Behavioral Genetics Topic

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Behavioral GeneticsTopic 13

• Human Alcohol Abuse and Alcoholism

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Outline

• Basic Epidemiology
• Genetic Epidemiology (men vs. women)
• Mediating Factors
• Alcohol Sensitivity
• Metabolism (Wall et al. 2001)
• Gene Identification

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WHAT IS ALCOHOLISM?(NCA, JAMA, 1992, 268
1012-14)

• Alcoholism is a chronic disease with genetic
  psychosocial and environmental factors
  influencing its development and manifestations.
• It is characterized by impaired control over
  drinking, preoccupation with alcohol, use of
  alcohol despite adverse consequences, and
  distorted thinking (e.g., denial).

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Alcohol Abuse vs. Dependence

• Alcohol Abuse maladaptive pattern of use
  manifested by recurrent and significant adverse
  consequences. E.g.,
• Job, school, or home troubles
• DWI
• Alcohol Dependence Cannot control use,
  compulsive use. E.g.,
• Continued use despite recurrent problems
• Physiological tolerance
• Organize live around drinking

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Some Basic Epidemiology

• Alcoholism is very common in our culture, with
  rates much higher in men than women
• Alcoholism rates vary markedly across cultures
• Major risk factors include
• Ethnicity
• Other psychiatric disorders
• Early initiation
• Positive family

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Prevalence of Alcoholism (DSM-IIIR)(Kessler et
al., Arch Gen Psychiatry, 1994 518-19)
Prevalence
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Cross-cultural Rates of Alcoholism (DSM-III)
(Helzer et al., 1990)
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Twin Adoption Studies

• In men, twin and adoption studies consistently
  implicate the importance of genetic factors, with
  heritability estimates of about 50
• In women, findings from twin and adoption studies
  are less consistent, with a wide range (0 to
  60) of heritability estimates being reported

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Rates of Temperance Board Registration in Male
Twins(Kendler et al. Arch Gen Psychiatry 1997
54 178-184)
Birth Cohort
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Gene-To-Behavior Pathway
P1
G1
B1
N1
P2
G2
N2
B2
P3
G3
N3
B3
P4
G4
Neurophy- siological
Genetic
Psychological
Behavioral
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Inherited Mediator - Criteria

• Associated with, but not a consequence of,
  alcoholism
• Transmitted in families of alcoholics
• Heritable
• Genetically correlated with alcoholism

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Inherited Mediator - Sensitivity

• Associated with, but not a consequence of,
  alcoholism
• Transmitted in families of alcoholics
• Heritable
• Genetically correlated with alcoholism

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Behavioral Sensitivity(Schuckit)
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Inherited Mediator - Sensitivity

• Associated with, but not a consequence of,
  alcoholism
• Transmitted in families of alcoholics
• Heritable
• Genetically correlated with alcoholism

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Inherited Mediator - Sensitivity

• Associated with, but not a consequence of,
  alcoholism
• Transmitted in families of alcoholics
• Heritable
• Genetically correlated with alcoholism

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Twin Study (Heath, et al.1999)
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Inherited Mediator - Sensitivity

• Associated with, but not a consequence of,
  alcoholism
• Transmitted in families of alcoholics
• Heritable
• Genetically correlated with alcoholism

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Reduced Sensitivity in MZ Co-twins
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Sensitivity and Drinking

• Schuckit Attenuated response to ETOH is an
  inherited risk factor for alcoholism
• Finn Heightened response to the (negatively)
  reinforcing effects of ETOH is an inherited risk
  factor for alcoholism

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Sensitivity and Drinking

• Schuckit Attenuated response to ETOH is an
  inherited risk factor for alcoholism
• Finn Heightened response to the (negatively)
  reinforcing effects of ETOH is an inherited risk
  factor for alcoholism
• Newlin Thompson Biphasic model

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Blood Alcohol Concentration
Ascending Limb
Descending Limb
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SONAgtSOA
SOAgtSONA
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Mediators of Alcoholism Inheritance

• Ethanol Sensitivity
• Comorbid Psychopathology Disinhibitory
  psychopathology
• Personality Impulsivity, Constraint
• Barin Wave Markers P3 Amplitude
• Metabolism

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Flushing Response

• Dysphoric effects that occur w/i 15 minutes of
  drinking
• Heart palpitation
• Facial reddening
• Nausea, dizziness
• There are large ethnic group differences in rate
  of flushing metabolic not cultural

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Pathway of Alcohol Metabolism
NAD
NAD
Alcohol
Acetaldehyde
Acetate
ADH
ALDH
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ALDH2 Deficiency

• Mutation (ALDH22 v wild-type ALDH21) is a
  single nucleotide change in exon 12 that results
  in a glu/lys exchange in position 487
• Deficient form of the enzyme carried by approx
  50 of Northern East Asians but only 2 of
  alcoholics from those regions

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Wall et al. (2001)
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Wall et al. (2001)
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ALDH2 Deficiency Among Japanese
Alcoholics(Higuchi et al. 1994)
Heterozygote Frequency
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Is ADH Important?

• Four forms, ADH1, ADH2, ADH3, ADH4
• Polymorphism in ADH2
• 1 lower activity
• 2 higher activity (reduced alcoholism rates)

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Efforts to Identify Genes Influencing Alcoholism
Risk

• Association Studies
• ALDH ADH
• Large of candidate gene studies (dopamine,
  serotonin, NP-Y, GABA receptor polymorphisms)
• Animal Models
• QTL
• Transgenic/Knockout
• Genome-wide Linkage Analyses
• COGA

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Summary

• Alcoholism is a common disorder with many known
  risk factors
• Alcoholism liability is clearly heritable in men
  evidence is less consistent in women
• Behavioral sensitivity as a model of an inherited
  mediator
• Metabolism and ALDH/ADH