2. z
INTRODUCTION
❑ A chronic disease characterized by uncontrolled drinking &
preoccupation with alcohol
❑ Also called alcohol dependence and alcohol addiction
❑ Inability to control drinking due to both a physical & emotional
dependence on alcohol
❑ Very common ( > 10M cases per year ) in India
❑ Treatment can help, but this condition can’t be cured
❑ Usually self-diagnosable
❑ Lab tests or imaging are not required
3. z
SYMPTOMS
❑ Includes repeated alcohol consumption despite related
legal and health issues
❑ May begin each day with a drink, feel guilty about their
drinking & have the desire to cut down on the amount of
drinking
❑ Whole body weakness, behavioral changes, mood swings,
gastrointestinal, psychological, physical substance
dependence, problems with coordination, slurred speech,
or tremor
4. z
WHAT CAUSES ALCOHOLISM?
❑ As with many illnesses in medicine,
alcoholism is a complex disorder
❑ Clusters in families
❑ Genetic contribution
❑ Changing environment influences the risk
(epigenetics)
❑ Stages involved in Alcoholism: Initiation,
Regular alcohol use, Alcohol Dependence &
Cessation
5. z
EVIDENCE FOR GENETIC FACTORS
❑ Adoptees and biological relatives
(Adoption Studies)
I. Adoptive parent
II. Biological parents
III. Adopted child
❑ Twins
I. Monozygotic
II. Dizygotic
❑ Experiments on inbred rodent strains
The pedigrees (family trees) above show affected
people in red and unaffected in white
6. z
GENETIC STRATEGY
i. Recruit families affected by alcoholism
ii. Genes are part of addiction vulnerability
iii. Initiation (limited genetic influence)
iv. Dependence
v. Withdrawal
vi. Medical Consequences
vii. Some specific genes have been implicated in addiction
viii. Analyses to identify chromosomal regions allele-sharing
ix. Association analyses to identify specific genes
7. z
APPROACHES TO THE STUDY OF GENETICS
APPROACHES USED FOR HUMAN AND
ANIMAL POPULATION
➢ Twin & Adoption Studies
➢ Association Studies
➢ Family Linkage Studies
➢ Microarray Expression Profiling
➢ Association Genome Scanning
➢ Haplotype Analyses
➢ Natural Mutations
➢ mRNA Differential Display
➢ QTL Mapping
UNIQUE APPROACHES USED FOR
ANIMAL POPULATIONS
➢ Targeted Mutation
➢ Viral Gene Transfection
➢ Antisense Approaches
➢ RNA interference
➢ Random Mutagenesis
➢ Selective Breeding
➢ Inbred Strain Studies
➢ Chimera Analysis
8. z
QUANTITATIVE TRAIT LOCUS
❑ The ultimate goal of QTL mapping and other genetic studies is to identify
the influential genes (the quantitative trait genes or QTG) and determine
what they do that heightens the risk for alcoholism or affords protection
❑ Genes that influence a quantitative trait may each have a small effect
❑ A QTL identifies the location of a gene that influences a complex trait
❑ QTL Mapping is a method for pinpointing chromosomal regions where
trait-specific genes reside
❑ Several QTLs can work together to account for individual differences;
their effects may “add up” or they may interact with each other
❑ A gene Found is MPDZ, a multiple PDZ domain proteins
9. z
GENES INVOLVED IN ALCOHOLISM
❑ Involvement of hundreds of different genes & polymorphism
❑ Two specific genes as having an effect on the risk of alcoholism
1. ALDH2 gene
2. ADH1B gene
❑ These genes affect how the body metabolizes alcohol, or breaks it down
and processes it
❑ Variations are linked to a buildup of acetaldehyde
❑ Higher levels of acetaldehyde after drinking alcohol, cause unpleasant
side effects like increased heart rate, flushing, and nausea
❑ A lower risk of alcoholism due to a genetic mutation in CYP2E1 gene
10. z
ALCOHOL- RELATED TRAITS
❑ γ-aminobutyric acid type A (GABA A )receptor genes
❑ A muscarinic cholinergic receptor gene (CHRM2)
❑ GABA is a widely-distributed inhibitory chemical in the brain that dampens nerve cell
activity
❑ The GABA A receptor is a pentameric molecule that forms a chloride ionophore
❑ Alcohol enhances the effects of GABA by acting at the GABA A receptor
❑ Associated genes,
Human Chr 5; Mouse Chr 11:
GABRA1 (Gabra1), GABRA6 (Gabra6), GABRB2, and GABRG2 (Gabrg2)
Human Chr 15: GABRG3
Human Chr 4: GABRA2
11. zMAPPING IN HUMAN POPULATION
❑ COGA- Collaborative Study on the Genetics of Alcoholism
❑ Multi-center
❑ More than 1000 alcoholic subjects and their families; primary linkage
data from ~250 of the most informative families
❑ Goal: to determine the location of genes that influence susceptibility to
develop alcohol dependence
❑ Genome-wide search for genetic relationships with alcohol dependence
and other traits
12. z
OTHER GENES
➢ CHRM2 – muscarinic cholinergic receptor
➢ DRD2 – dopamine D2 receptor
➢ GAL – the neuropeptide, galanin
➢ OPRM1 – mu-opioid receptor
➢ hTAS2R16 – a taste receptor for bitter substances
➢ Researchers believe that a part of the DNA that contains the
CYP2E1 gene affects tolerance to alcohol
13. z
GENOMICS ALLOWS DIRECT TRANSLATIONAL
RESEARCH
❑ There is remarkable synteny, between
human and other species (including mice)
❑ Synteny means that functionally and
ancestrally identical genes are found in the
same order on the chromosomes of two
species
❑ About 90% of the human and mouse
genomes lie in conserved syntenic
segments
14. z
EVOLUTION OF BETTER GENETIC ANIMAL
MODELS: TRANSLATION
❑ More systematic alignment of animal and
human data
❑ Concerted efforts to develop new genetic
animal models that truly model human
alcohol problems
o Uncontrolled and escalated drinking
o Adolescent to adult transitions
❑ Examination of the dynamic nature of
addiction, rather than addiction as a static
trait; movement beyond diagnostic
categories
15. z
CONCLUSION
➢ The genetic risk for alcoholism is high, it runs in families
➢ Identifying genetic factors may lead to better intervention
➢ But the study is difficult because the influence is not monogenic- alcoholism does not
exhibit a mendelian pattern of inheritance
➢ Genetic findings open valuable possibilities for the future of medicine
➢ Greater understanding of biological pathways is disorders
➢ Understanding of environmental influences
➢ New targets for personalized medicine
➢ Every human cell has approximately 30,000 genes, some turned on and some turned
off in the addicted state
➢ Microarray technology can simultaneously analyze the activity of thousands of genes,
and thereby provide an overall pattern of gene expression for alcoholism