Genetics Schizophrenia

Study Notes

Exam: PG exams MD Psychiatry, Sep 2026

1. Basic Genetics Review

1.1 DNA, Genes, and Alleles

• DNA = double-stranded helix of nucleotide bases (A, T, G, C)
• Gene = functional unit of heredity; a segment of DNA that codes for a protein or regulatory RNA
• Allele = one of two or more alternative forms of a gene at the same locus
• Homozygous = two identical alleles; Heterozygous = two different alleles
• Genotype = genetic makeup; Phenotype = observable expression

1.2 Types of Mutations

Swipe to compare →

Trinucleotide repeat disorders relevant to psychiatry:

• Huntington disease -- CAG repeat on chromosome 4 (>36 repeats); anticipation (worsens across generations)
• Fragile X -- CGG repeat on FMR1 gene (>200 = full mutation); most common inherited cause of intellectual disability
• Myotonic dystrophy -- CTG repeat; associated with cognitive decline

1.3 Chromosomal Abnormalities

• Aneuploidy -- abnormal chromosome number (e.g., trisomy 21, Turner 45,X, Klinefelter 47,XXY)
• Deletions -- loss of chromosomal segment (e.g., 22q11.2 deletion in DiGeorge/VCFS)
• Duplications -- extra copy of a segment
• Translocations -- transfer between non-homologous chromosomes (balanced vs unbalanced)
• Inversions -- segment reversal within a chromosome

1.4 Mendelian vs Complex Inheritance

1.5 Key Genetic Concepts

• Penetrance = probability a genotype produces the phenotype
• Complete penetrance = 100% of carriers show phenotype
• Incomplete/reduced penetrance = <100% show phenotype
• Schizophrenia has incomplete penetrance (MZ concordance ~48%, not 100%)

• Expressivity = degree to which a phenotype is expressed
• Variable expressivity = same genotype, different severity

• Genetic heterogeneity
• Locus heterogeneity = different genes produce the same phenotype
• Allelic heterogeneity = different mutations in the same gene produce the same phenotype

• Pleiotropy = one gene affects multiple phenotypes (e.g., 22q11.2 deletion causes cardiac defects + psychosis + learning disability)

• Epistasis = one gene modifies the effect of another

• Endophenotype (intermediate phenotype) = heritable trait closer to the gene than the clinical phenotype
• Examples in schizophrenia: smooth pursuit eye movements, P50 sensory gating, working memory deficits, prepulse inhibition

2. Genetic Study Designs

2.1 Family Studies

• Purpose: Determine if a disorder runs in families
• Method: Compare prevalence in relatives of affected individuals (probands) vs general population
• Recurrence risk = risk of disorder in relatives of an affected individual
• Relative risk (lambda) = recurrence risk in relatives / population prevalence

Schizophrenia family data:

Limitation: Cannot separate genetic from environmental factors (shared family environment)

2.2 Twin Studies

• MZ (monozygotic) twins = 100% shared DNA
• DZ (dizygotic) twins = ~50% shared DNA (like siblings)
• Concordance rate = probability that both twins are affected when one is affected

Heritability estimation:

Where r = concordance rate. For schizophrenia:

Equal environments assumption: Assumes MZ and DZ twins share environment equally. If violated (MZ treated more similarly), heritability may be overestimated.

2.3 Adoption Studies

Separate genetic from environmental contributions by studying individuals raised away from biological parents.

Key conclusion: Genetic factors are the primary driver; being raised by a schizophrenic parent alone does not increase risk.

2.4 Linkage Analysis

• Purpose: Locate genes by tracking co-inheritance of genetic markers with the disease in families
• Method: Uses microsatellites (short tandem repeats) or SNPs as markers
• LOD score (logarithm of odds): statistical measure of linkage
• LOD >= 3.0 = significant linkage (1000:1 odds)
• LOD <= -2.0 = linkage excluded
• Best for: Mendelian disorders with large effect sizes
• Limitation in psychiatry: Most psychiatric disorders are polygenic; linkage has low power for small-effect variants

2.5 Association Studies

• Purpose: Test if a specific allele is more common in affected vs unaffected individuals
• Case-control design: Compare allele frequencies between cases and controls
• Transmission Disequilibrium Test (TDT): Family-based; tests if a particular allele is transmitted from heterozygous parents to affected offspring more than expected by chance. Avoids population stratification bias.
• Candidate gene studies: Hypothesis-driven; test specific genes based on known biology
• Problem: poor replication, publication bias, underpowered

2.6 GWAS (Genome-Wide Association Studies)

• Hypothesis-free: Scans the entire genome (~1 million+ SNPs)
• SNP = Single Nucleotide Polymorphism (single base pair variation)
• Genome-wide significance threshold: p < 5 x 10^-8 (Bonferroni correction for ~1 million tests)
• Manhattan plot: Graph of -log10(p-value) vs chromosomal position; peaks above significance line = associated loci
• Linkage disequilibrium (LD): Non-random association of alleles at different loci; explains why a significant SNP may tag a nearby causal variant

Strengths: Unbiased, can discover novel pathways

Limitations: Detects only common variants (MAF >1%), small effect sizes (OR typically 1.05-1.2), requires enormous samples (tens of thousands), explains only a fraction of heritability

2.7 Copy Number Variants (CNVs)

• Definition: Deletions or duplications of DNA segments (>1 kb)
• Detected by array comparative genomic hybridization (aCGH) or SNP arrays
• De novo CNVs: New mutations not present in parents; enriched in schizophrenia
• Individual CNVs are rare but have larger effect sizes than common SNPs (OR 2-60)

2.8 Whole Exome / Whole Genome Sequencing

• Whole exome sequencing (WES): Sequences all protein-coding regions (~1.5% of genome)
• Whole genome sequencing (WGS): Sequences entire genome including non-coding regions
• Detects rare variants, de novo mutations, structural variants
• Important for identifying rare, high-penetrance mutations in psychiatric disorders

3. Genetics of Schizophrenia (MAIN FOCUS)

3.1 Overview

• Heritability: ~80% (from twin and adoption studies)
• MZ concordance: ~48%
• DZ concordance: ~17%
• First-degree relative risk: ~10% (10x general population)
• Inheritance pattern: Complex, polygenic, non-Mendelian
• Missing heritability: GWAS loci explain only ~7% of variance; rest may be due to rare variants, epistasis, gene-environment interaction, epigenetics

3.2 Candidate Gene Era

These genes were studied based on the dopamine and glutamate hypotheses. Most findings from candidate gene studies have not replicated in GWAS, but they remain important for exam answers and understanding neurobiology.

