1. Appreciate the concepts, complexities and clinical relevance of aetiology in mental disorders 2. Knowledge of the genetic factors involved in mental disorders 3. Knowledge of the environmental factors involved in mental disorders

• History-taking: You must elicit predisposing, precipitating, and maintaining factors — this is the direct clinical translation of aetiological theory (see 2017 SAQ Q10) ^[3].
• Formulation: The biopsychosocial model and diathesis-stress model are the frameworks you use to organise the aetiological factors into a coherent clinical story.
• Past papers: Exam questions frequently test: heritability rankings, gene-environment interaction examples, the meaning of "predisposing/precipitating/perpetuating," and specific genetic loci (e.g., APOE in Alzheimer's — see 2025 MCQ Q20) ^[4][5].

Aetiology is the study of the causes of a disorder. ^[1]

This seems simple, but the lecturer immediately emphasises that causes are typically complex. He uses two illustrative examples:

Key teaching point: Even disorders with a single identifiable cause still involve multiple factors at the individual level. Different factors [are] involved in different patients. ^[1]

This is a critical framework. The lecture classifies aetiological factors along three axes:

Classification according to:

• Temporal relationship: Distal (Remote) / Proximal (Recent); Predisposing / Precipitating / Maintaining
• Nature of factor: Intrinsic / Extrinsic; Biological / Psychosocial; Genetic / Environmental
• Relationship to other disorders: Primary / Secondary

The Predisposing / Precipitating / Maintaining Framework

This is THE framework used in psychiatric formulation and is directly tested in SAQs ^[3]:

The lecture references Burton's Anatomy of Melancholy to show that even in the 17th century, clinicians recognised multiple causes — supernatural, congenital/hereditary, and environmental (nurses, education, terrors, loss of liberty, poverty). This is a precursor to the modern biopsychosocial model.

Most disorders are caused by the complex interplay of multiple genetic and environmental factors — Multifactorial ^[1]

A minority of psychiatric disorders have simple (single-factor) causality:

But the vast majority of psychiatric disorders are multifactorial — meaning many genes of small effect plus environmental exposures combine to produce disease.

Just because something is associated with a disorder doesn't mean it causes it. The lecture outlines the methodology:

Definitive demonstration:

• Putative cause associated with disorder
• Removing putative cause prevents disorder (interventional study)

Exclusion of confounding via stratified analysis and regression models

Bradford Hill Criteria:

• Strong and consistent association
• Correct temporal relationship
• Dose-response relationship
• Biologically plausible mechanisms

Causal modelling including Mendelian randomization ^[1]

Mendelian randomization is a clever technique: because genetic variants are randomly allocated at conception (like a natural randomized trial), you can use genetic variants as "instruments" to test whether an exposure (e.g., alcohol) causally affects an outcome (e.g., depression), free from confounding.

The same clinical disorder can have different aetiological subtypes.

The lecture uses Alzheimer's disease as the prime example:

This is the fundamental quantitative model for understanding multifactorial diseases:

All-or-none traits (diseases) arise from an underlying continuous "liability" that follows a normal distribution (by the central limit theorem). When liability exceeds a threshold, disease develops. ^[1]

Why a normal distribution? Because liability is the sum of many independent genetic and environmental factors — by the central limit theorem, the sum of many independent random variables tends toward a normal (Gaussian) distribution regardless of the distribution of each individual factor.

Why does this matter clinically?

