AN OVERVIEW OF GENETIC INFLUENCES IN ALCOHOLISM Marc A. Schuckit

Copyright Alcohol Medical Scholars Program 2

LECTURE REVIEWS Genetic Influences Overall Intermediate Phenotypes Specific Genes Environment

COMPLEX GENETIC INFLUENCED DISORDERS MI Type 2 Diabetes Cancer

GENES AND ALCOHOLISM 4 x  Risk for COAs 4 x  Risk for Adopted out COAs Higher Risk for ID Twins of Alcoholics

VARIANCE OF RISK (Heterogeneous and Polygenic)

ENDOPHENOTYPE  GENETIC  OBSERVED EARLY  PREDICTS DX

POSSIBLE FAMILIES OF RISK FACTORS n Alcohol Metabolizing Enzymes n Level of Response (LR) n Impulsivity n Psychiatric Disorders

ALCOHOL METABOLISM Alcohol ADH Acetaldehyde ALDH CO 2 + H 2 O

POSSIBLE FAMILIES OF RISK FACTORS n Alcohol Metabolizing Enzymes n Level of Response (LR) n Impulsivity n Psychiatric Disorders

LR RATIONALE Youth Drink for Effects If Need More for Effect Will Drink More Then Heavy Drinking Affects Peers Expectations Stress

LOW LEVEL OF RESPONSE TO ALCOHOL (LR) 1.Less Alcohol Related Change on a Challenge. 2.The Need for a Relatively High Number of Drinks for an Effect.

SRE TIME FRAME: DRINKS 1st 5 Recent Heaviest NEEDED TO: Times 3 Mos Feel Effect Feel Dizzy or Slur Speech Stumble Fall Asleep

LR LowHigh COAJews Native Americans Most Asians Koreans? Blacks

12 YEAR OLD CORRELATES Maximum Drinks.49 Frequency.11 Problems.28

LR CORRELATES 1° RELATIVES.20 2° RELATIVES.15 UNRELATED.02 FATHER/OFFSPRING (20yr).40 TWINS h 2 =.6

LR PREDICTS OUTCOME San Diego Prospective Study Australian Twins Danish Adoptees Colorado Twins

CORRELATIONS OF LR TO OUTCOME Alcoholic Outcome LR-.25 Control for: FREQ-.23 QUANT-.21 BOTH-.19

SRE PREDICTS OUTCOMES rOR Max Drinks Problems.28 3 Dependence Items AUD

ENDOPHENOTYPE  GENETIC  OBSERVED EARLY  PREDICTS DX

LR 60% Genetics LR Relates to Risk COA Native Americans Koreans Low LR Predicts Outcome

SEARCH FOR GENES FOR LR n Association n Linkage n Animal Models

BACKGROUND 5 HTT Relates to drinking  Animals  Humans GABRA6 Animal

GENOTYPES, LR, & ALCOHOL DEPENDENCE 5HTTGABA A  6 BOTH LL+ SS+ LL SL SS Pro/Ser Pro/Pro Pro/Ser Pro/Pro LR %ALC

Copyright Alcohol Medical Scholars Program 27 CHROMOSOME 10

CANDIDATES: ASSOCIATION GABRA6COMT5HTT GABRG2DRD2/ANKK1 ADORA GABRA5DRD4 NPY GABRA1 KCNMA1DGKZ ADHIB GNAS ADH1C PK CYP2E

VARIANCE OF RISK (Heterogeneous and Polygenic)

“ENVIRONMENT” Child Home Expectancy Peers Religion Stress Coping

Fhalc sex age Fhalc LR HOME EXPECT.25 ALC OUT

POSSIBLE FAMILIES OF RISK FACTORS n Alcohol Metabolizing Enzymes n Level of Response (LR) n Impulsivity n Psychiatric Disorders

LECTURE REVIEWS Genetic Influences Overall Intermediate Phenotypes Specific Genes Environment

IMPLICATIONS FOR PREVENTION Enhance Education of Vulnerabilities Find Environmental / Psychosocial Protective Factors Specific to Risk

IMPLICATIONS FOR TREATMENT Develop Rx for Specific Risk Factors Evaluate Rx Separately in Subgroups