Behavioral Genetics Topic

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Behavioral GeneticsTopic 13

• Human Alcohol Abuse and Alcoholism - ALDH

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Some Basic Epidemiology

• Alcoholism is very common, with rates much higher
  in men than women
• Alcoholism rates vary markedly across cultures
• Alcoholism is heritable, especially in males
• Major risk factors include
• Ethnicity
• Other psychiatric disorders
• Early initiation
• Positive family history
• Other, especially externalizing, psychopathology
• Disinhibited personality traits

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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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Inherited ALDH2 Deficiency
NAD
NAD
Alcohol
Acetaldehyde
Acetate
ALDH2 Mutation
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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ALDH2 Deficiency Among Japanese
Alcoholics(Higuchi et al. 1994)
Heterozygote Frequency
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Asian-American Adopted Youth
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Is ALDH Deficiency Protective in Adopted Youth?
p .39
p .04
p .02
Irons et al. (2007)
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Do Environmental Factors Diminish ALDH Effect?

• ParAlc Adoptive parent DSM Sx of Alcohol
  Dependence
• ParTol Perceived adoptive parent tolerance for
  adolescent substance use
• SibAlc Sibling alcohol use at initial
  assessment
• SibTol Perceived sibling tolerance for
  adolescent substance use

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Sibling Factors DO Appear to Diminish ALDH Effect
p .24
p .69
p .01
p .04
Irons et al. (2006)
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Gateway Model
Other Drug Use
Delinquency
Adolescent Alcohol
Adolescent Tobacco
Bad Peer Models
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Will Reducing Adolescent Drinking Reduce Other
Adolescent Problems?
Experimental Approach
?
Intervention
Reduced Drinking
Reduced Disinhibition
Population
Control
No Effect
No Effect
Mendelian Randomization
Reduced Disinhibition
?
ALDH -
Reduced Drinking
Population
ALDH
No Effect
No Effect
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Intake Disinhibition in Adolescents With and
Without ALDH2 Deficiency
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Association of ALDH2 Deficiency with NOT using
Substances in Past Year at Follow-up
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ALDH and Adolescent Drinking

• Is protective ALDH deficiency associated with
  lower rates of being drunk
• Is NOT deterministic Rearing environment can
  diminish ALDH protective effects
• Source of environmental effect Siblings are an
  important but perhaps underappreciated factor
• Mendelian Randomization Drinking interventions
  may reduce drinking and drinking-related
  problems. Their effect on other indicators of
  disinhibitory psychopathology or adolescent
  substance use are less clear.

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Topic 14 Conclusion

• Definition
• Behavioral genetics - that area of psychology
  that is concerned with the application of genetic
  methods and research designs to study the nature
  and origins of individual differences in human
  and animal behavior.

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Methodologies

• Mendelian (single-gene) inheritance
• PKU, Huntingtons, CAH
• Chromosomal anomalies/Structural Variation
• Down Syndrome, Williams Syndrome, VCFS
• Twin/Adoption Studies
• Complementary methodologies
• Biometric Analysis
• Variance component estimation
• Gene Identification in Humans
• Linkage, Association, Linkage Disequilibrium
• Animal Methods
• Selection, Inbred Strains, Forward Genetics (QTL,
  mutagenesis, microarray), Reverse Genetic
  (transgenics, knock-outs)

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Nature of Genetic Influence

• Heritability
• Virtually all behavioral traits are in part
  heritable
• Common heritable factors may account for
  correlations among disorders
• Heritability estimates are approximations
• Heritability is neither an index of immutability
  nor an explanation of behavior

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Nature of Genetic Influence

• Genes and the Human Genome Project
• 20,000 to 25,000 genes and 11,000,000 SNPs, and
  large amount of structural variation (e.g., CNVs)
  
• Gene identification has been difficult
• Mendelian vs. oligogenic vs. polygenic
• Positional cloning strategy has produced few
  successes
• But there are some leads (5-HTT, DAT1, DRD4,
  ALDH2, GABRA2, COMT)
• Prospects for the Future
• Large-scale LD studies in humans (500,000 SNPs)
• Focus on regulatory as well as structural (i.e.,
  coding) variability
• Animal models based on homology synteny

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Benefits of finding genes for human behavior?

• Better understanding of the nature and origins of
  behavior
• Pharmacological interventions based on genotype
  (the 5-HTT example)
• Targeted early prevention (e.g., treating
  unaffected siblings of schizophrenics)

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Merikangas, K.R. Risch, N. (2003). Genomic
priorities and public health. Science, 302
599-601.
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Nature of Environmental Influence

• Familial resemblance is potentially a function of
  both shared genes and shared environment
• Have we overestimated the impact of parents?
• Shared vs. non-shared environmental effects
• Changing balance across development for some
  traits
• SZ, BP, Depression, ADHD
• Gene-environment interplay
• GxE and the diathesis-stress model
• PKU
• MAO-A and aggression
• 5HTTLPR and depression
• G-E correlation
• Ge et al. adoption study
• Epigenesis

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Principled Critiques of BG

• For psychologists, as well as for medical
  researchers, the purpose of identifying
  undesirable predispositions of individuals should
  be to devise more effective health-promoting
  interventions, not to discourage such attempts on
  the supposition that these predispositions are
  genetically based and therefore intractable.
  
• D. Baumrind (1993)

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Final Admonitions

• Dont believe it unless it is replicable
• Single studies are not definitive, require a
  coherent pattern of results
• Study for the final attend review session on
  Friday 14 December 100 PM in N227 Elliott Hall
• Arrive for the final on time (800 AM, Monday 17
  December in N119 Elliott Hall), and