• It explains why most people in the population don't get the disease (they're below threshold)
• It explains why relatives of affected individuals have higher risk (they share aetiological factors, so their liability distribution is shifted right)
• It explains the continuum between "normal" and "pathological" — the threshold is somewhat arbitrary

This is the clinical application of the liability-threshold model:

Liability = Diathesis (vulnerability) + Stress (proximal factors) There is a negative correlation between diathesis and stress in patients (collider bias). ^[1]

What this means in plain English:

• To cross the disease threshold, you need some combination of vulnerability (diathesis) and trigger (stress)
• Patients with high diathesis (e.g., strong family history, multiple risk genes) need less stress to become ill
• Patients with low diathesis need more stress to become ill
• When you look only at patients (i.e., people who crossed the threshold), you see an artificial negative correlation between diathesis and stress — this is called collider bias (selecting on the outcome creates a spurious association between the causes)

Clinical implication: When taking a history, if a patient has strong family history (high diathesis), don't be surprised if the precipitating stressor seems trivial. Conversely, a massive trauma can trigger illness even in someone with no family history.

Mediators are the mechanisms through which aetiological factors produce the disorder (A → M → D pathway):

Biological mediators: stress reactivity, brain connectivity Psychological mediators: cognitive function, personality, resilience Social mediators: lifestyle, support network

Potential biomarkers ("endophenotypes") — measurable traits that lie between genotype and clinical phenotype Potential points for intervention ^[1]

Why do mediators matter? Because even if you can't change the root cause (e.g., genetics), you might be able to intervene at the mediator level (e.g., improving resilience through therapy, enhancing social support).

Comorbidity [is] more frequent than expected by chance. ^[1]

The lecture presents three possible explanations (from the Johansson et al. 2013 diagram):

Environmental exposures influenced by behaviour of individual or parents. Behaviours partially genetically determined → gene-environment correlation. ^[1]

This is subtle but important. It means that what we measure as "environmental" exposure may partly be genetically driven:

• Example 1: Exposure to carcinogens in tobacco smoke is an "environment," but the behaviour of smoking is partly genetic (genes affecting nicotine dependence)
• Example 2: Exposure to social adversities due to drug addiction — the addiction itself has genetic components

Why this matters: It complicates aetiological research. When we find that "childhood adversity" is associated with depression, some of that association may be because parents with psychiatric genetic risk create more adverse environments for their children (passive gene-environment correlation).

Three types of gene-environment correlation (from genetics theory):

1. Passive: Parents provide both genes and environment (e.g., depressed parent provides depression-risk genes AND an emotionally neglectful home)
2. Evocative: Child's genetically influenced behaviour evokes environmental responses (e.g., a temperamentally difficult child provokes harsh parenting)
3. Active: Individual selects environments based on genetically influenced preferences (e.g., sensation-seeking genes → choosing risky peer groups)

Environmental factors increasing disease risk especially in those with specific genetic susceptibility. ^[1]

This is different from correlation — here the effect of the environment depends on the genotype:

Statistically: Gene-environment interaction means the combined effect of gene + environment is greater (or less) than what you'd predict from adding their individual effects.

History taking: Family/Development, Personality/Lifestyle/Habits, Stressors (acute and chronic), Social resources Formulation: Predisposing/precipitating/maintaining factors + protective factors Management: Promote understanding, reduce contributing factors, strengthen protective factors ^[1]

The lecture references using a genogram to map family history of psychiatric illness — this is a practical clinical tool that maps genetic loading visually.

The lecture traces the historical arc:

1. 19th century: Familial/social/racial "degeneracy" → stigmatization, eugenics, even genocide
2. Post-WWII: Rejection of eugenics → rise of psychodynamic/psychological theories (Freud)
3. Modern era: Scientific methods to disentangle nature from nurture

Freud: repression of early traumatic memories → psychoanalysis recalls memories into consciousness (catharsis). "Exonerates" patient as victim of external circumstances. Parents/Adults responsible for "traumatizing" children. ^[1]

The lecture references the classic Gottesman and Shields (1976) data. Key concordance rates (approximate, from multiple studies):

Heritability of schizophrenia ≈ 80% — one of the highest in psychiatry.

