An Overview of Genetic Influences in Alcoholism: 2007  (Slide 1).

                                                                                                           

I.  Introduction

 

    A.  Genetic influences for alcoholism (Alc): typical of many disorders.1

    (Slide 2).

 

            1.  People born with higher and lower risks.

 

            2.  A key is to discover the vulnerabilities; take steps to avoid problems.

 

    B.  This lecture reviews  (Slide 3).

                                                                                                                       

            1.  Data showing alcoholism is genetically influenced.

 

            2.  Genes affect intermediate characteristics.

 

            3.  The search for genes related to these characteristics.

 

            4.  The importance of the environment.

                                                                                                                                   

    C.  Examples of a similar complex genetic disorder  (Slide 4).

 

            1.  Heart attacks are genetically influenced.

 

            2.  Genes impact on the blood pressure in some families and blood fats in others.

 

            3.  Environmental – e.g. eating, smoking, and exercise affect risk.

 

            4.  Other examples include Type 2 diabetes and cancer.

 

II.  Genetic influences in Alc overall.

 

    A.  Data supporting genetic influences in Alc  (Slide 5).2

 

            1.  Children of alcoholics have 4x 8 risk.

 

            2.  Even if adopted away and raised by nonalcoholics.

 

            3.  Identical twin of alcoholic has higher risk than fraternal twin of alcoholic.

 

    B.  Twin and family studies indicate 60% genetics  (Slide 6).

 

            1.  Environment 40%.

 

            2.  Genes affect multiple characteristics.

 

            3.  Multiple genes affect each characteristic.

 

III.  The importance of intermediate phenotypes.1,3

 

    A.  Intermediate characteristics can be endophenotypes  (Slide 7).4

 

            1.  These are genetically influenced.

 

            2.  Observed before the disorder.

 

            3.  Predict the disorder.

 

    B.  Alcoholism-related endophenotypes include  (Slide 8):1,3

 

            1.  Metabolizing enzymes.

 

            2.  Level of response to alcohol (8risk for alcoholism alone).

 

            3.  Impulsivity (8risk for all substance disorders).

 

            4.  Some psychiatric disorders (e.g., bipolar and schizophrenia) (8risk for all).

 

    C.  Metabolism: most via 2 enzymes  (Slide 9).5,6

 

            1.  Aldehyde dehydrogenase (ALDH) mutation (ALDH2*2).

 

                a.  Produces high acetaldehyde (breakdown product).  This 68 intense response.

 

                b.  Seen only in Asians.

 

                c.  Homozygotes (both alleles).

 

                        1.  Very high acetaldehyde.

 

                        2.  Become sick when drink.

 

                        3.  Almost none become alcoholic.

 

                d.  Heterozygotes (only 1 allele mutation).

 

                        1.  Moderate 8 acetaldehyde.

 

                        2.  Modest 8response (e.g., facial flush).

 

                        3.  Not get sick.

 

4.      Moderate 9 Alc risk.

 

            2.  Alcohol dehydrogenase (ADH) mutations.

 

                a.  Only slight 8 acetaldehyde.

 

                b.  Seen in all racial groups.

 

                c.  " 9 Alc risk.      

 

IV.  Another endophenotype: Low level of response (LR) to alcohol  (Slide 10, 11).1,3

 

    A.  Lower LR 68 drinks/occasion  (Slide 12).

 

            1.  Because people drink for effect.

 

            2.  If they need more for effect.

 

            3.  May take more to get desired effect.

                                                                                               

            4.  LR measured 2 ways (Slide 13).

 

                        a.  Give alcohol and see effect at given blood alcohol level.

 

                        b.  Retrospective report of number of drinks needed for specific effects.

 

    B.   Children of alcoholics and other high risk groups have 9 LR (Slide 14).1,7

 

            1.  Slide compares 20-yr-old children of alcoholics (COA) (dark line) with controls.

 

            2.  BACs identical across groups (not shown).

 

            3.  Groups matched on usual quantity/frequency drinking.

 

            4.  COA low LR on: intoxication feelings; motor performance; hormone changes.

 

    C.  Low LR = 8 drinks for an effect on Self-Report questionnaire (SRE)  (Slide 15).8

 

            1.  1st column asks drinks for effect ~ 1st 5 times drink.

 

            2.  Score = sum of number of drinks divided by number of effects endorsed.

 

            3.  If score of 3.5+ = low response per drink.

 

    D.  Low LR also: Native Americans and Koreans.  High LR in Jews and flushing Asians               (Slide 16)8,9 – i.e., low LR in high risk groups and vice versa.

