Genetic Influences on Addiction: Empirical Evidence, Functional Mechanisms, and Clinical Implication

1
Genetic Influences on AddictionEmpirical
Evidence, Functional Mechanisms, and Clinical
Implications

• James MacKillop, PhD
• Center for Alcohol and Addiction Studies,
• Brown University
• John E. McGeary, PhD
• Providence VMAC
• Center for Alcohol and Addiction Studies,
• Brown University

2
Overview

• Evidence of Genetic Influences
• Recent Research on Potential Genetic Mechanisms
• Implications of Genetic Influences

3
I. Empirical Evidence of Genetic Influences

• Genetic Epidemiology
• Genetic Linkage Analysis
• Candidate Gene Studies
• Animal Models

4
I. Empirical Evidence of Genetic Influences

• Genetic Epidemiology
• Genetic Linkage Analysis
• Candidate Gene Studies
• Animal Models

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Alcoholism in Adopted Children of Alcoholic and
Nonalcoholic Biological Parents
Alcoholism Hx Study - Odds-Ra
tio Males Goodwin et al. (1973) 18 5 4.11 C
loninger et al. (1981) 23 15 1.73 Cadoret et
al. (1985) 61 24 5.02 Cadoret et al.
(1987) 63 20 6.51 Sigvardsson et al.
(1996) 24 13 2.20 Females Goodwin et al.
(1973) 2 4 0.49 Bohman et al.
(1981) 5 3 1.73 Cadoret et al.
(1985) 33 5 8.88 Sigvardsson et al.
(1996) 1 1 0.80
p lt .05
Table from McGue (1999a)
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I. Empirical Evidence of Genetic Influences

• Genetic Epidemiology
• Genetic Linkage Analysis
• Candidate Gene Studies
• Animal Models

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Prevalence of Alcoholism in Monozygotic and
Dizygotic Twins
Total n 17,780
Data from Kendler et al. (1997) table from McGue
(1999b)
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I. Empirical Evidence of Genetic Influences

• Genetic Epidemiology
• Genetic Linkage Analysis
• Candidate Gene Studies
• Animal Models

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Genetic Linkage Analysis COGA

• Collaborative Study on the Genetics of Alcoholism
• Proband gt two siblings with alcoholism
• Sample 262 families, n 2282
• Multiple highly significant overlapping portions
  of the genome

Foroud et al. (2000)
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I. Empirical Evidence of Genetic Influences

• Genetic Epidemiology
• Genetic Linkage Analysis
• Candidate Gene Studies
• Animal Models

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Candidate Genes

• Metabolic
• ALDH2
• CYP1A6
• CNS Neurotransmission
• GABRA2
• DRD2 TaqIA
• DRD4 VNTR
• SLC6A3
• OPRM1

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I. Empirical Evidence of Genetic Influences

• Genetic Epidemiology
• Genetic Linkage Analysis
• Candidate Gene Studies
• Animal Models

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Maze Bright vs. Maze Dull Rodents
Plomin (2001) adapted from Tryon (1940)
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Alcohol Preferring and Abstaining Mice
C57BL/6
DBA/2J

• High Alcohol Preference

• Low Alcohol Preference

Crabbe (2005)
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Alcohol Consumption by Mouse Strain
Crabbe (2005)
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I. Empirical Evidence of Genetic Influences

• Genetic Epidemiology
• Genetic Linkage Analysis
• Candidate Gene Studies
• Animal Models

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Overall Variance of Risk
(Heterogeneous and Polygenic)
Schuckit Crabbe (2000)
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II. Functional Mechanisms Underlying Genetic
Influences
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II. Functional Mechanisms Underlying Genetic
Influences
One does not inherit risk One inherits
specific risk-promoting or risk-protective genes.
Crabbe (2003)
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II. Functional Mechanisms Underlying Genetic
Influences
One does not inherit risk One inherits
specific risk-promoting or risk-protective genes.

• Which genes? And how?