The lecture includes a chart ranking disorders by heritability. While exact figures vary by study, the exam-relevant ranking is:

Implications of heritability: ^[1]

• High heritability → role of genetic/biological factors → emphasis on biological interventions
• Low heritability → role of environmental/psychosocial factors → emphasis on psychosocial interventions

Nature 511, 421-427 (24 July 2014) — the landmark PGC2 study identified 128 independent associations spanning 108 loci for schizophrenia ^[1]

GWAS for depression (Howard et al. 2019) identified 103 significant loci and 269 significant genes ^[1]

Biological mechanisms: key molecules or biological pathways → novel treatment targets → heterogeneity (precision/stratified medicine) Prediction: disease risk, prognosis, treatment response ^[1]

The lecture specifically names these gene categories and loci:

Dopamine: DRD2 Glutamate: GRM3, GRIN2A, SRR Calcium channels: CACNA1C, CACNA1L, CACNB2 ^[1]

Why these matter clinically:

• DRD2: The dopamine D2 receptor is the primary target of all antipsychotic medications → validates the dopamine hypothesis of schizophrenia from a genetic angle
• Glutamate genes: Support the glutamate hypothesis (NMDA receptor hypofunction) → potential future therapeutic targets
• Calcium channels: CACNA1C is shared between schizophrenia and bipolar disorder → suggests shared biology and may explain why mood stabilisers (which affect calcium signalling) can help in both

The lecture shows co-expression networks of genes in top pathways with q < 0.1, illustrating that schizophrenia-associated genes cluster in specific biological pathways related to synaptic function, neurotransmission, and neurodevelopment.

Polygenic risk score: Predicts person's disease risk by combining effects of genotypes at multiple loci → Risk stratification → Clinical implications in future ^[1]

A PRS sums the weighted effects of thousands to millions of SNPs. Currently used in research; not yet clinically actionable for psychiatric disorders but is an area of active development.

Chromosome 22q11.2 deletion syndrome (Velocardiofacial / DiGeorge syndrome):

• Copy number variant (CNV)
• Frequency ~1/4000 live births
• 22-31% develop SZ or schizoaffective disorder
• 1.1% of SZ patients have the deletion ^[1]

Clinical features of 22q11.2 deletion (from supporting material): cardiac defects, palatal abnormalities, characteristic facies, hypocalcaemia (absent parathyroids), thymic hypoplasia → immunodeficiency. The psychiatric manifestations (psychosis, intellectual disability, autism) are major features.

Risk CNVs implicate synaptic proteins:

• CNVs that do not overlap exons: no significant enrichment
• Enrichment depends on how many genes CNVs affect (OR 1.21 per gene)
• Copy number loss (OR 1.40) more enriched than copy number gains (OR 1.12)

Significant enrichment in:

• Presynaptic adhesion molecules: NRXN1, NRXN2
• Post-synaptic scaffolding proteins: DLG1, DLG2, DLGAP1, SHANK1, SHANK2
• Glutamatergic ionotropic receptors: GRID1, GRID2, GRIN1, GRIA4
• Dystrophin and synaptic partners: DMD, DTNB, SNTB1, UTRN ^[1]

Clinical significance: These converge on synaptic structure and function — supporting a "synaptopathy" model of schizophrenia.

This is an elegant evolutionary genetics argument:

Reduced fecundity in schizophrenia:

• Males FR = 0.23 (95% CI 0.23-0.24)
• Females FR = 0.47 (95% CI 0.46-0.48) (Power et al, JAMA 2013 — Swedish cohort of 2.3M) ^[1]

The puzzle: If schizophrenia has such high heritability (~80%) and reduces reproductive fitness so dramatically, why hasn't natural selection eliminated the risk alleles?