 

    E.  SRE-based low LR correlates with maximum drinks at age 12  (Slide 17).10

 

            1.  Also with problems.

 

            2.  Less well with frequency.

 

    F.   LR genetically influenced: portion of effect of genes ~ 60%  (Slide 18).

 

            1.  Parents - children - sibs correlate 0.2.

 

            2.  Unrelateds correlate 0.

 

            3.  ID twins more similar than fraternal twins (heritability = .60)

 

    G.  Low LR on alcohol challenge predicts outcome.  Data from:

 

            1.  All 4 follow-ups of alcohol challenge  (Slide 19).1,3

 

            2.  LR predicts even when controlling for drinking pattern when first tested (Slide 20).

 

            3.  SRE also predicts 5-yr outcome (Slide 21).11

 

                a.  Correlates with future drinking and problems.

 

                b.  Increases odds (OR) of heavy drinking and problems.

 

    H.  Thus, low LR is an endophenotype  (Slide 22, 23).

 

            1.  Genetic influence.

 

            2.  Seen before Alc.

 

            3.  Predicts Alc.

 

    I.  The search for genes for LR uses: (Slide 24).12

 

1.  Association - compares gene candidates in subjects with high vs. low LR.

 

            2.  Linkage - searches for chromosomal regions for low LR.

 

            3.  Animal models - using genes found in animals for LR as candidates in humans.

 

    J.  Example of 2 candidates (Slide 25).12,13

 

            1.  Serotonin transporter (5HTT).

 

                        a.  L form results in faster uptake of serotonin (5HT) from synapse.

 

                        b.  Thus, is less 5HT in synapse.

                        c.  Associated with increased drinking animals and humans.

 

            2.  GABA A alpha 6 receptor (GABRA6).

 

                        a.  Alc affects GABA.

 

                        b.  Proline/serine substitution in animal GABRA6 gene leads to lower LR.

 

                        c.  This usually related to higher drinking.

 

    K.  Example of association (candidate genes) (Slide 26).13

 

                1.  Follow up 90 men at age 35 with LR measured at age 20.

 

            2.  Each mutation related to LR and Alc.

 

            3.  If have both, all were very low LR and alcoholic.

 

    L.  Example of linkage (Slide 27).14,15

 

            1.  350 pairs of siblings with alcohol challenge.

 

            2.  800 markers across 23 chromosomes.

 

            3.  Computer indicates chromosome 10 area related to LR: LOD (odds score) = 3.0.

 

            4.  We now search for genes in that region (e.g., potassium channel-related KCNMA1).

 

    M.  Example of family extension for rare mutations (Slide 28).

 

            1.  Find mutation in alcohol challenge.

 

            2.  Then test relatives with SRE, genetic analyses.

 

            3.  See if same mutation relates to LR in relatives.

 

    N.  Other candidates for LR from animals include: (Slide 29).

 

            1.  Several GABA receptors.

 

            2.  Potassium channels (e.g., KCNMA1 on chromosome 10).

 

            3.  Serotonin-related (e.g., 5HTT).

 

            4.  Alcohol dehydrogenase (ADH) genes.

 

5. Etc.

 

    O.  Models being tested for how LR relates to environment (40% of risk) (Slide 30, 31).16,17

 

            1.  Peer drinking.

 

            2.  Drinking attitudes (Expectancies or EXPECT).

 

            3.  Coping mechanisms.

 

    P.  Model shows how LR mediates how Family History (FHalc) leads to alcoholism (ALC

            OUT) (Slide 32).

 

            1.  Also, how LR affects expectations to lead to ALC OUT.

 

            2.  Same model fit adults and teens.

 

V.  A third intermediate phenotype: impulsivity (Slide 33).18-20  Another relates to psychiatric

     disorders.21  These not covered here.

 

VI.  To conclude this lecture:

 

    A.  I’ve reviewed (Slide 34).

 

            1.  How genes affect Alc risk.

 

            2.  Role of intermediate characteristics (phenotypes).

 

            3.  Search for genes for the phenotypes.

 

            4.  Evaluation of the environment.

 

    B.  Sets stage for future (Slide 35).

 

            1.  Regarding prevention (Slide 36).

 

                        a.  ID person before alcoholism develops.

 

                        b.  Use models16,17 to find best environment aspects to change.

                                                                                                           

            2.  And for treatment (Slide 37).

 

                        a.  See if different genetic background results in different treatment response.

 

                        b.  Develop new treatments based on chemistry affected by genes.