Crabbe (2003)
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II. Functional Mechanisms Underlying Genetic
Influences

• The Endophenotype Approach
• Empirical Studies of Genetic Influences
• General Genetic Predispositions
• Genetic Influences on Reactions to Drug
  Consumption
• Genetic Influences on Reactions to Drug Cues
• A Behavioral Framework for Genetic Influences

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The Endophenotype Approach
Unaffected
Intermediate Phenotype
Gene
Disorder
Endophenotype
E.g., Gottesman Shield, (1967) Gottesman
Gould (2003)
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II. Functional Mechanisms Underlying Genetic
Influences

• The Endophenotype Approach
• Empirical Studies of Genetic Influences
• General Genetic Predispositions
• Genetic Influences on Reactions to Drug
  Consumption
• Genetic Influences on Reactions to Drug Cues
• A Behavioral Framework for Genetic Influences

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Genetic Influences on General Predispositions

• Personality
• Extraversion
• Reward Dependence
• Sensation Seeking
• Novelty Seeking
• Impulsivity
• Harm avoidance
• Meta-analysis suggests that the vast majority of
  findings are not robust (Munafo et al., 2003)

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Dopamine Genes and Delay Discounting
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Dopamine Genes and Delay Discounting

• A behavioral measure of impulsivity may be more
  sensitive to genetic influences

Eisenberg, MacKillop et al. (2006)
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Dopamine Genes and Delay Discounting

• A behavioral measure of impulsivity may be more
  sensitive to genetic influences
• Two Dopamine Gene Polymorphisms
• DRD2 TaqI A
• DRD2 - A2 typical D2 binding
• DRD2 - A1 ? D2 receptor density, binding
  unknown mechanism
• DRD4 VNTR
• DRD4 - Short (lt7 repeats) typical receptor
  sensitivity
• DRD4 - Long ( gt 7 repeats) ? receptor
  sensitivity (? cAMP)

Eisenberg, MacKillop et al. (2006)
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Dopamine Genes and Delay Discounting

• A behavioral measure of impulsivity may be more
  sensitive to genetic influences
• Two Dopamine Gene Polymorphisms
• DRD2 TaqI A
• DRD2 - A2 typical D2 binding
• DRD2 - A1 ? D2 receptor density, binding
  unknown mechanism
• DRD4 VNTR
• DRD4 - Short (lt7 repeats) typical receptor
  sensitivity
• DRD4 - Long ( gt 7 repeats) ? receptor
  sensitivity (? cAMP)
• Sample n 195 (42 male modal age 19)
• Three self-report measures and a delay
  discounting task (100 delayed from 1 week to 25
  years)

Eisenberg, MacKillop et al. (2006)
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Dopamine Genes and Delay Discounting
Eisenberg, MacKillop et al. (2006)
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Dopamine Genes and Delay Discounting
Eisenberg, MacKillop et al. (2006)
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II. Functional Mechanisms Underlying Genetic
Influences

• The Endophenotype Approach
• Empirical Studies of Genetic Influences
• General Genetic Predispositions
• Genetic Influences on Reactions to Drug
  Consumption
• Genetic Influences on Reactions to Drug Cues
• A Behavioral Framework for Genetic Influences

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Genetic Influences on Reactions to Drugs

• Small but robust empirical literature
• Differential response to alcohol
• ALDH2
• OPRM1

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ALDH2 and Response to Alcohol
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ALDH2 and Response to Alcohol

• Alcohol is metabolized via a two-step process
• alcohol dehydrogenase (ADH)
• Alcohol ? Acetaldelhyde ? Acetate
  aldehyde dehydrogenase (ALDH)

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ALDH2 and Response to Alcohol

• Alcohol is metabolized via a two-step process
• alcohol dehydrogenase (ADH)
• Alcohol ? Acetaldelhyde ? Acetate
  aldehyde dehydrogenase (ALDH)
• ALDH2 is responsible for relative ALDH activity
• ALDH2/1 typical levels of activity
• ALDH2/2 reduced ALDH activity

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ALDH2 and Response to Alcohol

• Alcohol is metabolized via a two-step process
• alcohol dehydrogenase (ADH)
• Alcohol ? Acetaldelhyde ? Acetate
  aldehyde dehydrogenase (ALDH)
• ALDH2 is responsible for relative ALDH activity
• ALDH2/1 typical levels of activity
• ALDH2/2 reduced ALDH activity
• Increased acetaldehyde is associated with an
  acute toxic response (i.e., nausea, tachycardia,
  flushing, etc.)

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Prevalence of ALDH2 Genotype in the General
Population and Alcoholics
Higuchi et al. (1994)
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OPRM1 and Response to Alcohol

• OPRM1 encodes the m opioid receptor
• AA typical receptor sensitivity
• AG/GG ? receptor sensitivity
• Activity at the m receptor is associated with
  euphoria, analgesia, and other rewarding aspects
  of an array of addictive drugs, including alcohol

Bond et al. (1998) Herz (1997) Gianoulkis (2001)
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OPRM1 and Reactions to Alcohol
Ray Hutchison (2004)
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OPRM1 and Reactions to Alcohol
Ray Hutchison (2004)
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OPRM1 and Reactions to Alcohol
Ray Hutchison (2004)
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OPRM1 and Reactions to Alcohol
Ray Hutchison (2004)
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Genetic Influences on Reactions to Drugs