The answer:

1. De novo mutations continuously replenish high-risk alleles before selection can eliminate them
2. Rate of de novo mutations positively associated with paternal age ^[1]
3. Increased risk of schizophrenia in individuals born to older fathers ^[1]
4. Alternative explanation: genetic predisposition associated with later fatherhood (reverse causation — people with schizophrenia-risk genes may have social difficulties that delay fatherhood) ^[1]

22q11.2 deletion syndrome associated with intellectual disability, autism AND psychosis ^[1]

Twin studies showed shared genetic aetiology between:

• Schizophrenia, mania and schizoaffective disorder (Cardno et al, 2002)
• Bipolar affective disorder and unipolar depression (McGuffin et al, 2003)
• Anxiety and depression (Kendler et al, 1992) ^[1]

GWAS confirm genetic overlap:

• Substantial shared SNP effects across psychiatric disorders (coheritability)
• Shared genetic aetiology partially explains excess comorbidity
• Challenge to the Kraeplinian dichotomy (the traditional distinction between schizophrenia and bipolar disorder)
• Common variants do not entirely account for heritability estimated from twin studies ("missing heritability") ^[1]

"Missing heritability": Twin studies estimate schizophrenia heritability at ~80%, but GWAS-identified common variants explain only ~25-30% of variance. The "missing" portion may be due to rare variants (CNVs, rare SNPs), gene-gene interactions, gene-environment interactions, and epigenetic effects.

Schizophrenia associated with obstetric history:

• Birth in winter months / urban areas
• Fetal growth retardation
• Fetal perinatal hypoxia
• Prenatal adversity:
  • Malnutrition: 1944 Dutch famine, and 1958 Chinese famine
  • Infections: 1957 influenza pandemic

Damage to developing brain which increases risk of psychiatric disorder in later life ^[1]

Why winter birth? Several hypotheses: (1) seasonal infections (maternal influenza in second trimester); (2) vitamin D deficiency; (3) nutritional factors. The Dutch Hunger Winter study showed that severe caloric restriction during the first trimester was associated with doubled risk of schizophrenia.

Why urban birth? Possibly related to higher rates of infection, overcrowding, pollution, and social stress.

Males more prone to intellectual disability, autism, conduct disorder, and substance use disorder Females more prone to childhood emotional disorder, anxiety and depression Age-of-onset of schizophrenia earlier in males than females ^[1]

Why the gender difference in schizophrenia onset? The oestrogen hypothesis suggests that oestrogen has neuroprotective effects (particularly on dopaminergic systems), delaying onset in females. This is supported by the observation that women have a second peak of schizophrenia onset around menopause when oestrogen levels fall.

Risk factors:

• Parental loss (death / divorce / separation)
• Maltreatment (Physical / Emotional)
• Sexual abuse

Associated disorders:

• Emotional disorders, Conduct disorders (Delinquency)
• Anxiety and depression, PTSD
• Substance use disorders
• Borderline personality disorder
• Schizophrenia ^[1]

The lecture references Bowlby's attachment theory: secure attachment in infancy (reliable, responsive caregiver) is protective; insecure/disorganised attachment increases vulnerability to later psychopathology.

Early adversity has wide-ranging effects (e.g. on stress response and neuroplasticity), partially mediated by epigenetic reprogramming, which increases psychiatric disorder risk ^[1]

The mechanism (from Li et al. 2020):

1. Early adversity → chronic stress → sustained activation of HPA axis
2. HPA axis dysregulation → epigenetic changes (DNA methylation, histone modification) in stress-response genes
3. Altered gene expression → abnormal stress reactivity, impaired neuroplasticity
4. These changes persist into adulthood → increased vulnerability to depression and other disorders

Key epigenetic mechanism: Methylation of the glucocorticoid receptor gene (NR3C1) promoter → reduced glucocorticoid receptor expression → impaired negative feedback of HPA axis → chronically elevated cortisol. This was demonstrated in both animal models (rat pup licking/grooming studies by Meaney) and human studies (hippocampal NR3C1 methylation in suicide victims with childhood abuse).

