Alcoholism and Our Genes

1. Alcoholism and Our Genes 0 Scientific American Current Issues in Biology Volume 5

2. Alcoholism and Our Genes • Concept Review • Twin and adoption studies show that genetics account for about 50% of an individual’s risk of alcoholism. • Alcoholism is genetically complex: multiple genes interact with one another and with the environment to affect the risk of alcohol dependence. • Distinguishing genetic and environmental influences is challenging.

3. Alcoholism and Our Genes • Concept Review • Variants of any particular gene contribute modestly to the risk of alcoholism, increasing risk no more than 20% to 40%. • Genes influence alcoholism risk by affecting physiological processes that in turn respond to an individual’s experiences. • Understanding the genes and physiological processes that contribute to alcohol dependency will improve prevention and treatment strategies.

4. Alcoholism and Our Genes • Concept Review • Dependency on any substance occurs when an individual shows at least three of the following symptoms over a year or more: • tolerance for large doses of the substance • withdrawal reactions • loss of control over the substance’s use • efforts to stop or cut down use of the substance • a great deal of time spent on use of the substance • giving up other activities to use the substance • continued substance use despite physical and psychological problems

5. Alcoholism and Our Genes • Concept Review • Endophenotypes are more useful than behavioral traits in the search for alcoholism risk genes. • An endophenotype is a biochemical or physiologicaltrait. • Endophenotypes often reflect the effects of individual genes more directly than complex behavioral traits.

6. Alcoholism and Our Genes • Concept Review • Endophenotypes useful in probing the effects of alcoholism risk genes include • Enzyme activity • Levels and types of receptor molecules, • Brainactivity (measured using electroencephalograms, or EEGs).

7. Alcoholism and Our Genes • Concept Review • EEGs differ characteristically in the brains of alcoholics and non-alcoholics. • EEGs can distinguish between the firing of excitatory and inhibitory neurons in brain regions that control behaviors. • Imbalances between excitation and inhibition can produce impulsivity, depression, anxiety, and susceptibility to substance abuse, including alcohol.

8. Alcoholism and Our Genes • Concept Review • The brains of many alcoholics show an imbalance in favor of excitatory neuron activity over inhibitory neuron activity. • This imbalance is known as disinhibition. • Disinhibition reflects a decrease in inhibitory neuron activity in brain regions responsible for judgment and decision-making.

9. Alcoholism and Our Genes • Concept Review • Disinhibition appears to be heritable, as it is seen frequently in the children of alcoholics. • The observation of a heritable endophenotype associated with alcoholism spurred the search for genetic risk factors. • So far, these studies have uncovered roughly one dozen gene variants that influence the risk of alcoholism.

10. Alcoholism and Our Genes • Concept Review • The Collaborative Study on the Genetics of Alcoholism (COGA) identified families deeply affected by alcoholism. • Alcoholics and family members provided DNA samples and personal information relevant to alcoholism.

11. Alcoholism and Our Genes • Concept Review • It is important to understand that there are no genes that “cause” alcoholism. • Instead, there are naturally occurring variants of genes. • Some variants reduce the risk of alcoholism, while others increase it.

12. Alcoholism and Our Genes • Concept Review Mapping Alcoholism-Associated Gene Variants

13. Alcohol is broken down in the following way: • alcohol acetaldehyde • dehydrogenase reductase • alcohol acetaldehyde acetic acid • (ethanol) • Alcohol and acetaldehyde are toxic. • Acetic acid is used by cells for energy. • Alcohol dehydrogenase and acetaldehyde reductase are enzymes that catalyze the reactions. Alcoholism and Our Genes • Concept Review

14. Alcoholism and Our Genes • Concept Review • alcohol acetaldehyde • dehydrogenase reductase • alcohol acetaldehyde acetic acid • (ethanol) • The first known genetic variant influencing the risk of alcoholism was discovered in the aldehydedehydrogenase gene, ALDH1. • An ALDH1 variant common in East Asian populations produces an alcohol dehydrogenase enzyme with reduced activity. • Individuals who carry this variant accumulate high levels of acetaldehyde after drinking.

15. Alcoholism and Our Genes • Concept Review • Acetaldehyde produces symptoms that include hot, flushed skin, heart palpitations, dizziness, and weakness. • For these reasons, people with the ALDH1 gene variant experience less pleasure while drinking. • Therefore, the ALDH1 gene variant protects against alcoholism.

16. Alcoholism and Our Genes • Concept Review • alcohol acetaldehyde • dehydrogenase reductase • alcohol acetaldehyde acetic acid • (ethanol) • A group of genes (ADHs) produces the enzyme alcohol dehydrogenase. • Variants in the ADH1 and ADH4 genes increase the risk of alcoholism.

17. Alcoholism and Our Genes • Concept Review • Brain neurotransmitters are molecules released by one neuron that control the activity of another neuron. • Neurotransmitters bind to receptor molecules on the surface of responsive cells. • Variants in genes that influence neurotransmitter receptors influence susceptibility to alcoholism. • The receptors important in alcoholism control excitation orinhibition of the brain’s decision-making centers.

