1. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Lectures by Greg Podgorski, Utah State University Alcoholism and Our Genes Scientific American Current Issues in Biology Volume 5

2. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes 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. Concept Review

3. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes 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. Concept Review

4. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes 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 Concept Review

5. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes Endophenotypes are more useful than behavioral traits in the search for alcoholism risk genes. An endophenotype is a biochemical or physiological trait. Endophenotypes often reflect the effects of individual genes more directly than complex behavioral traits. Concept Review

6. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes Endophenotypes useful in probing the effects of alcoholism risk genes include Enzyme activity Levels and types of receptor molecules, Brain activity (measured using electroencephalograms, or EEGs). Concept Review

7. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes 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. Concept Review

8. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes 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. Concept Review

9. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes 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. Concept Review

10. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes 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. Concept Review

11. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes 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. Concept Review

12. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes Concept Review Mapping Alcoholism-Associated Gene Variants

13. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes Concept Review 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.

14. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes alcohol acetaldehyde dehydrogenase reductase alcohol acetaldehyde acetic acid (ethanol) The first known genetic variant influencing the risk of alcoholism was discovered in the aldehyde dehydrogenase 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. Concept Review

15. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes 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. Concept Review

16. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes 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. Concept Review

17. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes 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 or inhibition of the brain’s decision-making centers. Concept Review

18. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes 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. Concept Review

19. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes 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. Concept Review

20. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes 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 different pathways and physiological mechanisms to alcoholism. Concept Review

21. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes 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. Concept Review

22. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings 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. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings Alcoholism and Our Genes Testing Your Comprehension Genetic factors contribute about _____ to an individual’s risk of alcoholism. c) 50%

24. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings 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. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings 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. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings 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. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings 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. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings 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. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings 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. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings 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 (GABA 2 ) that inhibits neurons. d) high levels of a receptor (CHRM2) that leads to depression.

31. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings 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. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings 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. Disagree Agree Strongly A B C D E Strongly

33. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings 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. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings 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. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings 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 becoming alcoholics 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. Copyright © 2009 Pearson Education, Inc. publishing as Benjamin Cummings 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.