3.3 GWAS Findings

Landmark study: Schizophrenia Working Group of the PGC (2014)

• 36,989 cases + 113,075 controls
• Identified 108 genome-wide significant loci
• Implicated dopaminergic, glutamatergic, calcium signaling, and immune pathways

Key GWAS findings:

C4 and synaptic pruning (Sekar et al., 2016):

• C4A gene in the MHC region
• Higher C4A expression = more complement-mediated synaptic pruning
• Explains: (a) adolescent onset timing (pruning peaks in adolescence), (b) reduced synaptic density in schizophrenia, (c) grey matter volume loss
• Bridges GWAS finding to neurodevelopmental model

3.4 Copy Number Variants in Schizophrenia

22q11.2 deletion syndrome (DiGeorge/VCFS) -- HIGH YIELD:

• Prevalence: 1 in 4000 births
• Features: cardiac defects, palatal abnormalities, hypocalcemia, T-cell deficiency, learning difficulties, characteristic facies
• 25-30% develop schizophrenia-like psychosis (highest known genetic risk factor for schizophrenia after having an MZ twin)
• Contains COMT gene (haploinsufficiency may contribute to dopamine dysregulation)

3.5 Polygenic Risk Scores (PRS)

• Aggregate the effects of thousands of common risk variants into a single score
• PRS for schizophrenia can distinguish cases from controls at a population level (AUC ~0.70-0.75)
• Higher PRS associated with: earlier onset, greater symptom severity, poorer response to treatment
• Not yet clinically useful for individual prediction (insufficient discrimination)
• Shared PRS between schizophrenia and bipolar disorder supports the genetic overlap between these conditions

3.6 Two-Hit Hypothesis

1. First hit: Genetic vulnerability (polygenic risk, CNVs, or rare mutations)
2. Second hit: Environmental insult (prenatal infection, obstetric complications, cannabis use, childhood adversity, urban living, migration)

Both hits are necessary for the disorder to manifest. Explains:

• Why MZ concordance is not 100%
• Why some carriers of high-risk CNVs remain unaffected
• Why environmental risk factors alone are insufficient

3.7 Neurodevelopmental Model

• Schizophrenia conceptualized as a disorder of brain development
• Prenatal insults (infection, malnutrition, hypoxia) + genetic vulnerability disrupt early brain development
• Abnormalities remain latent until adolescence, when:
• Normal synaptic pruning (now excessive due to C4A) unmasks deficits
• Prefrontal cortex maturation fails
• Dopamine system dysregulation emerges
• Evidence: premorbid cognitive deficits, minor physical anomalies, obstetric complications, ventricular enlargement at first episode

4. Epigenetics in Psychiatry

4.1 Core Concepts

Epigenetics = heritable changes in gene expression that do NOT involve changes in DNA sequence.

4.2 Epigenetics in Schizophrenia

• RELN (Reelin) gene: Hypermethylation of promoter region in schizophrenia → reduced reelin expression → impaired neuronal migration and synaptic plasticity
• GAD67 (GAD1) gene: Promoter hypermethylation → reduced GAD67 → decreased GABA synthesis in cortical interneurons
• Both findings are consistent with the GABAergic deficit hypothesis of schizophrenia

4.3 Environmental Triggers of Epigenetic Change

• Cannabis: THC exposure alters DNA methylation patterns at dopamine-related genes
• Prenatal stress: Maternal cortisol exposure alters methylation of glucocorticoid receptor (NR3C1)
• Prenatal infection: Maternal immune activation → inflammatory cytokines → epigenetic changes in offspring
• Early life adversity: Childhood abuse alters NR3C1 methylation (McGowan et al., 2009 -- initially in rats, replicated in humans)

4.4 Transgenerational Epigenetic Effects

• Epigenetic marks can be transmitted across generations
• Dutch Hunger Winter: Offspring of famine-exposed mothers had altered DNA methylation decades later
• Relevance: May partly explain familial aggregation beyond DNA sequence variation

5. Gene-Environment Interactions (GxE)

A GxE interaction occurs when the effect of an environmental exposure on a phenotype depends on the individual's genotype (or vice versa).

5.1 Classic GxE Studies

5.2 Important Caveats

• 5-HTTLPR x stress: Most debated finding in psychiatric genetics. Large collaborative meta-analysis (Culverhouse et al., 2018) found no support for the interaction. However, the broader concept of GxE in depression remains valid.
• MAOA x maltreatment: Better replicated than 5-HTTLPR; considered a robust GxE finding
• GxE studies require very large samples to have adequate power

5.3 Diathesis-Stress vs Differential Susceptibility

• Diathesis-stress: Risk alleles increase vulnerability to negative environments
• Differential susceptibility (Belsky): The same alleles that increase vulnerability to negative environments also increase benefit from positive environments ("orchid vs dandelion" or "for better and for worse")
• Example: 5-HTTLPR short allele carriers may have worse outcomes with adversity but better outcomes with supportive environments

6. Pharmacogenetics and Pharmacogenomics

6.1 Definitions

• Pharmacogenetics = study of how single genes affect drug response
• Pharmacogenomics = study of how the entire genome affects drug response
• Goal: Personalized medicine -- right drug, right dose, for the right patient

6.2 CYP450 System

The cytochrome P450 enzymes are the primary drug-metabolizing system. Four enzymes metabolize the majority of psychotropic medications.

6.3 Metabolizer Phenotypes

CYP2D6 examples:

• PM + codeine → Cannot convert codeine to morphine → No analgesic effect
• UM + codeine → Excessive morphine production → Respiratory depression (fatal in neonates via breast milk)
• PM + TCAs → Drug accumulation → Cardiotoxicity
• PM + risperidone → Elevated levels → EPS

6.4 HLA Pharmacogenetics

6.5 Pharmacogenomic Testing in Clinical Practice

• CPIC (Clinical Pharmacogenetics Implementation Consortium): Provides evidence-based dosing guidelines based on genotype
• Genes with CPIC guidelines in psychiatry: CYP2D6, CYP2C19, HLA-B
• Current status: Routine testing not yet standard of care, but gaining traction
• Strongest evidence: CYP2D6 for TCAs, CYP2C19 for citalopram/escitalopram, HLA-B*1502 for carbamazepine
• Growing evidence: Panel-based testing for treatment-resistant depression (GUIDED trial)
• Limitations: Testing only covers pharmacokinetics; pharmacodynamic variation (receptor sensitivity) not captured. Cost, turnaround time, and clinician knowledge are barriers.

6.6 Personalized Medicine

• Moving from "one size fits all" to genotype-guided prescribing
• Combines pharmacogenomics with clinical factors (age, renal/hepatic function, drug interactions)
• Future directions: Polygenic risk scores for drug response, AI-guided prescribing algorithms, integration of pharmacogenomic data into electronic health records

7. Genetics of Other Psychiatric Disorders (Brief)

7.1 Bipolar Disorder

• Heritability: ~85% (highest among psychiatric disorders along with ASD)
• MZ concordance: ~40-70%
• Key GWAS loci: CACNA1C (shared with schizophrenia), ANK3, ODZ4
• Significant genetic overlap with schizophrenia (~60% shared loci)
• This overlap supports the spectrum concept of psychosis

7.2 ADHD

• Heritability: ~76%
• Candidate genes (historical): DRD4 (7-repeat allele), DAT1/SLC6A3 (dopamine transporter)
• GWAS (Demontis et al., 2019): 12 significant loci; enriched for genes expressed in brain, involved in neurodevelopment
• Genetic correlation with educational attainment (negative), substance use disorders