Chronic unremitting stress → sustained activation of HPA axis → chronically raised levels of glucocorticoids → impairments in brain, immunological and metabolic functions ^[1]

Immigrants:

• 2-4 fold increased rates of schizophrenia
• Greater effect in second-generation migrants
• Greater effect in areas with lower density of migrants
• Social exclusion ^[1]

Why is the effect stronger in second-generation migrants and in areas with fewer migrants? This argues against a simple "stress of migration" explanation. The leading hypothesis is social defeat / social exclusion: being a visible minority in an area where your ethnic group is rare leads to chronic social adversity and sensitisation of the dopamine system.

Recent adverse life events (e.g. bereavement, divorce, injury or illness, loss of employment or wealth, failure or humiliation) can trigger mental disorders such as depression, mania and schizophrenia ^[1]

From Ryan Ho's notes: ↑6× risk of adverse life events before onset of MDD; less important in established melancholic depression and strong family history (because diathesis is high, less stress needed) ^[2].

Ability to cope with stress and recover from stressful situations Increased by repeated brief parental separations / appropriate challenges during childhood Partly mediated by greater self-efficacy and coping skills Individual differences in optimal level of challenges ^[1]

This is a nuanced concept: stress inoculation — small, manageable doses of stress during development can build coping skills and resilience. Too much stress overwhelms; too little leaves the individual unprepared. There is an inverted-U relationship.

Good social support:

• Protective against the onset of mental disorders
• Helps maintain remission from illness

High expressed emotions (EE) in family:

• Hostility, over-involvement, critical comments
• Increase risk of relapse of schizophrenia ^[1]

Expressed Emotion (EE) is a well-validated predictor of relapse in schizophrenia. Families with high EE (measured by the Camberwell Family Interview) have relapse rates of ~50% at 9 months vs ~15% in low-EE families. This is why family psychoeducation and intervention is a key part of schizophrenia management.

Prolonged and heavy usage of psychoactive substances increase mental disorder risk:

• Alcohol: Psychosis, Dementia
• Amphetamines: Psychosis
• Cannabis: Psychosis ^[1]

Cannabis and psychosis: The relationship is dose-dependent and appears causal (supported by Mendelian randomization studies). Heavy cannabis use in adolescence approximately doubles the risk of schizophrenia, with higher potency (high-THC strains) carrying greater risk.

1. Which psychiatric disorder has the highest heritability?

   • Answer: Autism (~90%). Among major adult disorders: schizophrenia (~80%) and bipolar disorder (~75-85%).

2. A 25-year-old male develops schizophrenia. His MZ twin is unaffected. What does this demonstrate?

   • Answer: Incomplete penetrance / role of environmental factors. MZ concordance is ~50%, not 100%, proving that genetics alone is insufficient.

3. What is the MOST COMMON gene contributing to risk of Alzheimer's disease? (Tested in 2025 MCQ Q20)

   • Answer: APOE gene ^[5].

4. Which neurotransmitter system's receptor gene (DRD2) was identified in schizophrenia GWAS?

   • Answer: Dopamine.

5. What percentage of patients with 22q11.2 deletion develop schizophrenia?

   • Answer: 22-31% ^[1].

6. A 50-year-old woman has chronic pain after a work injury, with depressive symptoms. List predisposing, precipitating, and perpetuating factors. (Based on 2017 SAQ Q10 ^[3])

   • Predisposing: Anxious premorbid personality, genetic vulnerability
   • Precipitating: Fall at work (physical injury + psychological trauma)
   • Perpetuating: Ongoing litigation/compensation, smoking/drinking, chronic pain, disability, loss of employment, lack of resolution

7. Explain the diathesis-stress model with a clinical example.

   • The diathesis-stress model states that disease arises from the interaction of vulnerability (diathesis — genetic, developmental, personality) and proximal stress. Example: A patient with strong family history of depression (high diathesis) develops MDD after a minor job setback (low stress), while a patient with no family history only develops MDD after a devastating bereavement (high stress).

8. Name two classic examples of gene-environment interaction in psychiatry.

   • (1) MAO-A low-activity variant × childhood maltreatment → antisocial behaviour
   • (2) 5HTTLPR short allele × stressful life events → depression