                                                                         References

 

1.  Schuckit MA (2002) Vulnerability factors for alcoholism, in Neuropsychopharmacology: The Fifth Generation of Progress, Chapter 98, pp. 1399-1411, Kenneth Davis (ed.),  Lippincott Williams & Wilkins Co., Baltimore.                                                         

                                                                                                                                               

2.  Goldman D (1998) General and specific inheritance of substance abuse and alcoholism (commentary). Arch Gen Psychiatry 55:964-965.

 

3.  Schuckit MA (in press) An overview of genetic influences in alcoholism. Alcohol Clin Exp Res.

 

4.  Gottesman I, Gould TD (2003) The endophenotype concept in psychiatry: Etymology and strategic intentions. Am J Psychiatry 160:636-645.

 

5.  Li T-K (2000) Pharmacogenetics of responses to alcohol and genes that influence alcohol drinking. J Stud Alcohol 61:5-12.

 

6.  Duranceaux NCE, Schuckit MA, Eng MY, Robinson SK, Carr LG, Wall TL (2006) Associations of variations in alcohol dehydrogenase genes with the level of response to alcohol in Non-Asians.  Alcohol Clin Exp Res 30:1470-1478.

 

7.  Eng MY, Schuckit MA, Smith TL (2005) The level of response to alcohol in daughters of alcoholics and controls. Drug Alcohol Depend 79:83-93.

 

8.  Wall TL, Johnson ML, Horn SM, Carr LG, Smith TL, Schuckit MA (1999) Evaluation of te self-rating of the effects of alcohol form in Asian-Americans with aldehyde dehydrogenase polymorphisms. J Stud Alcohol 60:784-789.

 

9.  Ehlers CL, Garcia-Andrade C, Wall TL, Cloutier D, Phillips E (1999) Electroencephalographic responses to alcohol challenge in Native American Mission Indians.

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10.  Schuckit MA, Smith TL, Waylen A, Horwood J, Danko GP, Hibbeln JR, Davis JM, Pierson J (2006) An evaluation of the performance of the SRE questionnaire in 12- and 35-year old subjects. J Stud Alcohol 67:841-850.

 

11.  Schuckit MA, Smith TL, Hesselbrock V, Bucholz K, Kramer J, Kuperman S, Dietiker C, Brandon R, Chan C (in press) The ability of the Self-Report of the Effects of Alcohol (SRE) scale to predict alcohol-related outcomes five years later. J Stud Alcohol.

 

12.  Schuckit MA, Smith TL, Kalmijn J (2004) The search for genes contributing to the low level of response to alcohol: Patterns of findings across studies. 28:1449-1458.

 

13.  Hu X, Oroszi G, Chun J, Smith TL, Goldman D, Schuckit MA (2005) An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk factor.  Alcohol Clin Exp Res 29:8-16.

 

14.  Schuckit MA, Wilhelmsen K, Smith TL, Feiler HS, Lind P, Lange LA, Kalmijn J (2005) Autosomal linkage analysis for the level of response to alcohol.  Alcohol Clin Exp Res 29:1976-1982.

 

15.  Wilhelmsen KC, Schuckit M, Smith TL, Lee JV, Segall SK, Feiler HS, Kalmijn J (2003) The search for genes related to a low-level response to alcohol determined by alcohol challenges.  Alcohol Clin Exp Res 27:1041-1047.

 

16.  Schuckit MA, Smith TL, Danko GP, Anderson KG, Brown SA, Kuperman S, Kramer J, Hesselbrock V, Bucholz K (2005) Evaluation of a level of response to alcohol-based structural equation model in adolescents. J Stud Alcohol 66:174-184.

 

17.  Schuckit MA, Smith TL, Anderson KG, Brown SA (2004) Testing the level of response to alcohol: social information processing model of alcoholism risk – a 20-year prospective study.  Alcohol Clin Exp Res 28:1881-1889.

 

18.  Schuckit MA, Smith TL (2006) The relationship of behavioral undercontrol to alcoholism in higher-functioning adults.  Drug Alcohol Rev 25:393-402.

 

19.  Dick DM, Bierut L, Hinrichs A, Fox L, Bucholz KK, Framer J, Kuperman S, Hesselbrock V, Schuckit M, Almasy L, Xuei X, Edenberg HJ, Foroud T (2006) The role of GABRA2 in risk for conduct disorder and alcohol and drug dependence across developmental stages.  Behav Genet 36:577-590.

 

20.  Schuckit MA, Smith TL (2006) An evaluation of the level of response to alcohol, externalizing symptoms, and depressive symptoms as predictors of alcoholism.  J Stud alcohol 67:215-227.

 

21.  Schuckit MA, Smith TL, Chacko Y (2006) Evaluation of a depression-related model of alcohol problems in 430 probands from the San Diego prospective study.  Drug Alcohol Depend 36:577-590.