7.3 Autism Spectrum Disorder

• Heritability: ~80-90%
• Strong role of de novo mutations (new mutations not inherited from parents)
• Rare variants: Large effect CNVs, de novo point mutations
• Fragile X syndrome: Single most common known genetic cause (2-3% of ASD cases)
• Other associated syndromes: Rett syndrome (MECP2), Tuberous sclerosis (TSC1/TSC2)
• Hundreds of genes implicated; converge on synaptic function and chromatin remodeling pathways

7.4 Alzheimer Disease

• Early-onset familial AD (<65 years) = ~5% of cases; Mendelian (APP, PSEN1, PSEN2)
• Late-onset sporadic AD = ~95% of cases; APOE e4 is the strongest genetic risk factor
• GWAS has identified 75+ loci for late-onset AD (immune system, lipid metabolism, endocytosis)

8. Summary: Key Numbers for Exam

9. Cross-References

• Neurobiology of schizophrenia: NB-04 (dopamine, glutamate, GABA hypotheses)
• Pharmacology: NB-03 (antipsychotics, clozapine monitoring, drug interactions)
• Schizophrenia clinical features and classification: NB-06
• Research methodology and statistics: NB-01 (study designs, epidemiology)
• Child psychiatry / ASD / ADHD: NB-12
• Organic psychiatry / Alzheimer: NB-08
• Substance use / Cannabis and psychosis: NB-10

Model Answers

Exam: PG exams MD Psychiatry, Sep 2026

Q1. "Describe the genetics of schizophrenia." (10 marks)

Answer:

Introduction (1 mark)

Schizophrenia is a complex, polygenic disorder with estimated heritability of approximately 80%. It does not follow Mendelian inheritance but results from the cumulative effect of multiple genetic variants interacting with environmental factors.

Evidence from Genetic Epidemiology (3 marks)

Family studies:

• Risk increases with degree of genetic relatedness to an affected individual
• General population risk: 1%; first-degree relatives: ~10%; offspring of two affected parents: ~46%
• Relative risk for first-degree relatives is approximately 10x the general population

Twin studies:

• MZ twin concordance: ~48%; DZ twin concordance: ~17%
• Heritability estimated using Falconer's formula: h2 = 2(rMZ - rDZ) = 2(0.48 - 0.17) = 0.62
• More sophisticated models estimate heritability at ~80%
• MZ concordance <100% indicates role of non-genetic factors

Adoption studies:

• Heston (1966): Children of schizophrenic mothers adopted at birth showed 10.6% risk vs 0% in controls
• Kety (1968): Danish adoption study found higher rates in biological relatives of adopted schizophrenics than adoptive relatives
• Cross-fostering studies: Children of healthy parents raised by schizophrenic parents show no increased risk
• Conclusion: Genetic factors are the primary driver of familial aggregation

Molecular Genetics (4 marks)

Candidate genes (historical):

• DISC1 (disrupted in schizophrenia 1) -- identified through a balanced translocation in a Scottish family; involved in neurodevelopment
• NRG1 (neuregulin 1) -- role in NMDA receptor function and myelination
• DTNBP1 (dysbindin) -- reduced expression in postmortem schizophrenia brains; glutamate signaling
• COMT (Val158Met) -- catechol-O-methyltransferase; Val allele associated with increased dopamine degradation in PFC
• Most candidate gene findings have not been replicated in GWAS

GWAS findings:

• PGC Schizophrenia Working Group (2014): 36,989 cases; identified 108 genome-wide significant loci
• Key findings: DRD2 (validates dopamine hypothesis), glutamate pathway genes (GRM3, GRIN2A), calcium channel genes (CACNA1C)
• MHC region / C4 complement gene (Sekar et al., 2016): C4A overexpression leads to excessive synaptic pruning in adolescence, connecting GWAS data to the neurodevelopmental model

Copy number variants (CNVs):

• 22q11.2 deletion (DiGeorge/VCFS) -- 25x risk for schizophrenia; strongest single genetic risk factor
• Other CNVs: 1q21.1, 15q13.3, NRXN1, 3q29 deletions
• Individually rare but confer larger effect sizes than common variants

Polygenic risk scores:

• Aggregate thousands of common risk variants into a single predictive score
• Can distinguish cases from controls at population level but not yet clinically useful for individuals

Integrative Model (2 marks)

The current understanding supports a polygenic, multifactorial model:

• Two-hit hypothesis: Genetic vulnerability (first hit) + environmental insult (second hit) required for illness expression
• Neurodevelopmental model: Prenatal genetic and environmental insults disrupt brain development; abnormalities remain latent until adolescent synaptic pruning (C4-mediated) unmasks them
• Gene-environment interactions (e.g., COMT x cannabis, AKT1 x cannabis) modulate risk
• Epigenetic mechanisms (DNA methylation of RELN and GAD67 promoters) may mediate environmental effects on gene expression

Q1 Extended: 20-Mark Long Essay Version

Introduction (2 marks) -- As above, expanded with: definition, lifetime prevalence 0.7-1%, classification as a complex genetic disorder, contrast with Mendelian disorders.

Genetic Epidemiology (5 marks) -- As above, expanded with:

• Full risk table across all degrees of relatedness
• Equal environments assumption in twin studies and its limitations
• Specific methodology of each adoption study design
• Endophenotypes: smooth pursuit eye movements, P50 gating, working memory deficits

Molecular Genetics (7 marks) -- As above, expanded with:

• Linkage analysis: LOD scores, why it failed for schizophrenia (small effect sizes, locus heterogeneity)
• Detailed description of GWAS methodology: SNPs, Manhattan plots, genome-wide significance threshold (p < 5 x 10^-8), LD
• Expanded candidate gene section with chromosomal locations and functional significance
• Whole exome/genome sequencing: role in detecting rare de novo mutations
• Detailed description of 22q11.2 deletion: prevalence (1:4000), clinical features, COMT haploinsufficiency

Neurodevelopmental and Integrative Models (4 marks) -- Expanded:

• Evidence for neurodevelopmental model: premorbid deficits, obstetric complications, minor physical anomalies, ventricular enlargement at first episode
• C4/MHC finding as bridge between genetics and neurodevelopment
• Two-hit hypothesis with specific examples
• Epigenetics: RELN, GAD67, NR3C1 methylation
• GxE interactions: COMT x cannabis, AKT1 x cannabis

Future Directions and Limitations (2 marks)

• Polygenic risk scores: promise and current limitations
• Missing heritability problem
• Pharmacogenomics: moving toward personalized treatment
• Genetic counseling in schizophrenia: challenges of communicating probabilistic risk

Q2. "The biological causes of schizophrenia. Genetics of schizophrenia." [5+5 marks]

Answer:

Part A: Biological Causes of Schizophrenia (5 marks)

Neurochemical hypotheses:

• Dopamine hypothesis: Mesolimbic hyperactivity (positive symptoms), mesocortical hypoactivity (negative/cognitive symptoms). Evidence: amphetamine psychosis, D2 receptor blockade by antipsychotics
• Glutamate hypothesis: NMDA receptor hypofunction. Evidence: PCP/ketamine psychosis mimics schizophrenia including negative symptoms
• GABA hypothesis: Reduced GABAergic interneuron function in cortex
• Serotonin: 5-HT2A involvement (atypical antipsychotics)