18. Alcoholism and Our Genes • Concept Review • The GABRA2 gene produces a receptor for a neurotransmitter that inhibits the activation of neurons. • A GABRA2 gene variant that reduces the amount of receptor leads to disinhibition by tipping the balance of brain activity to overstimulation. • This GABRA2 gene variant is a genetic risk factor in alcoholism and impulsivity.

19. Alcoholism and Our Genes • Concept Review • The CHRM2 gene produces a receptor for a neurotransmitter that excites neurons. • A CHRM2 gene variant that reduces the amount of receptor weakens brain activity involved in decision making. • This CHRM2 gene variant is a genetic risk factor in alcoholism and depression.

20. Alcoholism and Our Genes • Concept Review • Gene variants that influence the risk of alcoholism also affect behavior in children: • GABRA2 risk-associated variants increase the incidence of conduct disorders. • CHRM2 risk-associated variants increase the incidence of depression. • These findings show there are differentpathways and physiological mechanisms to alcoholism.

21. Alcoholism and Our Genes • Concept Review • As more alcoholism-associated genes are discovered, they will be used to determine who is at risk and how to tailor treatments to help those with alcohol problems. • Findings about alcoholism-associated genes may help in the prevention and treatment of other types of substance abuse.

22. Alcoholism and Our Genes • Testing Your Comprehension Genetic factors contribute about _____ to an individual’s risk of alcoholism. a) 5% b) 20% c) 50% d) 90%

23. Alcoholism and Our Genes • Testing Your Comprehension Genetic factors contribute about _____ to an individual’s risk of alcoholism. c) 50%

24. Alcoholism and Our Genes • Testing Your Comprehension Disorders caused by multiple genes that interact with each other and with an individual’s environment are: a) Mendelian diseases. b) genetically complex disorders. c) endophenotypes. d) disinhibition disorders.

25. Alcoholism and Our Genes • Testing Your Comprehension Disorders caused by multiple genes that interact with each other and with an individual’s environment are: b) genetically complex disorders.

26. Alcoholism and Our Genes • Testing Your Comprehension Endophenotypes are useful in searches for alcoholism-associated gene variants because they: a) reflect gene activity more directly than behavioral phenotypes. b) are internal rather than external phenotypes. c) are the DNA sequences that cause alcoholism. d) exist on the same chromosomes as alcoholism-associated gene variants.

27. Alcoholism and Our Genes • Testing Your Comprehension Endophenotypes are useful in searches for alcoholism-associated gene variants because they: a) reflect gene activity more directly than behavioral phenotypes.

28. Alcoholism and Our Genes • Testing Your Comprehension In the brain’s decision-making centers, alcoholics often show: a) no nerve cell activity. b) nerve cells that are active only when alcohol levels are high. c) a shift in the balance of inhibitory and excitatory inputs in favor of excitation. d) a shift in the balance of inhibitory and excitatory inputs in favor of inhibition.

29. Alcoholism and Our Genes • Testing Your Comprehension In the brain’s decision-making centers, alcoholics often show: c) a shift in the balance of inhibitory and excitatory inputs in favor of excitation.

30. Alcoholism and Our Genes • Testing Your Comprehension One gene variant that protects against alcoholism does so by producing: a) a low-activity form of aldehyde dehydrogenase. b) a high-activity form of alcohol dehydrogenase. c) low levels of a receptor (GABA2) that inhibits neurons. d) high levels of a receptor (CHRM2) that leads to depression.

31. Alcoholism and Our Genes • Testing Your Comprehension One gene variant that protects against alcoholism does so by producing: a) a low-activity form of aldehyde dehydrogenase.

32. StronglyA B C D E Strongly DisagreeAgree Alcoholism and Our Genes • Biology and Society Since genetic factors play such a large role in alcoholism, alcoholics cannot be held accountable for their drinking.

33. Alcoholism and Our Genes • Thinking About Science The CHRM2 gene produces a receptor for a stimulatory neurotransmitter. Some CHRM2 gene variants increase the risk of alcoholism. Which of the following is a plausible hypothesis for how CHRM2 variants increase the risk of alcoholism? a) They produce receptors that cannot bind to the neurotransmitter. b) They produce half the normal amount of receptor. c) They produce receptors that are activated at unusually low levels of neurotransmitter. d) They produce unstable receptors that are rapidly degraded.

34. Alcoholism and Our Genes • Thinking About Science The CHRM2 gene produces a receptor for a stimulatory neurotransmitter and some CHRM2 gene variants increase the risk of alcoholism. Which of the following is a plausible hypothesis for how CHRM2 variants increase the risk of alcoholism? c) They produce receptors that are activated at unusually low levels of neurotransmitter.

35. Alcoholism and Our Genes • Interpreting Charts and Graphs Which of the following conclusions is supported by the graph? a) Children of alcoholics are at risk of becomingalcoholics as adults. b) Alcoholism is caused by an altered response to stimulation. c) Alcoholics show a delayed response to stimulation. d) Alcoholics show a reduced response to stimulation.

36. Alcoholism and Our Genes • Interpreting Charts and Graphs Which of the following conclusions is supported by the graph? d) Alcoholics show a reduced response to stimulation.