Slide 1 The Level of Response to Alcohol and the Predisposition Toward Alcoholism


                                                            Marc A. Schuckit, M.D.


                                       Prepared for the Alcohol Medical Scholars Program


                                                                   January, 2001



I.   Introduction


A.  Alcohol dependence is genetically-influenced.


      1.  Runs in families;


      2.  Similarity higher in identical vs. fraternal twins;


      3.  Adopted-away COAs still have 4X risk;


      4.  Conclusions supported by animal studies (Slide 2).1


B.  All genetic influences together explain 60% of the risk; 40% environment (Slide 3).2


C.  Genetic risk represents different families of influences1 including:


      1.   alcohol-metabolizing enzymes;


      2.   disinhibition and impulsivity;


      3.   independent psychiatric disorders (Slide 4).


D.  Additional set of genes contributes to low level of response (LR) to alcohol.3 Can  measure by:


      1.   giving alcohol and observing response,


      2.   retrospective history of the number of drinks required for various effects (Slide 5).


II.   LR as a Marker for the Alcoholism Risk.


A.  Gold standard for LR requires acute administration three+ drinks.


      1.  Original studies matched COAs (at high risk) and controls at approximately age 20

      on smoking, drug use, quantity and frequency of drinking, and percent body fat.3


      2.  Family-history-positive (FHP) and family-history-negative (FHN) groups showed                       identical BACs (Slide 6).


B.  About 40% of the COAs, vs. <10% of controls showed a low response to alcohol. 


      1.  Slide 7 shows changes in cortisol following alcohol.


      2.  Similar data reported on other hormones, electrophysiological measures, the        amounts of body sway, and subjective feelings of intoxication.


C.  LR relatively reliable as shown in Slide 8.


D.  Data from both animals and humans demonstrate that LR is genetically influenced (Slide 9).


      1.  Higher correlations for the indirect measure of alcohol response among first-

      degree relatives than second-degree relatives or unrelated individuals (Slide 10).4


       2.  Similar results if compare correlations in pairs of siblings vs. unrelated                         individuals (Slide 11).5


E.  All four follow-ups show low LR associated with high risk for alcohol problems.


      1.  Slide 12 shows the 99.3% follow-up rate of 453 sons of alcoholics and controls.6


      2.  Slide 13 shows men who went on to abuse or dependence by age 30 had lower               LRs at age 20.


      3.  Additional follow-up studies agree.7,8


F.  LR not related to other markers of the alcoholism risk (Slide 14).9


G.  Data also come from paper-and-pencil test, the Self-Rating of the Effects of Alcohol scale (the SRE).


      1.  Can be used when alcohol challenges inappropriate (Slide 15).


      2.  Simple, easy: asks to report number of drinks for each of four effects at three                  different points.  Score is average drinks per effect (Slide 16).10


      3.  Slide 17: high retest reliability; correlates well with alcohol challenge.


III.   A Search is Being Carried Out for Genes that Contribute to a Low LR, and thus, to the Alcoholism Risk.


A.  Candidate gene study on 25 high LR and 25 low LR men identified the ll genotype of the serotonin transporter and a proline/serine insertion for the GABAα6 (Slide 18).11


B.  Slides 19 and 20 show two promising areas on chromosome 2 and chromosome 21 for SRE scores on 103 affected sib-pairs (both with low LR scores).4


C.  Sib-pair, genome scan alcohol challenge being done as collaboration between UCSD and the Gallo Institute at UCSD.


      1.  Four populations of sibling pairs being tested (Slide 21).


      2.  Subjects:


a.  old enough to drink but not have passed through the major age of risk for            alcoholism,


b.  non-Asians (to control for alcohol-metabolizing enzymes),


c.   without high levels of impulsivity or independent psychiatric disorders, etc. (Slide 22).


      3.  3+ drinks over 10 min. for both members of a sibling pair plus blood for genome           scans.


      4.   Bloods and SRE from at least one of the parents (Slide 23).


IV.   Also Identify: Environmental Influences for Alcoholism.


A.  Both genes and environment explain the alcoholism risk (Slide 24).


B.  Importance of domains of life functioning being tested in the 15-and 20-year follow-ups.3, 6   A path analysis with 453 men shows:


      1.  Low response to alcohol predicts alcoholism (Slide 25).


      2.  Explains much of relationship between FH and alcoholism (Slide 26).


      3.  Also measuring impact of six domains of life functioning (Slide 27).


      4.  The personality characteristic of behavioral undercontrol added little in the context         of FH of alcoholism, a low level of response, and alcoholic outcome (Slide 28).


      5.  When alcohol expectancies added, both behavioral undercontrol and alcohol                  expectancies contributed to risk (Slide 29).


      6.  Slide 30 demonstrates how each domain can be evaluated in the context of all       

      others in a path analysis.


V.   The study now turns to offspring of original subjects.


A.  The study of the original 453 sons of alcoholics and controls now focuses on the original subjects, their spouses, and their offspring (Slide 31).


B.  Prospective tests involve the attributes on Slide 32.


C.  Studies hope to help individuals carrying a low LR to become resilient toward alcoholism (Slide 33).


D.  Data also impact on treatment (Slide 34).





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


2. Prescott CA, Kendler KS: Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins.  Am J Psychiatry 1999; 156:34-40.


3. Schuckit MA, Smith TL: The relationships of a family history of alcohol dependence, a low level of response to alcohol and six domains of life functioning to the development of alcohol use disorders. J Stud Alcohol 2000; 61:827-835.


4. Schuckit MA, Edenberg HJ, Kalmijn J, Flury L, Smith TL, Reich T, Bierut L, Goate A, Foroud T: A genome-wide search for genes relating to a low level of response to alcohol. Alcohol Clin Exp Res 2001; 25:323-329.


5. Schuckit MA, Smith TL, Kalmijn J, Wilhelmsen K: Heritability of the level of response to alcohol in a sib-pair study. Alcohol Clin Exp Res, in press.


6. Schuckit MA, Smith TL: An 8-year follow-up of 450 sons of alcoholic and control subjects. Arch Gen Psychiatry 1996; 53:202-210.


7. Volavka J, Czobor P, Goodwin DW, Gabrielli WF Jr, Penick EC, Mednick SA, Jensen P, Knop J, Schulsinger F: The electroencephalogram after alcohol administration in high-risk men and the development of alcohol use disorders 10 years later: Preliminary findings. Arch Gen Psychiatry 1996; 53:258-263.


8. Heath AC, Madden PA, Bucholz KK, Dinwiddie SH, Slutske WS, Bierut LJ, Rohrbaugh JW, Statham DJ, Dunne MP, Whitfield JB, Martin NG: Genetic differences in alcohol sensitivity and the inheritance of alcoholism risk. Psychol Med 1999; 19:1069-1081.


9. Schuckit MA, Smith TL, Kalmijn JA, Raimo EB: The relationship of a low response to alcohol to ERP and personality measures. Alcohol Clin Exp Res 2000; 24:27A.


10. Schuckit MA, Tipp JE, Smith TL, Wiesbeck GA, Kalmijn J: The relationship between the self-rating of the effects of alcohol and alcohol challenge results in ninety-eight young men. J Stud Alcohol 1997; 58:397-404.


11. Schuckit MA, Mazzanti C, Smith TL, Ahmed U, Radel M, Iwata N, Goldman D: Selective genotyping for the role of 5-HT2A , 5-HT2C , and GABAα6 receptors and the serotonin transporter in the level of response to alcohol: A pilot study.  Biol Psychiatry 1999; 45:647-651.