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Next - Psychology & Neuroscience of Addiction [Private] > Addiction: genes and environment > Flashcards

Addiction: genes and environment Flashcards

1
Q

How do we know genes matter in addiction differences between individuals, compared to the environmental causation?

A

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

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2
Q

What is the simple theory of phenotype variation?

A

Phenotype = genes + environment

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3
Q

What is the aim of genetic studies?

A

Identify genes that contribute to variation in a phenotype

e.g. age of first use

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4
Q

What is the method of genetic studies?

A

Twin studies

- controlled experiments would be unethical

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5
Q

What do twin studies indicate on the variation of addiction-related phenotypes?

A

> Genes account for 50/70% of variation of addiction-related phenotypes
= heritability

> Environmental factors can be considered “errors”, but not always

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6
Q

What is the complex theory of phenotype variation?

A

There are interactions and correlations between genes and environments

  • e.g.: no environmental factor -> no gene expression
    (= no expression of predisposition)
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7
Q

How did Caspi and Moffitt (2006) show that environmental factors alter the expression of genes (gene-environment interactions)?

A

> 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

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8
Q

What is a gene-environment correlation?

A

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

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9
Q

How can gene-environment relationships influence addictive behaviours in the real world?

A

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
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10
Q

Which studies allow us to know which genes matter?

A

Gene association studies:

  • Candidate gene association studies
  • Genome-wide association studies
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11
Q

What do candidate gene association studies consist of?

A

Investigating small number of genes
- based on known information

-> “usual suspects”

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12
Q

What do genome-wide association studies consist of?

A

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

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13
Q

What characterises candidate gene association studies?

A

> Hypothesis driven

> Focus on few, selected genes

> Genes chosen from knowledge of phenotype mechanisms

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14
Q

Which type of genes are chosen in candidate gene association studies on addiction phenotypes?

A
  • 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)
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15
Q

How is a candidate gene study carried out?

A

> Target neurotransmitter gene from controls and cases

> We calculate the number of controls and cases who have the target genetic variant
-> odds ratio

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16
Q

What is the procedure to obtain the odds ratio?

A
  1. Create two-way table of outcomes
  2. Multiply the diagonals
  3. Divide one product by the other
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17
Q

How is an odds ratio of 10 considered for a genetic variant?

A

Odds ratio of 10 for genetic variant is extremely large

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18
Q

What are the limitations of candidate gene studies?

A

> 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
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19
Q

What characterises genome-wide studies?

A

> 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

20
Q

What constitutes a Manhattan plot in a genome-wide study?

A

> 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

21
Q

How is a genome wide study carried out?

A

> 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

22
Q

What are the limitations of genome-wide studies?

A

> 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
23
Q

What is the problem of an identified genetic variant that is not functional?

A

If the genetic variant has no known function, it’s difficult to understand its role in the addiction phenotype

24
Q

What are the 4 identified genes associated to alcohol addiction?

A

> Alcohol metabolism

  • ALDH2
  • ADH1B

> Receptors related to behavioural side of alcohol use

  • GABRA2
  • DRD2 (ANKK1)
25
Q

What is the ALDH2 gene associated to?

A

Alcohol metabolism:
- Decreased capacity to metabolise acetaldehyde to acetate

  • Cause high concentrations of acetaldehyde and ‘alcohol flush reaction’
  • Decreases alcohol use and the risk of alcohol dependence
26
Q

What is the ADH1B gene associated to?

A

Alcohol metabolism:
- Increased rate of conversion of ethanol to acetaldehyde

  • Causes slightly higher concentrations of acetaldehyde
  • Similar deterrent effects on alcohol use and dependence risk
27
Q

What is the GABRA2 gene associated to?

A

Receptor related to behavioural side of alcohol use:
- Repeatedly associated with alcoholism (non-replications exist)

  • Also associated with impulsivity and alcohol-related endophenotypes
28
Q

What is the DRD2 (ANKK1) gene associated to?

A

Receptor related to behavioural side of alcohol use:
- recognised as risk factor for alcoholism

  • presence of considerable across-study heterogeneity
29
Q

What are the 3 identified genes associated to nicotine addiction (tobacco use)?