Structural brain abnormalities:

• Ventricular enlargement (lateral and third ventricles)
• Reduced grey matter volume (PFC, temporal lobe, hippocampus)
• Present at first episode (not progressive medication effects)

Neurodevelopmental factors:

• Obstetric complications (hypoxia, preeclampsia)
• Prenatal infection (influenza, toxoplasmosis)
• Season of birth effect (winter/spring excess)
• Minor physical anomalies

Neuroimmune/neuroinflammation:

• Microglial activation
• Elevated pro-inflammatory cytokines
• C4 complement gene and excessive synaptic pruning

Part B: Genetics of Schizophrenia (5 marks)

• Heritability ~80%; MZ concordance 48%, DZ 17%, first-degree relative risk 10x
• Adoption studies (Heston, Kety) confirm genetic over environmental transmission
• Candidate genes: DISC1, NRG1, DTNBP1, COMT -- mostly not replicated in GWAS
• GWAS (PGC 2014): 108 loci including DRD2, MHC/C4, glutamate genes, calcium channels
• CNVs: 22q11.2 deletion (25x risk), 1q21.1, 15q13.3, NRXN1
• Polygenic inheritance with gene-environment interaction (two-hit model)
• Epigenetic mechanisms: RELN and GAD67 promoter methylation

Cross-reference: D1 sections 3 and 4; NB-04 (neurobiology)

Q3. "Biopsychosocial model of schizophrenia. Recent advances in genetics." [5+5 marks]

Answer:

Part A: Biopsychosocial Model (5 marks)

Biological factors:

• Genetic: 80% heritability, polygenic risk, CNVs (22q11.2)
• Neurochemical: Dopamine, glutamate, GABA dysregulation
• Structural: Ventricular enlargement, cortical thinning
• Neurodevelopmental: Obstetric complications, prenatal infection

Psychological factors:

• Expressed emotion (EE): High criticism, hostility, overinvolvement in family increases relapse risk
• Cognitive biases: Jumping to conclusions, externalizing attributional style
• Childhood trauma: 2-3x increased risk; dose-response relationship

Social factors:

• Urbanicity: Urban birth/upbringing increases risk 2-3x
• Migration/ethnic minority status: Increased risk, especially in low ethnic density areas
• Social isolation and deprivation
• Cannabis use: Dose-dependent risk, especially adolescent use

Integration: The stress-vulnerability model (Zubin and Spring, 1977) proposes that the disorder emerges when environmental stressors exceed the individual's threshold, which is determined by genetic and neurodevelopmental vulnerability.

Part B: Recent Advances in Genetics (5 marks)

GWAS:

• PGC 2014: 108 loci in ~150,000 subjects; largest psychiatric GWAS at the time
• PGC3 (2022): >270 loci in expanded samples
• Implicates glutamate, dopamine, calcium, and immune pathways

C4 complement gene (Sekar et al., 2016):

• Strongest GWAS signal maps to MHC region
• C4A overexpression leads to excessive complement-mediated synaptic pruning
• Provides a mechanistic link between genetics and the neurodevelopmental model
• Explains adolescent onset and grey matter loss

Copy number variants:

• Rare but large-effect deletions/duplications
• 22q11.2 deletion: 25x risk; 3q29 deletion: ~40x risk
• De novo CNVs enriched in sporadic schizophrenia

Polygenic risk scores:

• Aggregate effect of thousands of common variants
• Can predict case-control status at population level (AUC ~0.70)
• Shared PRS with bipolar disorder supports dimensional/spectrum concept

Epigenetics:

• DNA methylation changes at RELN, GAD67 promoters
• Environmental factors (cannabis, stress, infection) mediate effects through epigenetic mechanisms
• Potential for reversibility -- therapeutic implications

Q4. "Genetics of Schizophrenia." (Short note, 10 marks)

Q5. "What is Genetic mutation and how does it occur?" (10 marks)

Answer:

Definition (1 mark)

A genetic mutation is a permanent change in the nucleotide sequence of DNA. Mutations may be neutral, beneficial, or pathogenic depending on their location and functional impact.

Types of Mutations (4 marks)

Point mutations (single nucleotide changes):

• Missense: Change in one amino acid (e.g., sickle cell disease: GAG→GTG, Glu→Val)
• Nonsense: Creates premature stop codon → truncated, non-functional protein
• Silent: No amino acid change due to codon redundancy

Insertions and deletions (indels):

• Frameshift: Insertion/deletion of nucleotides not in multiples of 3 shifts the reading frame → completely altered downstream protein
• In-frame: Insertion/deletion in multiples of 3 adds/removes amino acids without shifting frame

Trinucleotide repeat expansions:

• Normal alleles have a set number of repeats; expansion beyond threshold causes disease
• Anticipation: Repeat number increases across generations → earlier onset, greater severity
• Examples: Huntington (CAG >36), Fragile X (CGG >200), Myotonic dystrophy (CTG)

Chromosomal mutations:

• Aneuploidy: Gain/loss of whole chromosomes (nondisjunction)
• Deletions: Loss of chromosomal segment (e.g., 22q11.2)
• Duplications: Extra copy of a segment
• Translocations: Transfer between chromosomes (balanced vs unbalanced)
• Inversions: Reversal of a segment

Mechanisms of Mutation (3 marks)

Spontaneous:

• DNA replication errors (base mismatch, slippage during repeat replication)
• Spontaneous depurination and deamination
• Failure of DNA repair mechanisms

Induced:

• Physical mutagens: ionizing radiation (X-rays, UV), causing thymine dimers, strand breaks
• Chemical mutagens: alkylating agents, base analogs, intercalating agents
• Biological: viral insertion, transposable elements

De novo mutations:

• New mutations not present in either parent
• Occur during gametogenesis or early embryonic development
• Paternal age effect: Older fathers have more de novo point mutations (relevant for schizophrenia and autism risk)

Clinical Relevance in Psychiatry (2 marks)

• Schizophrenia: De novo CNVs (22q11.2 deletion), de novo point mutations, trinucleotide repeats in associated conditions
• Autism: High rate of de novo mutations; hundreds of genes implicated
• Huntington disease: Trinucleotide repeat expansion with anticipation
• Fragile X: Most common inherited intellectual disability; CGG expansion
• Pharmacogenetics: CYP2D6 gene duplications/deletions affect metabolizer status

Q6. "What is pharmacogenetics? Describe its research and implications in treatment." [2+4+4 marks]

Answer:

What is Pharmacogenetics? (2 marks)

Pharmacogenetics is the study of how genetic variation in individual genes influences drug response, including drug efficacy, dosing requirements, and adverse drug reactions. The broader term pharmacogenomics encompasses the influence of the entire genome on drug response. The goal is to move from empirical "trial and error" prescribing to personalized, genotype-guided treatment.

