Addiction: genes and environment Flashcards
How do we know genes matter in addiction differences between individuals, compared to the environmental causation?
e. g. Smokers
- differ in amounts of cigarettes smoked per day
- some can be explained by environment (time, money)
- However: even in controlled environments, there are differences
- > genes play a role
=> genetic studies of addiction
- we need to understand both genetic and environmental factors to understand addiction
What is the simple theory of phenotype variation?
Phenotype = genes + environment
What is the aim of genetic studies?
Identify genes that contribute to variation in a phenotype
e.g. age of first use
What is the method of genetic studies?
Twin studies
- controlled experiments would be unethical
What do twin studies indicate on the variation of addiction-related phenotypes?
> Genes account for 50/70% of variation of addiction-related phenotypes
= heritability
> Environmental factors can be considered “errors”, but not always
What is the complex theory of phenotype variation?
There are interactions and correlations between genes and environments
- e.g.: no environmental factor -> no gene expression
(= no expression of predisposition)
How did Caspi and Moffitt (2006) show that environmental factors alter the expression of genes (gene-environment interactions)?
> 2 versions of dopamine receptor gene (DRD4 VNTR) in tobacco smokers
> DRD4 short:
- no differences in self-reported craving between before and after exposure to lit cigarette (environmental stimulus)
> DRD4 long:
- higher level of reported craving after exposure vs. before exposure to lit cigarette
What is a gene-environment correlation?
Genetic predisposition that influences likelihood of exposure to particular environmental factors
e. g. people with predisposition toward novelty-seeking behaviours
- not directly predisposed toward drug-taking
- BUT may be more likely to seek out drugs as novel experience
How can gene-environment relationships influence addictive behaviours in the real world?
Genetic variation is key, but the strength of genetic expression seems to depend on context
e.g.:
> Public health policies
- some US states have more restrictive smoking legislation -> difficult access to substance
- lower heritability of adolescent daily smoking
> Peer influence
- some social environments are more likely to encourage drug-taking -> easy access to substance
- higher heritability of substance abuse in these groups
Which studies allow us to know which genes matter?
Gene association studies:
- Candidate gene association studies
- Genome-wide association studies
What do candidate gene association studies consist of?
Investigating small number of genes
- based on known information
-> “usual suspects”
What do genome-wide association studies consist of?
Investigating genetic variation across the whole genome
- large sample
-> “finding needle in a hay stack”, by making needle bigger so it’s easier to find
What characterises candidate gene association studies?
> Hypothesis driven
> Focus on few, selected genes
> Genes chosen from knowledge of phenotype mechanisms
Which type of genes are chosen in candidate gene association studies on addiction phenotypes?
- Genes involved in behaviour
(e. g. dopamine reward pathway) - Genes involved in drug’s mechanism of action
(e. g. drug metabolism -> enzymes or receptors involved)
How is a candidate gene study carried out?
> Target neurotransmitter gene from controls and cases
> We calculate the number of controls and cases who have the target genetic variant
-> odds ratio
What is the procedure to obtain the odds ratio?
- Create two-way table of outcomes
- Multiply the diagonals
- Divide one product by the other
How is an odds ratio of 10 considered for a genetic variant?
Odds ratio of 10 for genetic variant is extremely large
What are the limitations of candidate gene studies?
> Circular logic
- selecting candidate genes requires prior knowledge
- > difficult to generate new knowledge of genes
> Small samples
- due to costs, genotyping studies have historically used small samples
> Lack of replication studies
- due to costs, replications are rare
- meta-analyses are often negative
- > no association between genetic variants and phenotypes of addiction studied
What characterises genome-wide studies?
> Attempt to examine “all” genes in genome
- millions of genetic variants analysed
> No possible hypothesis -> agnostic approach
-> look at the genome and see what pops up
What constitutes a Manhattan plot in a genome-wide study?
> The variants with high statistical significance cluster around particular genes
-> identification of genes associated with a trait
> Each dot represents the statistical significance of the case control test for one specific variant
How is a genome wide study carried out?
> Genome of controls and cases
> We can look at different variants in different genes at the same time
-> identification of associations of known genes AND unexpected genes
What are the limitations of genome-wide studies?
> Require very large samples (1000s)
- even harder to perform replications
> Testing 1000s of variations raises the statistical threshold
- p-value of 5x10^8 required (rather than 0.05)
> Does not cover all variation in human genome
- designed for single nucleotide polymorphisms (SNPs), where one letter of DNA sequence is different between individuals
- for SNPs, that difference is frequent in the population (approx. 5% of people carry that version)
> Not all genetic variants are biologically plausible
- i.e. they’re not all functional
- > if the identified variant has no known function, it’s difficult to understand its role in the addiction phenotype
What is the problem of an identified genetic variant that is not functional?
If the genetic variant has no known function, it’s difficult to understand its role in the addiction phenotype
What are the 4 identified genes associated to alcohol addiction?
> Alcohol metabolism
- ALDH2
- ADH1B
> Receptors related to behavioural side of alcohol use
- GABRA2
- DRD2 (ANKK1)
