SYLLABUS MATERIAL AND OUTLINE
Genetics of Alcoholism Susceptibility and Protection
Marc A. Schuckit and John Crabbe
For presentation at RSA, 2000
I. Introduction.
S1 A. Goals: The lecture demonstrates the way several different
genetically influenced characteristics increase and decrease the alcoholism
risk. The paradigm is typical of many complex genetic disorders in
medicine and psychology. References include Hyman, 1999; Malhotra and
Goldman, 1999; Baumeister, 1999).
S2 Genetic influences contribute to a variety of characteristics. These
include the choice of drinking, sensitivity to reinforcement, vulnerability
to dependence (the main topic of this lecture), and a differential risk for
different problems (levels of intoxication, a differential vulnerability
toward liver disease, Wernicke-Korsakoff's Syndrome, withdrawal, etc.).
The slide describes these characteristics, highlighting the focus on
dependence. Relevant references include McGue et al., 1999; Schuckit, in
press; Goldman, 1999).
S3 C. It is worthwhile to briefly describe what is meant by abuse or
dependence. The slide briefly outlines the criteria for these two DSM-IV
disorders. A reference is the American Psychiatric Assn., The Fourth
Diagnostic and Statistical Manual, 1994.
II. Alcoholism is genetically influenced and is typical of complex genetic disorders.
S4 A. The overall genetic influence in both men and women is supported
by family, twin, and adoption studies. The slide presents the familial
nature (four-fold increased risk in first degree relatives), twin studies (with
monozygotic (MZ) twins demonstrating a further two-fold higher
concordance over dizygotic (DZ) twins), and adoption studies where the
increased risk remains in adopted-away children of alcoholics. References
include Prescott and Kendler, 1999; Schuckit, in press; Goodwin et al.,
1974).
B. Animal studies support genetic factors influencing a wide range of
related phenomena such as levels of intoxication, acute tolerance, the
tendency to drink, vulnerability to withdrawal, seizures, etc. Genetic
factors in mice, rats, and primates also influence heavy repeated intake
despite consequences. This is covered on the same slide. Useful references
include Li, 2000; Crabbe, 1999; Schuckit, in press, Prescott and Kendler,
1999).
S5 C. The complex nature of genetic influences in alcoholism reflects the
fact that at least 40% of the risk is explained by environment; many of the
genetically influenced characteristics are controlled by multiple genes; and
there are multiple avenues of increased and decreased risk. The remainder
of the lecture discusses many of these potential avenues that impact on the
risk. The slide describes the importance of environment, the polygenic
nature of the disorder, and the fact there are multiple avenues in or away
from alcohol problems.
S6 D. Among the characteristics that impact on the alcoholism risk and
which will be discussed in this lecture are some risk-related genes (e.g.,
ALDH2-2) and broader phenotypes which reflect, at least in part, other
risk-related genes. Examples include alcohol metabolizing enzymes;
disinhibition (or impulsiveness/ASPD/low P3 amplitude/etc.); a low level
of intensity of response to alcohol; independent psychiatric disorders such
as manic depressive disease and schizophrenia; the opioid system;
functioning of many different neurotransmitter systems, etc. The slide
introduces these topics which will then become the focus of a discussion
in themselves in the following sections. Useful references include
Schuckit, in press; Goldman, 1999; Hyman, 1999.
III. The best documented set of genetic influences in alcoholism relates to
alcohol metabolizing enzymes. These are generally protective of the
alcoholism risk. References for the following data include Li, 2000; Wall
et al., 1999; Higuchi et al., 1995; Neumark et al., 1998; Whitfield et al.,
1998).
S7 A. There are multiple pathways for metabolizing alcohol (e.g.,
nonenzymatic avenues, the microsomal ethanol oxidizing system or
MEOS, and catalase), but most of the data relate to alcohol and aldehyde
dehydrogenases (ADH and ALDH). The slide shows the metabolism of
alcohol by enzymes controlled by alleles of ADH and ALDH,
emphasizing the importance of the production of acetaldehyde. The same
slide highlights the relevant alleles associated with high acetaldehyde
levels.
B. If alcohol is metabolized more rapidly, or (probably even more
importantly) if the first breakdown product (acetaldehyde) is broken down
more slowly, there is both an increased intensification of response to
alcohol (as described by Wall et al., 1999) and a potentially adverse
reaction to alcohol. This doesn't require a slide by itself, and the prior slide
should remain on.
