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Case Ellen why?:
- Genetic sensitivity for RA & depression
- Neurobiological: functional and structural changes in brain network
- Neuroendocrine system: role serotonin in depression; depression & RA more in females than males
- Immune system: immunological changes due to depression & chronic inflammation in RA
- Interaction between all these psychobiological processes → multidimensional target for
intervention
Interaction psychobiological processes:
Genetics:
- Mechanisms:
*Phenotype = observable outward appearance of a cell or organism (e.g. eye color, organ
structures, blood group, personality traits and behavior)
*Genotype = the genetic make up of a cell or organism
*Nature/heredity = transmission of characteristics of a person is based on genetic material
*Nurture/environment = the surroundings of a person affect the development &
characteristics of the person
- Nature and nurture are inseparable:
*Genes contributing to a certain pathology do not always lead to that disease
*”Sensitivity” genes merely set a threshold for the environmental factors to
cross
Genome: chromosomes, DNA and genes
*Chromosomes: entire set of human DNA = genome
- Autosome = non sex chromosomes
- Consist of DNA, which is winded by histones to fit in the cell’s nucleus
*DNA consists of:
- Sugar-phosphate group
- Bases in pairs (A – T & G – C) (sugar-phosphate group + base = nucleotide)
*Genes encode for proteins:
- Gene = part of DNA encoding for 1 protein
- Gene = specific base pair order is template for proteins: building blocks of body;
starts with promotor region and ends with terminator region
- From gene to protein:
*DNA transcribed into mRNA:
*mRNA translated into protein
,From genotype to phenotype:
- Genetic variation:
*Genotype = individuals genetic constitution, overall or at specific gene
*> 99% of DNA is similar across humans → genes are “fixed”
*< 1% differs across individuals (due to mutations or polymorphisms (inherited))
1. Mutations in DNA cause a permanent change in DNA, for example:
- Base-change
Deletions or duplications of DNA stretch (>
- Deletion of base segments
1000 nucleotides)
- Duplication of base segments
- When DNA is not repaired, it can lead to changes in proteins
2. Polymorphisms: multiple frequent variants of gene in population (transmitted to
subsequent generations without causing major defects in biological functions)
- Variable number of tandem repeats
- Single nucleotide polymorphisms = SNPs
- Mendelian inheritance
*Dominant vs. recessive alleles (= variants of genes)
*Homozygous vs. heterozygous
- Not for every cell all proteins encoded in the DNA are needed
*Protein production is dynamic & continuously influenced by various factors:
1. Interactions of genes (= epistasis)
*Allele at one locus interferes or masks an allele at another locus
2. Regulation of gene expression (= epigenetics)
*A series of biochemical processes through which changes in gene expression
are achieved throughout the lifecycle of an organism without change in DNA sequence
*Genes are switched on or off by environmental factors
Epigenome:
- Is changeable
*During different times in life (development, requires epigenetic memory)
*Constantly throughout the day
*Epigenetic signals come from inside the cell, neighbouring cells and from the exterior (e.g.
queen bee: has same DNA but different diet which makes her more suitable for creating offspring).
*There are risk factors as well as protective factors, they are both as important
- Examples of environmental epigenetic factors: Diet, Season (daylight), Exercise, Diseases exposed
to, Drugs used, Negative life events, e.g., childhood maltreatment, Social support
Epigenetic gene regulation:
- Example of baby rats and maternal care:
*Offspring of caring mother rats show different expression of cortisol receptor and
decreased stress response than offspring of mother rats caring less
*Humans: maltreatment decreased glucocorticoid receptor expression and increased stress
response
- Environment → chemical modifications (epigenetic factors) to histones or DNA → changes
accessibility to DNA transcription machinery
*Gene modification: e.g. tags on promotor region (start of gene)
*Histone modification (affecting a stretch of DNA)
- Thus, phenotype (observable characteristics) is dependent on genetic constitution and the
expression of genes (phenotype = G x E, nature + nurture)
,Studying G x E:
- Comparing cases and controls in:
*Pedigree (family) studies
- Particularly good for rare diseases caused by rare mutationF
*Twin studies:
- Similar genes (monozygotic twins)
- Different epigenomes due to different environment
*Population studies
- Genetic association studies → 2 approaches:
*Candidate-gene association study: testing a priori hypothesis that specific genes (also with
low allele frequencies) are associated with disease, e.g. based on biological mechanisms
*Genome-wide association study: test over 1 billion genetic variants that are frequent in the
population (SNPs). Requires very large sample size to indicate small contribution of frequent alleles.