Research in Pharmacogenetics (4 marks)

CYP450 enzyme polymorphisms:

• CYP2D6: Most studied in psychiatry. Metabolizes most SSRIs, TCAs, risperidone, aripiprazole, haloperidol. Over 100 allelic variants identified. Gene duplications (ultrarapid) and null alleles (poor metabolizer) have clear clinical consequences.
• CYP2C19: Metabolizes citalopram, escitalopram, sertraline, diazepam. Poor metabolizers at risk for citalopram toxicity (QTc prolongation).
• CYP1A2: Metabolizes clozapine, olanzapine. Induced by smoking (polycyclic aromatic hydrocarbons, not nicotine). Critical for clozapine monitoring.
• CYP3A4: Metabolizes quetiapine, lurasidone, benzodiazepines. Many drug interactions.

HLA pharmacogenetics:

• HLA-B*1502 and carbamazepine: Strong association with Stevens-Johnson Syndrome/TEN in Asian populations. FDA mandates testing before prescribing.
• HLA-A*3101 and carbamazepine: Associated with hypersensitivity reactions in European and Japanese populations.

Pharmacodynamic targets:

• Serotonin transporter (SLC6A4): 5-HTTLPR variants may influence SSRI response (evidence mixed)
• DRD2/DRD3 polymorphisms: May influence antipsychotic response
• HTR2A variants: Associated with clozapine response

Key research approaches:

• Candidate gene studies of drug-metabolizing enzymes
• GWAS for drug response phenotypes
• Clinical trials incorporating pharmacogenomic testing (GUIDED trial for treatment-resistant depression)

Implications in Treatment (4 marks)

Clinical applications:

• CYP2D6 genotyping before starting TCAs: Poor metabolizers need 50% dose reduction; ultrarapid metabolizers may need higher doses or alternative drug
• CYP2C19 genotyping for citalopram/escitalopram: Poor metabolizers should not exceed 20mg citalopram (QTc risk)
• HLA-B*1502 testing before carbamazepine in Asian populations: Prevents life-threatening SJS/TEN
• CYP1A2 monitoring for clozapine: Smoking cessation requires dose reduction; smoking resumption requires dose increase

Metabolizer phenotype-based dosing:

• Poor metabolizers: Lower starting dose, slower titration, or choose alternative drug not metabolized by that enzyme
• Ultrarapid metabolizers: Higher doses or alternative drug; standard doses may be subtherapeutic
• CPIC guidelines provide specific dosing recommendations based on genotype

Current limitations:

• Cost and accessibility of testing
• Limited clinician knowledge of how to interpret results
• Pharmacokinetic genes (CYP450) are better understood than pharmacodynamic genes
• Most evidence is for avoiding adverse effects rather than predicting efficacy
• Turnaround time may be too slow for acute clinical situations

Future directions:

• Pre-emptive panel testing (test once, use for life)
• Integration into electronic health records with clinical decision support
• Polygenic risk scores for treatment response
• AI-guided prescribing algorithms combining pharmacogenomics with clinical data
• Potential to reduce time to response and number of failed trials, particularly in treatment-resistant illness

Cross-reference: D1 section 6; D4 comparison tables 5 and 6

Q6 Extended: 20-Mark Long Essay Version

Expand each section:

• Definition (3 marks): Include distinction between pharmacogenetics vs pharmacogenomics, historical context (genetic variation in drug acetylation, isoniazid in TB), concept of personalized medicine
• Research (8 marks): Detailed CYP450 table with substrates/inhibitors/inducers, full metabolizer phenotype descriptions, HLA associations, pharmacodynamic targets, research methodology (candidate gene vs GWAS), key studies (STAR*D pharmacogenomic analyses, GUIDED trial)
• Implications (7 marks): Clinical decision algorithms, case examples (clozapine + smoking, carbamazepine + HLA), cost-effectiveness data, ethical considerations (genetic discrimination, incidental findings), pharmacogenomic testing panels commercially available
• Future directions (2 marks): As above, expanded

Q7. "What is pharmacogenetics? Role in medical disorders with examples." (10 marks)

Answer:

Definition (2 marks)

Pharmacogenetics is the study of how inherited genetic variation affects individual responses to drugs. It encompasses drug efficacy, required dosing, and susceptibility to adverse drug reactions. It is a key component of personalized/precision medicine.

Role in Medical Disorders (4 marks)

Oncology:

• BRCA1/BRCA2 mutations: Guide use of PARP inhibitors (olaparib) in breast/ovarian cancer
• HER2 amplification: Trastuzumab (Herceptin) for HER2-positive breast cancer
• EGFR mutations: Gefitinib for non-small cell lung cancer
• TPMT polymorphisms: Thiopurine (azathioprine/6-MP) dosing in leukemia and IBD. Poor metabolizers at risk of fatal myelosuppression.

Cardiology:

• CYP2C19 and clopidogrel: Poor metabolizers cannot activate the prodrug → therapeutic failure → increased cardiac events. Alternative: prasugrel or ticagrelor.
• VKORC1 and warfarin: Genetic variants affect warfarin sensitivity. Combined CYP2C9 + VKORC1 genotyping guides dosing.

Infectious disease:

• HLA-B*5701 and abacavir (HIV): Mandatory testing before prescribing. Positive test = do not use (risk of fatal hypersensitivity).

Rheumatology:

• HLA-B*5801 and allopurinol: SJS/TEN risk in Southeast Asian populations

Psychiatric Examples (4 marks)

• CYP2D6: Metabolizer status affects dosing of TCAs, SSRIs, risperidone, aripiprazole. PMs at risk for toxicity; UMs for treatment failure.
• CYP2C19: Poor metabolizers should have reduced citalopram/escitalopram dosing (QTc prolongation risk).
• CYP1A2 + smoking + clozapine: Smoking induces CYP1A2; cessation raises clozapine levels; resumption lowers them.
• HLA-B*1502 + carbamazepine: SJS/TEN in Asian populations. FDA-mandated pre-prescription testing.
• HLA-A*3101 + carbamazepine: Hypersensitivity in European/Japanese populations.

Q8. "What are pharmacogenomics & pharmacogenetics? Relevance in Psychiatry." [4+6 marks]

Answer:

Pharmacogenetics and Pharmacogenomics: Definitions and Distinction (4 marks)

Pharmacogenetics:

• Study of how variation in a single gene affects drug response
• Focuses on individual gene polymorphisms (e.g., CYP2D6 variants)
• Historical term; narrower scope
• Example: CYP2D6 poor metabolizer status predicting TCA toxicity

Pharmacogenomics:

• Study of how the entire genome (multiple genes, interactions, regulatory regions) affects drug response
• Uses GWAS, whole-genome approaches
• Broader and more contemporary term
• Example: Polygenic prediction of antidepressant response using genome-wide data

Key distinction: Pharmacogenetics = single gene → drug response. Pharmacogenomics = whole genome → drug response. In practice, the terms are often used interchangeably.

Both fall under the umbrella of personalized/precision medicine: selecting the right drug at the right dose for the right patient based on their genetic profile.