• Small but robust empirical literature
• Differential response to alcohol
• ALDH2
• OPRM1

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II. Functional Mechanisms Underlying Genetic
Influences

• The Endophenotype Approach
• Empirical Studies of Genetic Influences
• General Genetic Predispositions
• Genetic Influences on Reactions to Drug
  Consumption
• Genetic Influences on Reactions to Drug Cues
• A Behavioral Framework for Genetic Influences

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Effects of DRD4 VNTR Genotype on Reactivity to
Smoking Cues
Hutchison et al.(2002)
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Effects of DRD4 VNTR on Cue-elicited Craving for
Alcohol

p lt .05
McGeary et al. (2006)
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DRD4 VNTR and Reactions to Heroin Cues

p lt .001
Shao et al. (2006)
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DRD4 Interacts with Craving in Choices for Alcohol
MacKillop et al. (2007)
R2 .36, p lt.01
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Caveats

• Small number of studies
• Multiple potential processes
• Laboratory studies typically study few genes

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A Behavioral Approach to Addiction Genetics
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A Behavioral Approach to Addiction Genetics

• Conventional Approach Emphasis on
  molecular/cellular explanations of gene effects

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A Behavioral Approach to Addiction Genetics

• Conventional Approach Emphasis on
  molecular/cellular explanations of gene effects
• Behavioral Approach Focus on how distal genetic
  variation translates into proximal differences in
  drug reinforcement
• Positive reinforcement
• Negative reinforcement
• Punishment

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A Behavioral Approach to Addiction Genetics

• Conventional Approach Emphasis on
  molecular/cellular explanations of gene effects
• Behavioral Approach Focus on how distal genetic
  variation translates into proximal differences in
  drug reinforcement
• Positive reinforcement
• Negative reinforcement
• Punishment
• Characterizing direct and indirect pathways

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Examples

• ALDH2/2 ? punishment
• OPRM1-AG ? positive reinforcement
• DRD4-L ? anticipatory reinforcement
  (positive/negative)

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III. Implications of Genetic Influences

• Implications for Treatment
• Implications for Theory

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Implications for Treatment

• Personalized Medicine

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Implications for Treatment

• Personalized Medicine
• Pharmacogenetics
• DRD2-A1 Nicotine Replacement Therapy
• OPRM1-AG Naltrexone for Alcoholism
• DRD4-L Olanzapine for Alcoholism
• Psychosocial Interventions Genetic
  Interactions?

Johnstone et al. (2004) Oslin et al. (2003)
Hutchison et al. (2004) Ray Hutchison (in
press) Yudkin et al. (2004)
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Implications for Treatment

• Personalized Medicine
• Pharmacogenetics
• DRD2-A1 Nicotine Replacement Therapy
• OPRM1-AG Naltrexone for Alcoholism
• DRD4-L Olanzapine for Alcoholism
• Psychosocial Interventions Genetic
  Interactions?
• Improved Secondary Prevention

Johnstone et al. (2004) Oslin et al. (2003)
Hutchison et al. (2004) Ray Hutchison (in
press) Yudkin et al. (2004)
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Implications for Theories of Addiction
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Implications for Theories of Addiction

• The etiology of addiction is substantially
  influenced by genetics
• Not exclusively
• Multifariously and heterogeneously
• Distally

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Implications for Theories of Addiction

• The etiology of addiction is substantially
  influenced by genetics
• Not exclusively
• Multifariously and heterogeneously
• Distally
• Proximal theories remain potentially valid
• Addiction qua Disordered Learning
• Addiction qua Dysregulated Affect
• Addiction qua Neuroadaptive Allostasis . . .

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Implications for Theories of Addiction

• The etiology of addiction is substantially
  influenced by genetics
• Not exclusively
• Multifariously and heterogeneously
• Distally
• Proximal theories remain potentially valid
• Addiction qua Disordered Learning
• Addiction qua Dysregulated Affect
• Addiction qua Neuroadaptive Allostasis
• Genetic variables represent the backdrop on which
  proximal pharmacological and experiential
  variables play out

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Acknowledgements

• Binghamton University (SUNY)
• Stephen Lisman, PhD
• David Sloan Wilson, PhD
• J. Koji Lum, PhD
• Daniel Eisenberg, BA

• Brown University
• John McGeary, PhD
• Lara Ray, PhD
• Peter Monti, PhD
• Extramural Funding
• NIAAA
• Alcoholic Beverage Medical Research Foundation
• Russell Sage Foundation