Genetics & psychobiology: applications
- GxE in:
*Medical diseases:
- allergy
*Psychopathology:
- Major depressive disorder
- Schizophrenia
*Clinical applications
- Gene environment interaction (G x E):
*The importance of G & E varies across medical diseases:
- 1 gene (/chromosome): down’s syndrome 100%, for example explained by trisomy
rd
21 (3 copy of chromosome 21- copy number variation)
- Multiple genes and environmental factors: interact and their expression may differ
= the case for most diseases
- G x E models to explain the interaction (see slide 54)
*Biological interaction: dependence of the effect of one factor at cellular or molecular level
on the presence or absence of the other
Allergy: indication for G x E
- Why:
*hay fever, asthma, eczema or food allergy
*Early manifestation of immune dysregulation
*Considered ‘classic psychosomatic disorder’: good example of G x E:
- Complex interactions
- Better understood than psychopathologies (clearer environmental factor?)
*Socially relevant: high prevalence (30% of Western population) & dramatically increasing
- Genes: higher allergy rate within families and twins (ca. 35-75% explained genetically)
- Environment:
, *Incidence increase too rapidly to be explained genetically
*More allergies in developed countries (hygiene hypothesis = better hygiene → allergy)
*Influence of psychological factors, e.g. psychosocial stress increasing incidence, probability
of symptom exacerbation and severity of condition
- G x E: allergy – complexity:
*Heterogenous disease: multiple genes and multiple environmental factors (&interactions)
*Time window of exposure of environmental risk factors
*Not all environmental factors usually measured
Complex G x E: psychopathology
- Based on twin studies
*Heritability gap: twin studies seem to overestimate genetic component → twins also share
environment
- G x E major depression:
*Mainly based on candidate-gene association studies: indications for higher risk of
depression:
-Short allele of serotonin transporter x stressful life events or childhood
maltreatment
→ Role of monoamines (including serotonin) in depression according to the
revised monoamine hypothesis
→ Antidepressants increase levels of monoamines
- Discrepancies between studies:
-Findings from candidate-gene association studies are not always replicated by GWAS:
*Candidate-gene studies often underpowered (too small sample size)
*Biological hypothesis difficult to formulate
*Multiple genes play role (polygenic)
*Environmental factors
*Differential susceptibility averages out the impact of genes (see slides 72)
G X E in major depression: based on GWAS & candidate gene association studies:
- Polygenic: > 100 loci involved
- Evidence for interaction with: childhood, trauma, socioeconomic adversity, social support and
physical activity
G X E: Schizophrenia
- Candidate gene studies: risk of schizophrenia COMT-gene (polymorphism determines efficiency of
dopamine metabolizing enzyme) x active cannabis use during adolescence
*Hypothesis of schizophrenia: cannabis triggers dopamine release
*Antipsychotic drugs suppress dopamine receptor
*Individuals with specific genotypes: suggested to avoid/limit cannabis use
- GWAS meta-analysis confirms role of dopamine
G x E: psychopathology in progress
- Because psychopathologies are polygenic & involve many environmental factors, there is a need
for:
*Systematic & replication of GWAS incorporating G x E: genome wide gene-environment
interaction studies (GWEIS) → though larger n required due to more statistical tests
*Careful assessment of environmental factors:
- Prenatal – adulthood
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