Lecture 62: Genetics of Alcohol and Nicotine Addiction Flashcards
What is the focus of this lecture?
- NA
- AA
- recurrent unipolar illness (RUP)
- Bipolar disorders (BPD)
- . Schizophrenia (SZ)
What is most predictive of a psychiatric disorder?
Rare alleles (because of the rarity, more likely that individual will have disorder) Epistasis
What is the polydrug addiction rule?
- 25% of cocaine persons are addicted to alcohol
- 80% of AA persons are narcotic addicts
- 30% of opioid persons are addicted to alcohol
Which type of alleles lead to addiction?
- Alleles that increase the euphoria from a given calss of drugs
Example: stimulants - Alleles which allow individual to experience aversive effects of a given calss of drugs in a MINIMAL manner
What is the structure of neuronal nicotinic receptors?
Pentamers
-mediate calcium and sodium conductance
-increase release of dopamine and serotonin when activated
Endogenously activated by acetylcholine
What are the genetics implicated in nicotine addiction?
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
What is the implication of the mutated subunit 5 nicotinic receptor?
- It makes people MORE desensitized to effects of nicotine
- 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
What is the allele for alcoholism?
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
What other mutations PREDISPOSE individual to alcoholism?
Allele for GABA-A alpha2 receptor
Haplotype 4, AA genotype
Those with this receptor report greater feeling of euphoria
What is the significance of the MUTATED GABA-A alpha2 receptor (halotype 4)?
Receptor that is associated alcoholism
What haplotype predisposes to nicotine addiction?
A haplotype at the CHRNA3/5 locuse increases risk for nicotine addiction, by REDUCING aversion
What is a haplotype that predisposes to alcoholism?
A haplotype at the GABA A alpha 2 receptor subunit increases risk for alcoholism, mediated through increase in euphoria
What is the definition of endophenotypes?
Measurable components UNSEEN by unaided eye along the pathway between disease and genotype
-not the obvious and external but the microscopic and internal
What are the criteria for an endophenotype?
- Endophenotypes associated with illness in population
- The endophenotype is heritable
- The endophenotype is primarily state-independent
- detectable in an individual whether or not illness
- Within families, endophenotype and illness co-segregate
- The endophenotype in affected family members is found in nonaffected family members at a higher rate than in the general population
What is point of endophenotypes?
Used to study mood disorders, schizophrenia and addiction
Common alleles
Explain tiny amount of risk
What is an example of an endophenotype for schizophrenia?
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
What gene was found to be associated with mood disorders and schizophrenia? Also with delayed latency of P300?
1;11 translocation
Mutation is DISC1
What is the association of hippocampus and MDD (RUP)?
MDD patients have a DECREASE IN
- neuronal density - glial density - neuronal size - hippocampal size
What is the significance of DISC1?
Susceptibility gene for SZ
What is the significance of ANK3?
Susceptibility gene for SZ and BPD
Associated with voltage gated Na and K channels
What is the significance of CACNA1c?
Susceptibility gene for BPD and SZ
Leads to Timothy syndrome
L-type calcium channel
What is the significance of MIR137?
Susceptibility gene for SZ
-associated with large ventricle and small hippocampus
What is the significance of CNV in schizophrenia?
Rare copy number variations may explain some of genetic risk for SZ
What are CNVs?
Copy number variations
-large segments of DNA that may explain some risk for SZ
What is nosology?
Branch of medical science dealing with the classification of diseases