotonin transporter gene (5HTT) that is associated with binge drinking in young people. And single base variations (single nucleotide polymorphisms) in genes encoding dopamine receptors have been identified that affect a person's ability to respond to this so-called pleasure chemical.

However, a large scale linkage study of American families with a history of alcoholism (USA Collaborative Study on the Genetics of Alcoholism – COGA) failed to show a link between regions of DNA encoding dopamine receptors and susceptibility to alcoholism. Instead they showed a link between alcoholism and areas of DNA on chromosomes 1, 2 and 7.

In conjunction with human genome sequence data, researchers can use this evidence to close in on suspect genes. As Howard Edenberg, one of COGA's principal investigators explains:

"Our strategy has been to localise regions for which there is evidence of linkage to alcohol dependence or a related phenotype, then select candidate genes within the region and analyse multiple SNPs (single nucleotide polymorphisms) within each to look for linkage disequilibrium."

This search for gene variants that are found more frequently in people with alcoholism has led researchers to genes coding for the body's major calming chemical - the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) - and its receptors.

"GABA receptor genes are found in clusters throughout the genome and most of them have been implicated in susceptibility to alcohol dependence by different studies," explained Dr Ball.

Alcohol and benzodiazepine drugs such as valium act on GABA receptors. So, when you drink alcohol or take valium, it stimulates the GABA system and acts as a sedative and relaxant. Anne Lingford-Hughes has used brain imaging techniques to look at the number of GABA receptors in the brains of alcoholics and found fewer receptors in the frontal lobes of their brains compared to non-alcoholics.

"We have shown that there is a reduced number of GABA receptors in areas of the brain that we know from neuropsychology tend to be impaired in alcoholics," she says, although it is still unclear whether the deficiency is a cause of their drinking or a result of it.

To date, the only genes that are known unequivocally to affect drinking habits are those that code for proteins involved in alcohol metabolism. Forty per cent of Asians have gene variants that code for inactive forms of alcohol dehydrogenase (ADH) and/or aldehyde dehydrogenase (ALDH2). Consequently, they cannot break down alcohol efficiently, and those with the ALDH2 deficit turn red and feel sick as soon as they taste the stuff. Similar symptoms befall a recovering alcoholic who succumbs to a tipple when taking the drug disulfiram. The drug blocks activity of the ALDH2 protein and helps prevent relapse.

Geneticists hope that before long, alcoholism will yield up more of its genetic secrets. This should lead to new therapies that target specific genes or their products, and possibly treatments tailored to individual genetic backgrounds.

Further reading

Edenberg HJ et al. Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations. Am J Hum Genet 2004 74: 705-14. Full text

Herman AI et al. Serotonin transporter promoter polymorphism and differences in alcohol consumption: behaviour in a college student population. Alcohol Alcohol 2003 38: 446-9. Abstract ; Full text

Rice JP et al. (2003) Alcoholism: the USA Collaborative study on the genetics of alcoholism (COGA). Encyclopedia of the human genome. Macmillan, Nature Publishing Group.

Tyndale RF. Genetics of alcohol and tobacco use in humans. Ann Med 2003 35: 94-121. Abstract

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