Relevance in Psychiatry (6 marks)

Why particularly relevant in psychiatry:

• Psychiatric drug prescribing is largely empirical ("trial and error")
• Time to response is weeks to months
• Adverse effects cause non-adherence (a major problem in psychiatry)
• Treatment-resistant illness is common (30% in depression, 25-30% in schizophrenia)

CYP450 polymorphisms:

• CYP2D6: Metabolizes majority of antidepressants and antipsychotics. Four phenotypes (PM, IM, NM, UM) with distinct dosing implications.
• CYP2C19: Critical for citalopram, escitalopram, sertraline dosing. FDA label for citalopram limits dose in PMs.
• CYP1A2: Clozapine and olanzapine metabolism. Smoking induces CYP1A2. Clinical scenario: hospitalized patient stops smoking → clozapine toxicity.
• CYP3A4: Quetiapine, lurasidone, benzodiazepines. Many drug-drug interactions (e.g., carbamazepine induction).

HLA testing:

• HLA-B*1502: Mandatory before carbamazepine/oxcarbazepine in Asian populations. Prevents SJS/TEN.
• HLA-A*3101: Carbamazepine hypersensitivity in Europeans/Japanese.

Clinical decision support (CPIC guidelines):

• CYP2D6 + TCAs: Dose reduction by 50% in PMs; avoid in UMs or increase dose
• CYP2C19 + SSRIs: Dose adjustment or alternative drug in PMs
• Pre-emptive panel testing: Test multiple genes once, use results throughout lifetime

Evidence from clinical trials:

• GUIDED trial (2019): Pharmacogenomic-guided prescribing improved response and remission rates in treatment-resistant depression compared to treatment as usual

Limitations and future:

• Most evidence relates to pharmacokinetics (drug metabolism) rather than pharmacodynamics (drug target sensitivity)
• Cost-effectiveness still debated
• Future: Integration with EHR, AI-guided prescribing, polygenic scores for treatment response

Q9. "What is pharmacogenetics? Current concept and future use in psychiatry." (10 marks)

Answer:

Definition (2 marks) -- As in Q6/Q8.

Current Concepts (4 marks)

• Pharmacogenetics has moved from theoretical to practical application in specific clinical scenarios
• CYP2D6 and CYP2C19 polymorphisms have the strongest evidence base for guiding psychiatric prescribing
• HLA-B*1502 testing before carbamazepine is now an FDA requirement for Asian patients
• CPIC guidelines provide actionable dosing recommendations based on genotype for TCAs, SSRIs, and carbamazepine
• Commercially available pharmacogenomic panels (e.g., GeneSight, Myriad) test multiple genes simultaneously
• Metabolizer phenotypes (PM, IM, NM, UM) form the basis of clinical decision-making
• CYP1A2 induction by smoking is a critical pharmacogenetic interaction for clozapine management

Future Use in Psychiatry (4 marks)

• Pre-emptive panel testing: Genotype patients once early in treatment; store results for lifetime use. Avoids delays when new medications are needed.
• EHR integration: Pharmacogenomic results embedded in electronic health records with automated clinical decision support alerts.
• Pharmacodynamic pharmacogenomics: Moving beyond drug metabolism to predict which drug will work best (e.g., serotonin transporter variants predicting SSRI response, dopamine receptor variants predicting antipsychotic response).
• Polygenic risk scores for treatment response: Aggregate genome-wide data to predict response to specific drugs or drug classes.
• AI-guided prescribing algorithms: Combining pharmacogenomic data with clinical variables (age, sex, comorbidities, co-medications) for optimal drug selection.
• Pharmacoepigenomics: How epigenetic marks (DNA methylation, histone modification) influence drug response; potential for modifiable targets.
• Ethical and practical considerations: Genetic privacy, insurance discrimination, equitable access to testing, need for clinician education.
• Cost-effectiveness: As testing costs decrease and evidence grows, routine pharmacogenomic testing may become standard of care, particularly in treatment-resistant illness.

Q10. "What is EBM? What is personalized medicine? Discuss pharmacogenetics." [2+3+5 marks]

Answer:

Evidence-Based Medicine (2 marks)

Evidence-based medicine (EBM) is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients (Sackett, 1996). It integrates three components:

1. Best available research evidence (systematic reviews, RCTs)
2. Clinical expertise
3. Patient values and preferences

Hierarchy of evidence: Systematic reviews/meta-analyses > RCTs > cohort studies > case-control > case series > expert opinion.

EBM provides population-level treatment guidelines. Its limitation is that it treats patients as homogeneous groups, not accounting for individual biological variation.

Personalized Medicine (3 marks)

Personalized (precision) medicine tailors medical treatment to individual characteristics -- genetic, environmental, and lifestyle -- of each patient. It moves beyond "one size fits all" prescribing.

Key components:

• Pharmacogenomics: Genetic testing to guide drug selection and dosing
• Biomarkers: Measurable indicators that predict disease course or treatment response
• Companion diagnostics: Tests paired with specific therapies (e.g., HER2 testing for trastuzumab)

In psychiatry, personalized medicine addresses the problem that:

• Response to any given psychotropic is only 50-60%
• Time to adequate trial is 4-8 weeks
• Treatment-resistant illness affects 25-30% of patients
• Adverse effects are a leading cause of non-adherence

Personalized medicine is the practical application of EBM at the individual level -- using the best evidence to make the best decision for this specific patient.

Pharmacogenetics (5 marks)

Definition: Study of how genetic variation affects drug response (efficacy, dosing, adverse effects).

Key applications in psychiatry:

• CYP2D6: Guides dosing of TCAs, SSRIs, risperidone, aripiprazole. PMs need dose reduction; UMs may need higher doses or alternative drugs.
• CYP2C19: Guides citalopram/escitalopram dosing. FDA limits citalopram to 20mg in PMs.
• CYP1A2: Clozapine + smoking interaction. Dose adjustment required with smoking changes.
• HLA-B*1502: Prevents SJS/TEN from carbamazepine in Asian patients.

Metabolizer phenotypes: PM, IM, NM, UM -- each with distinct clinical implications.

CPIC guidelines: Evidence-based, gene-drug specific dosing recommendations.

Challenges: Cost, clinician education, limited pharmacodynamic evidence, ethical considerations.

Future: Pre-emptive testing, EHR integration, AI-guided prescribing, polygenic response scores.

Cross-reference: D1 section 6; D4 tables 5 and 6

Q11. "What is genetic epidemiology? Describe three types of genetic studies." (10 marks)

Answer:

Genetic Epidemiology: Definition (2 marks)

Genetic epidemiology is the study of the role of genetic factors and their interaction with environmental factors in the occurrence of disease in populations. It uses epidemiological methods to determine:

1. Whether a disease has a genetic component (familial aggregation)
2. The relative contribution of genetic vs environmental factors (heritability)
3. The mode of inheritance
4. The location and identity of specific genes involved

It bridges classical epidemiology (population-level disease patterns) and molecular genetics (specific genetic variants).

Three Types of Genetic Studies (8 marks)

1. Family Studies (2.5 marks)

Design: Compare the prevalence of a disorder in relatives of affected individuals (probands) with the prevalence in the general population or in relatives of unaffected controls.

