Genetics of Alcoholism Susceptibility and Protection

1
Genetics of Alcoholism Susceptibility and
Protection

• Marc A. Schuckit, M.D.
• Professor of Psychiatry UCSD School of Medicine
• Director Alcohol Research Center
• VA San Diego Healthcare System

John Crabbe, Ph. D. Professor, Dept. of
Behavioral Neurosciences Oregon Health Science
University VA Medical Center, Portland, Oregon
For presentation at RSA, 2000
2
Genetic Influences in Alcoholism

• Reviews how a range of genetically influenced
  characteristics increase and decrease the risk

3
Genetic Influences Operate in

• Choice to Drink
• Level of Response
• Reinforcement
• Consequences
• DEPENDENCE

4
Dependence

• Any 3 of 7 in Same 12 months
• Tolerance, Withdrawal, Use more or longer, Need
  control, Much time spent, Give up activities,
  Continued use after phys or psychol problems
• ABUSE (If Not Dependent)
• Any 1 or More of These Problems in Same 12
  months
• Role obligations, Hazardous use, Legal,
  Continues despite social/interpers problems

5
Data Supporting Genetic Influences

• 4x ? risk in 1? relatives
• MZ / DZ concordance 2 / 1
• Adopted away children 4x ? risk
• Animal breeding / QTL work

6
Variance of Risk
(Heterogeneous and Polygenic)
7
Genetic Factors in

• I. Alcohol Metabolism
• II. Disinhibition / Impulsivity
• III. Level of Response to Alcohol
• IV. Independent Psychiatric Disorders
• V. Others
• Opioids
• CRF and the HPA
• Neuropeptide Y
• Second Messenger Systems

8
Alleles Related to Higher Acetaldehyde

• Alcohol Acetaldehyde
• ADH 2-2
• ADH 2-3
• ADH 3-1
• Acetaldehyde Acetate
• ALDH 2-2

9
Possible Markers for Disinhibition / Impulsivity

• P3 Amplitude
• Conduct Disorder (CD)
• Antisocial Personality (ASPD)
• Type 2 Type B
• Dopamine DRD2 / DRD4 / DAT
• Low Serotonin (5-HT)

10
Characteristics of Markers

• ASPD P3 DA Low
  Receptors 5-HT
• Genetic
• Influences X X X X
• Overlap with Alcoholism 70 30 ?
  
• Predict Alcoholism X X ? ?

11
Level of Response (LR) to Alcohol

• Observe less response when test with alcohol
• Self report of more drinks for an effect

12
LR

• Genetically influenced (heritability ? 40)
• Low LR in animals, twins, 1? relatives, 40
  offspring of alcoholics
• Predicts alcoholism over 4 - 20 years

13
Markers Possibly Related to LR

• EEG
• Adenylyl Cyclase (AC)
• Serotonin Transporter (SERT)
• Protein Kinase C (PKC)
• Neuropeptide Y (NPY)
• Gamma Aminobutyric Acid (GABA)

14
Independent Psychiatric Disorders

• 40 of alcoholics carry another diagnosis
• Some are temporary or substance induced ASPD or
  other substance diagnoses
• Higher than expected independent disorders
  include
• Bipolar Schizophrenia
• Panic disorder Social phobia

15
Independent Psychiatric Disorders

• Genetically influenced
• Might ? alcoholism risk by
• Poor judgement
• Unemployment / poverty
• Changes in neurotransmitters (e.g.,
  NPY,GABA,5-HT,DA)
• ? Self medication

16
Markers Related to Second Messengers

• Adenylyl Cyclase (AC)
• G Proteins
• Protein Kinase C (PKC)

17
Additional Possible Markers

• Opioid systems
• Neuropeptide Y

18
Other Possible Risk Markers

• EEG
• Corticotrophin Releasing Factor (CRF)
• Hypothalamic Pituitary Adrenal Axis (HPA)

19
Genetic Influences In

• Wernicke - Korsakoff
• Cirrhosis
• Pancreatitis
• Withdrawal seizures

20
Implications for Prevention

• Enhance education of vulnerabilities
• Find environmental / psychosocial protective
  factors specific to risk

21
Implications for Treatment

• Develop Rx for specific risk factors
• Evaluate Rx separately in subgroups

22
Summary

• Genetic influences explain 60 of risk
• There are several different genetic influences
• Relevant phenotypes relate to
• Alcohol metabolism
• Disinhibition / impulsivity
• Level of reaction
• Independent psychiatric disorders
• Etc.