C. There are a number of important alleles that produce different forms of
ALDH, with ALDH2-2 having a major impact on the alcoholism risk. The
importance of homozygotes versus heterozygotes should be presented; the
associated risks for alcoholism discussed; along with the increased risk for
potential organ damage in heterozygotes who choose to drink heavily. The
impact of environment in moderating the consequences of the ALDHrelated alleles should also be discussed. The same slide demonstrates the
different alleles and the different forms of ALDH.
D. A similar case can be made regarding alcohol dehydrogenase
isoenzyme forms, especially those that relate to ADH2-2, 2-3, and 3-1.
The impact that these relevant alleles might have on Caucasians as well
should be mentioned.
E. A summary of the importance of alcohol-metabolizing enzymes should
be presented. Emphasis can be placed on the fact that this is one genetic
road of influence relating to alcoholism, and that this appears to be
relatively independent of the other roads discussed in other sections of this
lecture. This is a good example of how genes and environment and
interact (e.g., with heterozygotes for ALDH).
IV. An increased genetic risk for alcoholism through disinhibition and/or
impulsivity.
S8 A. Neuronal disinhibition and/or high levels of impulsivity form the
core of this possible domain and might relate to a number of additional
overlapping phenomena. These include the low amplitude of the P3 wave
of the event related potential (ERP), the antisocial personality disorder
(ASPD)/conduct disorder (CD), as well as Type II and Type B alcoholism.
A slide presents this group of characteristics. These phenotypes might
relate to several physiological phenomena. Useful references for this
section include Begleiter and Porjesz, 1999; Bauer and Hesselbrock, 1999;
Hill et al., 1999; Ehlers et al., 1998; Cloninger et al., 1999; Disney et al.,
1999.
S9 B. There are a number of potentially important additional
characteristics that might relate to the disinhibition domain. These might
include genetic material that impacts on low levels of serotonin (5-HT)
functioning, and, perhaps, the D2 dopamine receptor (DRD2) gene
(although the latter is more controversial. The student should be reminded
that these additional characteristics might operate independently of
disinhibition, but for heuristic purposes they are being discussed together.
Markers related to the disinhibition domain, however, appears to be
independent of alcohol-metabolizing enzymes and the intensity of
response to alcohol (the next topic). Useful references include Hill, 2000;
Lappalainen et al., 1998; Edenberg et al., 1999.
C. The potential mechanisms of the increase in risk might occur via
impulsivity and problems learning from mistakes, as well as difficulty in
modifying behavior when living in a heavy drinking environment. It is
also possible these people use alcohol to decrease symptoms related to
neuronal disinhibition.
D. Data support the importance of genetic influences in these
characteristics. A brief description of genetic influences in ASPD and the
P3 amplitude should be reviewed. A slide outlines these basic findings.
E. There are data that these characteristics are involved with an increased
alcoholism risk. There are also data that children of alcoholics are more
likely than controls to have some of these characteristics. No specific slide
is needed for this point as the prior slide can remain on the screen.
V. A low level of response to alcohol as it relates to the alcoholism risk.
S10 A. A low response to alcohol can be documented as less change in
body functioning at a given blood alcohol level, or a report of the need for
a greater number of drinks to have a particular effect early in the drinking
career. A low response can also be bred into animals. Useful references for
this section include Schuckit and Smith, submitted; Volavka et al., 1996;
Health et al., 1999; Wall et al., 1999; Tecott and Heberlein, 1998; Erblich
and Earleywine, 1999; Thiele et al., 1998; Hodge et al., 1999; Schuckit et
al., 1999.
B. The low response to alcohol might increase the risk for heavier
drinking per occasion as people have less feedback that they are becoming
intoxicated. It is also possible that they require more alcohol to get the
level of intoxication others experience, so they drink more to gain that
experience. The prior slide should remain on.
S11 C. The intensity of response to most substances, including alcohol, is
likely to be genetically influenced with heritabilities of between 0.4 and
0.6. Useful references include Martin, 1988; Heath et al., 1999; Schuckit
et al., submitted. The slide highlights the material in C and D.
D. The low response to alcohol correlates with the family history of
alcoholism and predicts alcoholism in 4- to 20-year prospective studies in
the U.S., Denmark, and Australia.
