Lecture 62: Genetics of Alcohol and Nicotine Addiction

Question 1

What is the focus of this lecture?

Answer 1

1. NA
2. AA
3. recurrent unipolar illness (RUP)
4. Bipolar disorders (BPD)
5. . Schizophrenia (SZ)

Question 2

What is most predictive of a psychiatric disorder?

Answer 2

Rare alleles (because of the rarity, more likely that individual will have disorder)
Epistasis

Question 3

What is the polydrug addiction rule?

Answer 3

1. 25% of cocaine persons are addicted to alcohol
2. 80% of AA persons are narcotic addicts
3. 30% of opioid persons are addicted to alcohol

Question 4

Which type of alleles lead to addiction?

Answer 4

1. Alleles that increase the euphoria from a given calss of drugs
   Example: stimulants
2. Alleles which allow individual to experience aversive effects of a given calss of drugs in a MINIMAL manner

Question 5

What is the structure of neuronal nicotinic receptors?

Answer 5

Pentamers
-mediate calcium and sodium conductance
-increase release of dopamine and serotonin when activated
Endogenously activated by acetylcholine

Question 6

What are the genetics implicated in nicotine addiction?

Answer 6

CHRNA5 is the gene that leads to nicotinic receptors
Missense mutation (A to G) leads to a receptor that removes the aversive effects of nicotine
Fucks with subunit 5

Question 7

What is the implication of the mutated subunit 5 nicotinic receptor?

Answer 7

1. It makes people MORE desensitized to effects of nicotine
2. receptor is HYPOfunciotnal
   -humans are able to get a shitload of nicotine while not feeling bad effects
   However, this explains VERY LITTLE of addcition…principle of common gene effect

Question 8

What is the allele for alcoholism?

Answer 8

ALDH2
If you have mutated ALDh2 (missense SNP), then you get greater toxic effects of alcohol
-mutation is PROTECTIVE among Asians
-Lysine mutation is protective against alcoholism

Question 9

What other mutations PREDISPOSE individual to alcoholism?

Answer 9

Allele for GABA-A alpha2 receptor
Haplotype 4, AA genotype
Those with this receptor report greater feeling of euphoria

Question 10

What is the significance of the MUTATED GABA-A alpha2 receptor (halotype 4)?

Answer 10

Receptor that is associated alcoholism

Question 11

What haplotype predisposes to nicotine addiction?

Answer 11

A haplotype at the CHRNA3/5 locuse increases risk for nicotine addiction, by REDUCING aversion

Question 12

What is a haplotype that predisposes to alcoholism?

Answer 12

A haplotype at the GABA A alpha 2 receptor subunit increases risk for alcoholism, mediated through increase in euphoria

Question 13

What is the definition of endophenotypes?

Answer 13

Measurable components UNSEEN by unaided eye along the pathway between disease and genotype
-not the obvious and external but the microscopic and internal

Question 14

What are the criteria for an endophenotype?

Answer 14

1. Endophenotypes associated with illness in population
2. The endophenotype is heritable
3. The endophenotype is primarily state-independent
   
   • detectable in an individual whether or not illness
4. Within families, endophenotype and illness co-segregate
5. The endophenotype in affected family members is found in nonaffected family members at a higher rate than in the general population

Question 15

What is point of endophenotypes?

Answer 15

Used to study mood disorders, schizophrenia and addiction

Question 16

Common alleles

Answer 16

Explain tiny amount of risk

Question 17

What is an example of an endophenotype for schizophrenia?

Answer 17

Decreased executive
Decreased memory
Decreased intellectual capability
2. Large lateral ventricles
3. failure to activate DLFC
4. delayed P300 EEG and impared gamma oscillations on EEG

Question 18

What gene was found to be associated with mood disorders and schizophrenia? Also with delayed latency of P300?

Answer 18

1;11 translocation

Mutation is DISC1

Question 19

What is the association of hippocampus and MDD (RUP)?

Answer 19

MDD patients have a DECREASE IN

- neuronal density
- glial density
- neuronal size
       - hippocampal size

Question 20

What is the significance of DISC1?

Answer 20

Susceptibility gene for SZ

Question 21

What is the significance of ANK3?

Answer 21

Susceptibility gene for SZ and BPD

Associated with voltage gated Na and K channels

Question 22

What is the significance of CACNA1c?

Answer 22

Susceptibility gene for BPD and SZ
Leads to Timothy syndrome
L-type calcium channel

Question 23

What is the significance of MIR137?

Answer 23

Susceptibility gene for SZ

-associated with large ventricle and small hippocampus

Question 24

What is the significance of CNV in schizophrenia?

Answer 24

Rare copy number variations may explain some of genetic risk for SZ

Question 25

What are CNVs?

Answer 25

Copy number variations

-large segments of DNA that may explain some risk for SZ

Question 26

What is nosology?

Answer 26

Branch of medical science dealing with the classification of diseases