A
  • CHRNA5/A3/B4
  • CHRNB3-CHRNA6
  • CYP450
30
Q

What is common about the identified genes associated to nicotine addiction?

A
  • No associations to behavioural phenotypes of nicotine addiction
  • All are associated with nicotine’s mechanisms of action
31
Q

What are the limitations of overall gene studies on addiction?

A

> Lack of replication
- no consistent biologically plausible results found

> Identified genes have small effects
- gene variations account for small amount of phenotype variations

32
Q

What is the consternation in the scientific community regarding gene association studies on addiction?

A

Even though twin studies show heritability explains 50-70% of phenotype variations between people,
gene variations explain small amount of phenotype variations

33
Q

What does the case of the missing heritability represent in the scientific community?

A

Different theories on why we’re not finding the genes of interest

  • search of rare variants of small effect that are hard to identify by genetic means
  • > need to improve methods
34
Q

What can be done against the lack of identification of the rare variants of small effect on addiction phenotypes?

A

Redefining addiction with:

  1. New characterisations of addiction phenotypes
  2. New ways to look at the genome
35
Q

How can we redefine addiction through the addiction phenotypes?

A

> Clinical definitions. (DSM-5) not optimised for research
-> new research definitions more heritable -> so it’s easier to find genes

> Administering drugs in controlled settings and recording effects
-> individual experiences that predict the capacity to develop drug dependency

> Use of endophenotypes
- traits more biologically related to addiction (e.g. brain waves)

> Use biomarkers
- focus on consequences of drug use

> Neuroimaging
- brain activation of users vs. non-users

36
Q

What is the problem of using neuroimaging techniques to investigate addiction phenotypes?

A
  • Brain scans are very expensive

- Lots of data = great statistical complexity

37
Q

How can we redefine addiction through the investigation of genotypes?

A

> Use “next-generation” sequencing to find the rare variants (<1% frequency)
(since candidate gene and genome wide association studies are focused on particular types of common variants)

> Use different statistical analyses and laboratory work (rather than candidate genome and wide genome studies)
to identify copy number variants

> Use risk scores

> Use epigenetics

38
Q

Why do we need to use different statistical analyses and lab work to identify copy number variants, rather than candidate genome and wide genome association studies?

A

Copy-number variants:

> Genes are duplicated or deleted during cell division

> Can result in under or over expression of genes

> Even if there’s no functional variant altering gene expression, we still end up with a change in expression
- can’t be seen by genome wide association study because there’s no functional variant

39
Q

What is the benefit of using risk scores when investigating the genome?

A

> Genome-wide association tests have stringent thresholds
-> arguably missing small effect size variants still contributing to phenotype variation

> Risk scores aggregate information for 1000s variants

40
Q

What is the limit of using risk scores when investigating the genome?

A

May not reveal individual gene mechanisms

41
Q

What is the benefit of using epigenetic when investigating the genome?

A

> Drugs alter gene expression
- methyl groups added to DNA, turning expression on/ooff

> Even in identical twins, epigenetics cause phenotype variation

42
Q

What could explain why epigenetics cause phenotype variation even in identical twins?

A

Possibly because identical twins share same DNA, they might have different patterns of methylation

  • > may have different levels of gene expression which can contribute to individual differences
  • > may be impacted by drug use
43
Q

What is the benefit of using pharmacogenomics?

A

Patients vary genetically -> respond differently to treatment

-> DNA profiling could make treatment more efficient
(good responders, non responders, negative side effects)

44
Q

Why is genetic research in addiction important?

A

> Genetic studies give us an understanding of underlying mechanisms of addiction
-> better treatment

> Understanding genetic factors improves understanding of environmental factors, and their interaction

45
Q

What does research show about addiction phenotypes?

A

Addiction phenotypes are complex combinations of genetic and environmental factors

-> genetic or environmental factors in isolation are not sufficient to develop addiction phenotypes

Next - Psychology & Neuroscience of Addiction [Private] (14 decks)

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