S12 E. The low response to alcohol might also relate to several
independent characteristics or markers. These include background cortical
EEG findings (low voltage and a relative deficiency of alpha);
neuropeptide Y; corticotropin releasing (CRF) and the hypothalamicpituitary adrenal axis (HPA); adenylyl cyclase (AC); protein kinase C
(PKC); aspects of gamma amino butyric acid (GABA) functioning; and
the serotonin transporter (SERT). The slide presents this information and
the student will be reminded that any or all of these associated findings
might also impact the risk for alcoholism through alternative mechanisms,
but that presenting them as a "package" makes many of these
characteristics easier to remember, and presents a potentially valid model.
A slide presents these data.
VI. A predisposition through genetically-influenced independent
psychiatric disorders.
S13 A. Forty percent or more of alcohol-dependent individuals meet
criteria for another major psychiatric disorder. Especially relevant are
bipolar manic depressive disease, schizophrenia, panic disorder, and social
phobia. Each of these conditions is genetically influenced, and the
disorders might themselves increase the risk for persistent alcohol
problems. The slide demonstrates the level of crossover between
alcoholism and other
psychiatric disorders as discussed in A and B. Useful references include
Kessler et al, 1997; Schuckit et al, 1997; Winokur et al., 1996.
B. The student should be reminded that this is a complex topic because
psychiatric symptoms (e.g., sadness) must be distinguished from full
blown disorders (depressive episodes), and temporary symptoms seen in
the context of heavy drinking (i.e., alcohol induced disorders) might not
represent independent psychiatric disorders.
S14 C. The crossover between alcoholism and other psychiatric disorders
is likely to be the result of a variety of factors. These include temporary
substance-induced disorders, escalating alcohol use in the context of poor
judgement as a result of schizophrenia or bipolar manic episodes, selfmedication of psychiatric symptoms with alcohol, poverty with an
associated heavy drinking environment, alterations in neurotransmitters
such as dopamine, and possible linkage between genes that impact the
psychiatric disorders and those that increase the risk for alcoholism. A
slide presents these possibilities.
D. The student should be reminded that this potential heterogeneous
domain of increased genetic influence appears to be independent of
alcohol-metabolizing enzymes, a low level of response to alcohol, and,
probably, disinhibition. However, the potential role of additional
genetically-influenced characteristics should be noted. Thus, while some
dopamine-related genetic markers might influence disinhibition, others
might impact on schizophrenia and, thus, indirectly increase the
alcoholism risk. Similarly, some neuropeptide Y receptors might have an
impact on level of response to alcohol or appetitive behaviors, while
others might relate to the predisposition toward anxiety disorders. Either
could enhance the alcoholism risk. A similar argument can be made
regarding different aspects of the GABA system. The slide demonstrates
these ideas.
VII. A brief overview of some other genetically-influenced characteristics
that impact on the alcoholism risk. Data from both human and animal
studies relate to most of these items. Useful references for this include
Menninger and Tabakoff, 1998; Wand et al, 1994; Hodge et al., 1999:
Thiele et al., 1998; Ehlers et al., 1998; Gianoulakis et al., 1996.
S15 A. Second messenger systems, including adenylyl cyclase, G proteins,
and protein kinase (PKC) can be reviewed. The brief discussion will
present the acute effects of alcohol on the system, the importance of genes,
and the possible relationship to the alcoholism risk. Useful information on
AC and G proteins is presented as Background for Slide 12. Slide 15
highlights this system.
B. Protein kinase C might also be discussed with an emphasis on PKCε.
This is also referred to in Slide 12.
S16 C. The slide notes the relationship between opioid receptor activity,
dopamine activity, and the effects of alcohol, and discusses the importance
of genes in opioid receptor functioning and number.
D. Neuropeptide Y is also interesting in this light. This is explained in the
Background of the slide copy and regarding Slide 12.
S17 E. Other possible markers can be mentioned, depending on the time
available. These include CRF, the HPA axis, and background cortical
EEG results.
S18 VIII. It is important to remember that the emphasis of this lecture has
been on genetic material related to the predisposition toward alcohol abuse
or dependence. At the same time, important genetic influences operate
regarding the vulnerability toward or away from specific sequelae of
alcohol dependence among alcoholics. This slide lists the following which
can then briefly be discussed.
A. Wernicke-Korsakoff's syndrome.
B. Cirrhosis of the liver.
C. Intensity of withdrawal including convulsions.
D. Psychotic symptoms.
IX. The genetic factors have a potential impact on prevention and
treatment.
