1. Considering Genetics/Heredity
How do biological factors contribute to the development of alcohol abuse and dependence?
Considering Genetics/Heredity

2. Some Behavioral Genetics Basics:
Genotype ≈ combination of genes
Identical twins have same set of genes
Phenotype ≈ how genes are expressed
genes + environment (shared+ unique)
Even identical twins are never identical
Endophenotypes (per Gottesman & Gould, 2003):
Genetically-influenced phenotype
Identifiable before a disorder develops
Associated with high risk of developing a disorder
Endophenotype = not the disorder, but an intermediate expression of genes that increases/decreases likelihood of developing disorder
Schucket describes 4 endophenotypes that meet these criteria and have been associated with AUD outcomes

3. 4 known sources of genetic influence on likelihood of developing AUDs:
Variations in alcohol-metabolizing enzymes
Low response to alcohol
Disinhibited, impulsive, externalizing temperament
Psychiatric comorbidity
(Schuckit, 2009)

4. 4 known sources of genetic influence on likelihood of developing AUDs:
Variations in alcohol-metabolizing enzymes
Beverage
Alcohol
Acetic acid,
CO2, HzO 
ADH 
acetaldehyde 
ALDH 
ADH1B*2 variant speeds up process
Flushing, nausea,
Vomiting, headache
The ADH1B*2 variant speeds up the process, causes acetaldehyde to build up
Adverse effects = flushing, nausea, vomiting, headache
PROTECTIVE – this variant lower in alcoholics than controls
(Schuckit, 2009)

5. 4 known sources of genetic influence on likelihood of developing AUDs:
Variations in alcohol-metabolizing enzymes
Lower levels, less aversive
Beverage
Alcohol
Acetic acid,
CO2, HzO 
ADH 
acetaldehyde 
ALDH 
ADH1C*2 variant slows process
ADH1C*2 is less active polymorphism, RISK FACTOR for alcohol dependence
(Schuckit, 2009)

6. 4 known sources of genetic influence on likelihood of developing AUDs:
Variations in alcohol-metabolizing enzymes
Beverage
Alcohol
Acetic acid,
CO2, HzO 
ADH 
acetaldehyde 
ALDH 
ALDH2*2 variant slows metabolism
(may have 1 allele or 2)
Flushing, nausea,
Vomiting, headache
Having the inactive form of ALDH causes acetaldehyde to build up in blood, leading to aversive physical effects
PROTECTIVE factor
Homozygous (2 mutated alleles) = least likely to develop AUDs because of strong flushing response
Heterozygous (1 mutated allele only) = some flushing but not as protective
(Schuckit, 2009)

7. 4 known sources of genetic influence on likelihood of developing AUDs:
Variations in alcohol-metabolizing enzymes
Low response to alcohol
always able to “hold my liquor”
less cognitive/motor impairment
seen in COAs, Native Americans
ability to drink heavily and develop tolerance
(Schuckit, 2009)

8. 4 known sources of genetic influence on likelihood of developing AUDs:
Variations in alcohol-metabolizing enzymes
Low response to alcohol
Disinhibited, impulsive, externalizing temperament
nonspecific to drinking
heavier drinking, more problems
early onset of AUDs
gene x environment interaction (more later)
(Schuckit, 2009)

9. 4 known sources of genetic influence on likelihood of developing AUDs:
Variations in alcohol-metabolizing enzymes
Low response to alcohol
Disinhibited, impulsive, externalizing temperament
Psychiatric comorbidity (cf. Hasin et al., 2007)
Antisocial personality (adj OR = 1.7, lifetime AD)
Bipolar mood disorder (adj OR = 2.1, lifetime AD)
Schizophrenia
(Schuckit, 2009)

10. Heritability = proportion of observable differences between individuals that is due to genetic differences
Varies according to how much variability is attributable to the environment
heritability is specific to a population in a given environment
Cf Rose & Dick (2004/2005) FinnTwin findings on differences between urban and rural twins
Gene x environment interaction
Heritability could increase if genetic variability increases, or if environmental variability decreases (in islamic countries); therefore heritability is specific to a population in a given environment.
Genetic influences on drinking frequency stronger among urban twins than rural twins– why?
The more that sociodemographic factors facilitated drinking (lots of young adults, more social mobility [less stability], higher alcohol sales/availability) the greater the expression of genetic risk
Conversely, strong environmental influences that protect against access to alcohol and restrict excessive drinking, the less genetic influence we will be able to detect.

11. Take away messages about the genetics of alcohol use disorders
Genes explain ~ 50% vulnerability (Schuckit, 2009)
Similar genetic contributions in both sexes
AUDs are polygenic
AUDs are multifactorial:
Genes x environments
Gene-environment correlations

12. Likely gene-environment correlations in alcoholism (Searles, 1988)
Passive: Environment is not independent of genes
prenatal exposure to alcohol
Parenting, parent/sib role models
Reactive/evocative: certain temperaments precede AUDs and evoke responses from parents, teachers, peers, etc.
high activity level / behavioral undercontrol
emotionality / low soothability / neuroticism
poor attention span / persistence
sociability / extraversion
(Tarter & Vanyukov, JCCP, 1994)

13. Likely gene-environment correlations in alcoholism - cont’d
Active (niche seeking): People actively seek environments that complement/support their genotype
self-selection into “partying” social groups
selection of mates
self-selection away from alcohol involvement (e.g., flushing response)
Genetic influences change over life course
Several pathways to development of AUDs

14. Cloninger’s Typology Type II : Type I: Affects both men and women
Age of onset after age 25
Periodic binge drinking, guilt about drinking
Progressive severity
Both genetic and environmental influences
Type II :
Affects primarily men
Early age of onset (before age 25)
Inability to abstain, assoc.with fights and arrests
Severity usually not progressive
Primarily genetic
Cloninger Type 1-2 distinction based on a cross-fostering adoption study in Sweden (862 men, 913 women);
Type 1 = 76%, most common type has substantial environmental influence
Type 2 = 24%; men and women have different patterns
demonstrates multiple pathways to alcohol problems