WCS44 Etiology Of Psychiatric Disorders Flashcards
Etiology
Causes of disorder, comprises:
- personal and environmental factors
***Etiology can be different for different patients with the same disease
Purpose of finding etiology:
1. Reduce incidence
2. Effective treatment strategy
Classification of etiological factors
- Temporal relationship
- distal / proximal (recent)
- predisposing (long time ago) / precipitating (just before onset) / maintaining (preventing recovery) - Nature of factor
- biological / psychosocial
- intrinsic (e.g. personality) / extrinsic
- genetic / environmental
Causality
Need to demonstrate:
1. Putative cause —> Disorder
2. Remove the cause —> Prevent the disorder
Criteria that ↑ likelihood of causality:
- Strong + Consistent association
- Correct temporal relationship
- Dose-response relationship
- Biologically plausible mechanism
Additional criterion: ***Exclusion of other explanations for the association (i.e. Exclude confounding factors)
Simple vs Complex causality
Simple:
- disorders caused by single genetic mutation
—> Chromosomal abnormalities: Down’s
—> Single-gene disorders: early onset familial Alzheimer’s (Dominant), Phenylketonuria (Recessive), Fragile X syndrome (X-linked)
Most disorders are caused by complex interplay of multiple genetic and environmental factors
Alzheimer’s disease
- APP, PS1, PS2 mutations are ***sufficient causes of AD (Familial AD)
- APOE, CLU, CR1 polymorphisms are ***predisposing risk factors of AD (Sporadic AD: Environmental factors also needed)
Liability-threshold model
- Disorder has multiple etiological factors
- Liability of that individual: Total effect of all etiological factors present in an individual
- Number of etiological factors ↑ —> Frequency distribution of liability in the population becomes bell-shaped normal curve
- Liability exceeds certain threshold value —> Individual will develop the disorder
Diathesis-Stress model
Liability is made up of 2 components:
- Diathesis (vulnerability)
- inherited / other distal factors which are relatively stable over the life span - Stress
- proximal factors which fluctuate depending on the circumstances of the individual
Stronger the diathesis —> Weaker the stress necessary for triggering the disorder
Genetic factors
Psychodynamic theories (by Freud):
- Mental disorder produced by repression of memories of early traumatic experiences into the unconscious
Adoption studies (by Heston):
- higher risk of schizophrenia (if parents have schizophrenia) even in foster home
Twin studies:
- Greater concordance for a disorder in MZ than DZ twins —> indicate presence of genetic factors
Heritability
Relative contributions of genetic and environmental factors to variation in liability in a population
***Genetic variance / (Genetic variance + Environmental variance)
1: Totally genetic
0: Totally environmental
Can be estimated from data on:
1. Population risk
2. MZ concordance rate
3. DZ concordance rate
Diseases with higher heritability:
- **Bipolar
- **Schizophrenia
Diseases with lower heritability:
- GAD
- Panic disorder
- Major depression
Why such high heritabilities?
- Reduced environmental variation in modern societies?
- Many environmental exposures do not occur at random but are influenced by an individual’s behaviour, which in turn is influenced by genetic factors
E.g. Exposure to carcinogens in smoke is influenced by cigarette smoking, which is influenced by genetic factors
Finding specific genetic loci
Modern genomic technologies have enabled gene-mapping strategies to be applied at the whole-genome scale
- ***Linkage scans
- following inheritance of disease by tracking inheritance of genetic markers
- done in families - ***Association studies
- statistical association of genes and diseases
- can be done in unrelated individuals
Genes implicated in Schizophrenia
Dopamine:
- DRD2
Glutamate:
- GRM3
- GRIN2A
- SRR
Ca channels:
- CACNA1C
- CACNA1L
- CACNB2
- Small effect from individual gene
- Moderate aggregate effect —> effect of multiple loci summarised in a single polygenic score —> much stronger relationship to disease risk than any individual locus
Missing heritability
SNP only explain 1/3 - 1/2 of overall heritabilities estimated from twin studies for psychiatric disorders
Missing heritability:
- Untagged common variation
- ***Gene-gene / Gene-environment interactions
- Rare variants
Why such small effects?