S19 This slide briefly outlines how understanding more about the
mechanism of risk can help people develop prevention strategies aimed
specifically at an individual's vulnerability. Thus, the impact of specific
environmental events on the alcoholism risk is best understood when they
are observed in the context of the specific vulnerabilities.
S20 Regarding treatment, it might be more efficient to be able to test
specific therapies if one can recognize potential subgroups of patients
based on their initial vulnerability toward alcoholism. These issues may
help explain why some treatment approaches appear promising
(naltrexone is an example), but the "signal" appears to be relatively weak,
perhaps because the groups being evaluated are heterogeneous with only a
small subsample responding relatively intensely to the intervention. Thus,
identifying subgroups of subjects carrying different risk factors could
facilitate interpretation of studies like Project Match.
S21 X. A brief summary of the major points made in the lecture will be
presented in a single summary slide.
References
American Psychiatric Association: (1994) Diagnostic Criteria from DSM-IV,
Washington, DC, American Psychiatric Association Press
Bauer LO, Hesselbrock VM: (1999) P300 decrements in teenagers with conduct
problems: implications for substance abuse risk and brain development. Biol Psychiatry
46:263-272
Baumeister M: (1999) Complex genetics and implications for psychiatry: Basic concepts
in the study of diseases with complex genetics. Biol Psychiatry 45:522-532
Begleiter H, Porjesz B: (1999) What is inherited in the predisposition toward alcoholism?
A proposed model. Alcohol Clin Exp Res 23:1125-1135
Cloninger CR, Adolfsson R, Svrakic NM: (1996) Mapping genes for human personality.
Nature Genetics 12:3-4
Crabbe JC, Phillips TJ, Buck KJ, Cunningham CL, Belknap JK: (1999) Identifying genes
for alcohol and drug sensitivity: recent progress and future directions. Trends Neurosci
22:173-179
Disney ER, Elkins IJ, McGue M, Iacono WG: (1999): Effects of ADHD, conduct
disorder, and gender on substance use and abuse in adolescence. Am J Psychiatry
156:1515-1521
Edenberg HJ, Foroud T, Koller DL, Goate A, Rice J, Van Eerdewegh P, Reich T,
Cloninger CR, Nurnberger JI, Jr, Kowalczuk M, Wu B, Li TK, Conneally PM, Tischfield
JA, Wu W, Shears S, Crowe R, Hesselbrock V, Schuckit M, Porjesz B, Begleiter H:
(1998) A family-based analysis of the association of the dopamine D2 receptor (DRD2)
with alcoholism. Alcohol Clin Exp Res 22:505-512
Ehlers CL, Garcia-Andrade C, Wall TL, Sobel DF, Phillips E: (1998) Determinants of P3
amplitude and response to alcohol in Native American Mission Indians.
Neuropsychopharmacology 18:282-292
Erblich J, Earleywine M: (1999) Children of alcoholics exhibit attenuated cognitive
impairment during an ethanol challenge. Alcohol Clin Exp Res 23:476-482
Gianoulakis C, De Waele JP, Thavundayil J: (1996) Implication of the endogenous
opioid system in excessive ethanol consumption. Alcohol 13:19-23
Goldman D: (1999) Big Mountain (Commentary). Arch Gen Psychiatry 56:553
Goodwin DW, Schulsinger F, Moller N, Hermansen L, Winokur G, Guze SB: (1974)
Drinking problems in adopted and nonadopted sons of alcoholics. Arch Gen Psychiatry
31:164-169
Heath AC, Madden PAF, Bucholz KK, Dinwiddie SH, Slutske WS, Bierut LJ,
Rohrbaugh JW, Statham DJ, Dunne MP, Whitfield JB, Martin, NG: (1999) Genetic
differences in alcohol sensitivity and the inheritance of alcoholism risk. Psychol Med
29:1069-1081
Higuchi S, Parrish KM, Dufour MC, Towle LH, Harford TC: (1994) Relationship
between age and drinking patterns and drinking problems among Japanese, JapaneseAmericans, and Caucasians. Alcohol Clin Exp Res 18:305-310
Hill SY: (2000): Biologic phenotypes associated with individuals at high risk for
developing alcohol-related disorders, Part 1. Addiction Biology 5:5-22