Key measures:

• Recurrence risk: Probability of the disorder in a relative of an affected individual
• Relative risk (lambda-R): Recurrence risk / population prevalence
• Risk decreases as genetic distance from the proband increases

Example in schizophrenia:

• General population: 1%
• First-degree relative: ~10% (lambda = 10)
• Second-degree relative: ~3%
• MZ twin: ~48%

Strengths: Simple, demonstrates familial aggregation

Limitation: Cannot distinguish genetic from shared environmental effects (families share both genes and environment)

2. Twin Studies (2.5 marks)

Design: Compare concordance rates between MZ twins (100% shared DNA) and DZ twins (~50% shared DNA). If genetic factors contribute, MZ concordance should exceed DZ concordance.

Key measures:

• Concordance rate: Probability that the co-twin is affected given that one twin is affected
• Heritability: h2 = 2(rMZ - rDZ) (Falconer's formula)

Example:

• Schizophrenia: MZ 48%, DZ 17% → h2 = 2(0.48 - 0.17) = 0.62
• Bipolar disorder: MZ ~60%, DZ ~12%
• ADHD: MZ ~80%, DZ ~30%

Strengths: Separates genetic from shared environmental effects (both twin types share family environment)

Limitations:

• Equal environments assumption: Assumes MZ and DZ twins share environment equally (may not hold)
• Ascertainment bias; small sample sizes for rare disorders
• MZ discordance may overestimate environmental contribution (includes stochastic/epigenetic effects)

3. Adoption Studies (2.5 marks)

Design: Study individuals separated from biological parents early in life. Compares rates of disorder in:

• Biological relatives vs adoptive relatives of affected adoptees
• Adopted-away children of affected vs unaffected biological parents
• Cross-fostering: Children of unaffected parents raised by affected adoptive parents

Key studies in schizophrenia:

• Heston (1966): 47 adopted-away children of schizophrenic mothers; 5/47 (10.6%) developed schizophrenia vs 0/50 controls
• Kety (1968): Danish adoption study; rates of schizophrenia spectrum disorders were higher in biological relatives of affected adoptees than in adoptive relatives
• Cross-fostering: No increased risk when raised by schizophrenic adoptive parents

Strengths: Most powerful naturalistic design for separating genetic and environmental effects

Limitations:

• Selective placement (adoption agencies may match families)
• Prenatal environment shared with biological mother
• Limited availability of adoption registries; small samples
• Historical: Adoption practices have changed, limiting replication

Summary (0.5 marks)

Family, twin, and adoption studies together form the foundation of genetic epidemiology in psychiatry. They establish that a disorder has a genetic component and estimate its magnitude (heritability), setting the stage for molecular studies (linkage, association, GWAS) to identify specific genes.

Q11 Extended: 20-Mark Long Essay Version

• Definition (3 marks): Expanded with historical development, relationship to other genetic disciplines
• Family studies (4 marks): Full risk tables for schizophrenia, bipolar, ADHD; recurrence risk calculations; lambda calculations
• Twin studies (4 marks): Detailed methodology, concordance vs correlation, heritability across disorders, limitations in detail
• Adoption studies (4 marks): Detailed study designs, all three paradigms, specific studies
• Molecular genetic epidemiology (3 marks): Linkage analysis (LOD scores), association studies (case-control, TDT), GWAS, CNV analysis
• Integration and future (2 marks): How designs complement each other, multi-omics approaches

Q12. "Genetic epidemiological studies in Psychiatry." (10 marks)

Answer:

Introduction (1 mark)

Genetic epidemiology in psychiatry employs a hierarchy of study designs to determine the genetic architecture of mental disorders. These range from classical designs that establish heritability to molecular approaches that identify specific genetic variants.

Classical Genetic Epidemiological Designs (4 marks)

Family studies: Establish familial aggregation. Example: Schizophrenia risk 10x in first-degree relatives. Limitation: Cannot separate genes from environment.

Twin studies: Compare MZ vs DZ concordance to estimate heritability. Example: Schizophrenia heritability ~80%. Key assumption: Equal environments.

Adoption studies: Separate genetic from environmental transmission. Heston (1966) and Kety (1968) studies confirmed genetic basis of schizophrenia. Most powerful naturalistic design.

Molecular Genetic Epidemiological Designs (4 marks)

Linkage analysis:

• Maps disease genes using co-inheritance of genetic markers in families
• LOD score >= 3.0 indicates significant linkage
• Limited success in psychiatry due to small effect sizes and locus heterogeneity

Association studies:

• Case-control design comparing allele frequencies
• TDT: Family-based, avoids population stratification
• Candidate gene studies: Hypothesis-driven but poorly replicated (e.g., COMT, NRG1, DTNBP1)

GWAS:

• Hypothesis-free genome-wide scan of millions of SNPs
• Significance threshold: p < 5 x 10^-8
• Key finding: PGC 2014 identified 108 loci for schizophrenia
• Detects common variants with small effects

CNV analysis:

• Identifies rare structural variants (deletions/duplications)
• 22q11.2 deletion: 25x risk for schizophrenia
• Higher effect sizes than common SNPs

Sequencing (WES/WGS):

• Detects rare mutations, de novo variants
• Important for autism (many de novo mutations)
• Emerging role in schizophrenia research

Conclusion (1 mark)

Modern psychiatric genetics integrates classical designs (establishing heritability) with molecular approaches (identifying specific variants) and is increasingly incorporating epigenetic and gene-environment interaction analyses. This multi-layered approach is essential given the polygenic, multifactorial nature of psychiatric disorders.

Q13. "What is gene mapping? How is it different from linkage and association studies?" [3+7 marks]

Answer:

Gene Mapping (3 marks)

Gene mapping is the process of determining the chromosomal location of a gene and the distance between genes. There are two types:

Genetic mapping:

• Uses recombination frequencies during meiosis to determine relative positions of genes and markers
• Measured in centimorgans (cM); 1 cM ≈ 1 million base pairs
• Tools: Linkage analysis using microsatellites or SNPs

Physical mapping:

• Determines actual physical position (base pairs) on a chromosome
• Tools: Fluorescence in situ hybridization (FISH), restriction mapping, sequencing
• Human Genome Project provided the complete physical map

Purpose in psychiatry: Identify specific genes contributing to complex disorders like schizophrenia, bipolar disorder, and depression.

Linkage vs Association Studies (7 marks)

Linkage analysis:

• Design: Family-based; tracks co-segregation of genetic markers with disease across generations in pedigrees
• Markers: Microsatellites (short tandem repeats), now also SNPs
• Statistical measure: LOD score (logarithm of odds ratio). LOD >= 3.0 = significant linkage; LOD <= -2.0 = excluded
• Resolution: Low (~10-20 Mb); identifies broad chromosomal regions, not specific genes
• Best for: Mendelian disorders with high penetrance, large effect sizes
• Limitations in psychiatry: Most psychiatric disorders are polygenic with small-effect variants; linkage studies have low power for these. Example: Multiple linkage studies in schizophrenia identified candidate regions (6p, 8p, 22q) but with inconsistent replication.