- Schizophrenia have reduced fecundity
- Mutation with large effect size would be subjected to strong ***negative selective pressure —> become extinct / very rare
- Only mutations with small effect size can become common
- In contrast Rare variants may have much larger effect sizes
Rare variants and Paternal age
Rare single nucleotide variant (SNVs) likely arose from recent mutational events including de novo mutations
De novo mutation rate ↑ with Paternal age
***De novo mutations may explain ↑ risk of schizophrenia associated with higher paternal age
Finding rare variants
Swedish exome sequencing study:
- No significant SNV, No significant gene, but significant ***gene sets
- Risk SNVs in hundreds of genes necessary to explain missing heritability
How specific are genetic effects?
- A genetic locus may cause an increased predisposition to multiple mental disorders
- Shared genetic etiology has been shown
- Comorbidity of complex mental disorders are often more common than expected by chance
- ***Substantial shared SNP effects across psychiatric disorders
—> Shared genetic etiology —> explain excess comorbidity of psychiatric disorder
What is inherited?
Appear to be a “predisposition” to develop >=1 mental disorders
Nature of such predisposition?
- Personality traits
- Cognitive impairments
Environmental factors
- Pregnancy and birth
Schizophrenia:
- birth in winter months, urban areas
- fetal growth retardation
- fetal perinatal hypoxia
- prenatal complications:
—> malnutrition
—> infections
Effect sizes are all very modest
- Gender
- males: more prone to **intellectual disability, autism, conduct disorder, substance use disorder
- females: more prone to **childhood emotional disorder, anxiety, depression
—> earlier age-of-onset of schizophrenia - Childhood and adolescence
- Parental loss
- Maltreatment
- Sexual abuse
- Emotional disorders
- Conduct disorders
- Anxiety and depression
—> Increased reactivity of emotional circuits of brain (e.g. amygdala) through neuronal epigenetic changes - Chronic difficulties
- chronic unremitting stress —> sustained activation of HPA axis —> ***chronically elevated glucocorticoid —> impaired brain, immunological, metabolic functions
- “social defeat” - Substance use
- prolonged and heavy usage of psychoactive substances
—> alcohol: psychosis, dementia
—> amphetamine: psychosis
—> cannabis: psychosis - Social support
- high expressed emotions (e.g. hostility, over-involvement, critical comments) of family members can ↑ risk of relapse of schizophrenia - Resilience
- people with more positive attitudes and better coping skills are more able to live through difficulties without becoming mentally ill
- exposure to mild levels of stress during childhood and adolescence ↑ resilience in later life (“immunisation”) - Life events
- adverse life events
***MAO-A, Childhood maltreatment —> Antisocial behaviour
***5HTT, Life events —> Depression
- MAO-A is coded by X-linked gene
- Stop-gain point mutation —> aggressive and antisocial behaviour in males
- Common low-activity variant interacts with and childhood maltreatment to ↑ adult antisocial behaviour
- Serotonin transporter (5HTT / SERT) is encoded by SLC6A4
- Short alleles interacts with stressful life events and childhood adversity to ↑ depression symptoms
Summary
- Small fraction of mental disorders is caused by chromosomal abnormalities / single-gene defect
- Most cases have ***multifactorial etiology
—> result of interaction between predisposition (gene / environment) and stress (acute / chronic) - GWAS identified over 100 loci for schizophrenia
—> Dopaminergic transmission
—> Glutamatergic transmission
—> Ca channels
—> Synaptic proteins - Environmental factors:
—> Obstetric events
—> Childhood adversity
—> Chronic difficulties
—> Stressful life events
—> Heavy and prolonged substance abuse
—> Lack of social support - Frequent co-morbidity of different mental disorder is due to ***Non-specificity (Context-dependency) of many genetic and environmental effects