Hill SY, Locke J, Steinhauer SR: (1999) Absence of visual and auditory P300 reduction
in nondepressed male and female alcoholics. Biol Psychiatry 46:982-989
Hodge C W, Mehmert KK, Kelley SP, McMahon T, Haywood A, Foster Olive M, Wang
D, Sanchez-Perez, AM, Messing RO: (1999) Supersensitivity to allosteric GABAA
receptor modulators and alcohol in mice lacking PKC. Nature Neuroscience 2:997-1002
Hyman SE: (1999) Introduction to the complex genetics of mental disorders. Biol
Psychiatry 45:518-521
Kessler RC, Crum RM, Warner LA, Nelson CB, Schulenberg J, Anthony JC: (1997)
Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other
psychiatric disorders in the National Comorbidity Survey. Arch Gen Psychiatry 54:313321
Lappalainen J, Long JC, Eggert M, Ozaki N, Robin RW, Brown GL, Naukkarinen H,
Virkkunen M, Linnoila M, Goldman D: (1998) Linkage of antisocial alcoholism to the
serotonin 5-HT1B receptor gene in 2 populations. Arch Gen Psychiatry 55:989-994
Li TK: (2000) Pharmacogenetics of responses to alcohol and genes that influence alcohol
drinking. J Stud Alcohol 61:5-12
Malhotra AK, Goldman D: (1999) Benefits and pitfalls encountered in psychiatric genetic
association studies. Biol Psychiatry 45:544-550.
Martin NG: (1988) Twin Studies of alcohol consumption, metabolism and sensitivity:
Australian Drug and Alcohol Review 7:9-12
McGue M: (1999) Phenotyping alcoholism. Alcohol Clin Exp Res 23:757-758
Menninger JA, Tabakoff B: (1997) Forskolin-stimulated platelet adenylyl cyclase activity
is lower in persons with major depression. Biol Psychiatry 42:30-38
Neumark YD, FriedlanderY, Thomasson HR, Li TK: (1998) Association of the ADH2*2
allele with reduced ethanol consumption in Jewish men in Israel: a pilot study. J Stud
Alcohol 59:133-139
Prescott CA, Kendler KS: (1999) Genetic and environmental contributions to alcohol
abuse and dependence in a population-based sample of male twins. Am J Psychiatry
156:34-40
Schuckit MA: Vulnerability factors for alcoholism. In Neuropsychopharmacology: The
Fifth Generation of Progress. Davis K (ed). The American College of
Neuropsychopharmacology and Lippincott Williams & Wilkins, Baltimore, MD in press
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, submitted
Schuckit MA, Mazzanti C, Smith TL, Umbereen A, Radel M, Iwata N, Goldman D:
(1999) 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
45:647-651
Schuckit MA, Smith TL: The relationships of family history of alcoholism, a low level of
response to alcohol and six domains of life functioning to alcohol abuse or dependence. J
Stud Alcohol, submitted
Schuckit MA, Tipp JE, Bergman M, Reich W, Hesselbrock VM, Smith TL: (1997)
Comparison of induced and independent major depressive disorders in 2,945 alcoholics.
Am J Psychiatry 154:948-957
Tecott LH, Heberlein U: (1998) Y do we drink? Cell 95:733-735
Thiele TE, Marsh DJ, Ste Marie L, Bernstein IL, Palmiter RD: (1998) Ethanol
consumption and resistance are inversely related to neuropeptide Y levels. Nature
396:366-369
Volavka J, Czobor P, Goodwin D, Gabrielli W, Penick E, Mednick S, Jensen P, Knop J,
Schulsinger F: (1996) The electroencephalogram after alcohol administration in high-risk
men and the development of alcohol use disorders 10 years later. Arch Gen Psychiatry
53:258-263
Wall TL, Johnson ML, Horn SM, Carr LG, Smith TL, Schuckit MA: (1999) Evaluation
of the self-rating of the effects of alcohol form in Asian Americans with aldehyde
dehydrogenase polymorphisms. J Stud Alcohol 60:784-789
Whitfield JB, Nightingale BN, Bucholz KK, Madden PAF, Heath AC, Martin NG:
(1998) ADH genotypes and alcohol use and dependence in Europeans. Alcohol Clin Exp
Res 22:1463-1469
Winokur G, Coryell W, Endicott J, Keller M, Akiskal H, Solomon D: (1996) Familial
alcoholism in manic-depressive (bipolar) disease. Am J Med Genet 67:197-201
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