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Genetics of Alcoholism Susceptibility and Protection

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

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Genetics of Alcoholism Susceptibility and Protection

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  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 Developed for the Alcohol Medical Scholars Program

  3. Genetic Influences Operate in: • Choice to Drink • Level of Response • Reinforcement • Consequences • DEPENDENCE Developed for the Alcohol Medical Scholars Program

  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 Developed for the Alcohol Medical Scholars Program

  5. Data Supporting Genetic Influences • 4x  risk in 1 relatives • MZ / DZ concordance = 2 / 1 • Adopted away children 4x  risk • Animal breeding / QTL work Developed for the Alcohol Medical Scholars Program

  6. Variance of Risk (Heterogeneous and Polygenic) Developed for the Alcohol Medical Scholars Program

  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 Developed for the Alcohol Medical Scholars Program

  8. Alleles Related to Higher Acetaldehyde Alcohol Acetaldehyde ADH 2-2 ADH 2-3 ADH 3-1 Acetaldehyde Acetate ALDH 2-2 Developed for the Alcohol Medical Scholars Program

  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) Developed for the Alcohol Medical Scholars Program

  10. Characteristics of Markers ASPD P3 DA Low Receptors5-HT Genetic Influences X X X X Overlap with Alcoholism 70% 30% ? + Predict Alcoholism X X ? ? Developed for the Alcohol Medical Scholars Program

  11. Level of Response (LR) to Alcohol • Observe less response when test with alcohol • Self report of more drinks for an effect Developed for the Alcohol Medical Scholars Program

  12. LR • Genetically influenced (heritability  40%) • Low LR in animals, twins, 1 relatives, 40% offspring of alcoholics • Predicts alcoholism over 4 - 20 years Developed for the Alcohol Medical Scholars Program

  13. Markers Possibly Related to LR • EEG • Adenylyl Cyclase (AC) • Serotonin Transporter (SERT) • Protein Kinase C (PKC) • Neuropeptide Y (NPY) • Gamma Aminobutyric Acid (GABA) Developed for the Alcohol Medical Scholars Program

  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 Developed for the Alcohol Medical Scholars Program

  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” Developed for the Alcohol Medical Scholars Program

  16. Markers Related to Second Messengers • Adenylyl Cyclase (AC) • G Proteins • Protein Kinase C (PKC) Developed for the Alcohol Medical Scholars Program

  17. Additional Possible Markers • Opioid systems • Neuropeptide Y Developed for the Alcohol Medical Scholars Program

  18. Other Possible Risk Markers • EEG • Corticotrophin Releasing Factor (CRF) • Hypothalamic Pituitary Adrenal Axis (HPA) Developed for the Alcohol Medical Scholars Program

  19. Genetic Influences In: • Wernicke - Korsakoff • Cirrhosis • Pancreatitis • Withdrawal seizures Developed for the Alcohol Medical Scholars Program

  20. Implications for Prevention • Enhance education of vulnerabilities • Find environmental / psychosocial protective factors specific to risk Developed for the Alcohol Medical Scholars Program

  21. Implications for Treatment • Develop Rx for specific risk factors • Evaluate Rx separately in subgroups Developed for the Alcohol Medical Scholars Program

  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. Developed for the Alcohol Medical Scholars Program

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