Association studies:

• Design: Population-based (case-control) or family-based (TDT)
• Method: Compare frequency of a specific allele/genotype between affected and unaffected individuals
• Resolution: High (~1 kb); can pinpoint specific SNPs
• Types:
• Candidate gene: Hypothesis-driven, tests specific genes. Example: COMT Val158Met in schizophrenia.
• GWAS: Hypothesis-free, scans millions of SNPs across genome. Example: PGC 2014 identified 108 loci.
• Statistical measure: Odds ratio with p-value (GWAS threshold: p < 5 x 10^-8)
• Strengths: Detects common variants with small effect sizes; high resolution
• Limitations: Population stratification (case-control), need for very large samples, detects association not causation, candidate gene studies suffered from poor replication

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Key conceptual point: Linkage detects co-segregation within families (are these loci transmitted together?). Association detects co-occurrence in populations (is this allele more common in cases?). They answer different questions and are complementary.

Mnemonics & Memory Tricks

Exam: PG exams MD Psychiatry, Sep 2026

Mnemonic 1: Candidate Genes of Schizophrenia

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Mnemonic 2: CYP1A2 -- Substrates

Mnemonic 3: CYP2D6 -- Substrates

Mnemonic 4: CYP2D6 Inhibitors

Fluoxetine, Paroxetine, Bupropion, Quinidine

Mnemonic 5: CYP3A4 -- "The Kitchen Sink Enzyme"

Mnemonic 6: Metabolizer Phenotypes

Mnemonic 7: Heritability Across Psychiatric Disorders

Mnemonic 8: Key GWAS Findings in Schizophrenia

• 108 loci identified (PGC 2014)
• C4 complement gene (MHC region) -- synaptic pruning
• D2 -- DRD2 dopamine receptor (validates dopamine hypothesis)
• Glut -- Glutamate pathway genes (GRM3, GRIN2A, SRR, GRIA1)
• Cal -- Calcium channel genes (CACNA1C, CACNB2) shared with bipolar

Mnemonic 9: Genetic Study Design Hierarchy

Mnemonic 10: Types of Mutations

Mnemonic 11: CNVs in Schizophrenia

Mnemonic 12: Gene-Environment Interactions (GxE)

Mnemonic 13: Trinucleotide Repeat Disorders

Mnemonic 14: HLA Pharmacogenetics

• HLA-B*1502 + Carbamazepine = SJS/TEN in Asian populations
• HLA-A*3101 + Carbamazepine = Rash/DRESS in European/Japanese
• HLA-B*5701 + Abacavir = Hypersensitivity (HIV -- for comparison)

Mnemonic 15: Schizophrenia Risk by Relatedness

High-Yield Comparisons

Exam: PG exams MD Psychiatry, Sep 2026

Table 1: Linkage vs Association Studies

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Table 2: GWAS vs Candidate Gene Studies

Table 3: Twin Studies vs Adoption Studies

Table 4: Heritability Across Major Psychiatric Disorders

Table 5: CYP450 Enzymes in Psychiatry

Table 6: Metabolizer Phenotypes -- Clinical Implications

Table 7: Copy Number Variants in Schizophrenia

Table 8: Epigenetics vs Genetics

PYQ Frequency Analysis

Executive Summary

Topic-Level Frequency

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Key PYQs Identified

Genetics of Schizophrenia

1. "The biological causes of schizophrenia. Genetics of schizophrenia." [10, split 5+5]
2. "Biopsychosocial model of schizophrenia. Recent advances in genetics in aetiology." [10, split 5+5]
3. "Describe genetics of schizophrenia." [10] (Notion QB, multiple entries)
4. "Genetics of Schizophrenia." [10] (short note format)
5. "What is Genetic mutation and how does it occur?" [10]

Pharmacogenetics

1. "What is pharmacogenetics? Describe its research and implications in treatment." [10, split 2+4+4]
2. "What is pharmacogenetics? Role in medical disorders with examples." [10]
3. "What are pharmacogenomics & pharmacogenetics? Relevance in Psychiatry." [10, split 4+6]
4. "What is pharmacogenetics? Current concept and future use in psychiatry." [10]
5. "What is EBM? What is personalized medicine? Discuss pharmacogenetics." [10, split 2+3+5]

Genetic Study Designs

1. "What is genetic epidemiology? Describe three types of genetic studies." [10]
2. "Genetic epidemiological studies in Psychiatry." [10]
3. "What is gene mapping? How is it different from linkage analysis and association studies?" [10, split 3+7]

Long Essay Candidates

Exam Strategy

Must-Prepare

1. Genetics of schizophrenia, heritability (~80%), twin concordance (MZ 48%, DZ 17%), adoption studies (Heston, Kety), candidate genes (DISC1, NRG1, DTNBP1, COMT), GWAS findings (108 loci, C4 complement gene), copy number variants (22q11 deletion), polygenic risk scores
2. Pharmacogenetics, CYP450 enzymes (2D6, 3A4, 1A2, 2C19), poor/intermediate/extensive/ultrarapid metabolizers, clinical examples (CYP2D6 and codeine/SSRIs, HLA-B*5701 and carbamazepine, CYP1A2 and clozapine/smoking), pharmacogenomic testing in clinical practice
3. Genetic study designs, family studies, twin studies (MZ vs DZ, heritability formula), adoption studies, linkage analysis (LOD scores), association studies (case-control), GWAS (Manhattan plots, genome-wide significance), epigenetics

Nice-to-Know

1. Gene-environment interaction (MAOA gene + childhood maltreatment → antisocial behaviour; 5-HTTLPR + stress → depression, though Caspi findings debated)
2. Epigenetics (DNA methylation, histone modification, non-coding RNA)
3. Endophenotypes (conceptual)

Analysis based on PG exams Dec 2011, Jun 2025 + PG exams 2013-2022.

Quick Review

Exam: PG exams MD Psychiatry, Sep 2026

RECALL (Q1-Q10)

Q1. What is the estimated heritability of schizophrenia?

Answer: Approximately 80%, derived from twin and adoption studies.

Q2. What are the MZ and DZ twin concordance rates for schizophrenia?

Answer: MZ: ~48%. DZ: ~17%. Using Falconer's formula: h2 = 2(0.48 - 0.17) = 0.62 (crude estimate; model-based estimates give ~0.80).

Q3. Name five candidate genes historically associated with schizophrenia.

Answer: DISC1 (disrupted in schizophrenia 1), NRG1 (neuregulin 1), DTNBP1 (dysbindin), COMT (catechol-O-methyltransferase), RGS4 (regulator of G-protein signaling 4). Note: Most have NOT been confirmed by GWAS.

Q4. What was the key finding of the PGC Schizophrenia Working Group (2014)?

Answer: Identified 108 genome-wide significant loci in a sample of 36,989 cases and 113,075 controls. Key loci included DRD2, MHC/C4, glutamate pathway genes, and calcium channel genes.

Q5. What is the genome-wide significance threshold for GWAS and why?

Answer: p < 5 x 10^-8. This is a Bonferroni correction for approximately 1 million independent SNP tests (0.05 / 1,000,000 = 5 x 10^-8).

Q6. What LOD score indicates significant linkage?

Answer: LOD >= 3.0 (indicating 1000:1 odds in favour of linkage). LOD <= -2.0 excludes linkage.

Q7. What is the heritability formula used in twin studies?

Answer: Falconer's formula: h2 = 2(rMZ - rDZ), where r = concordance rate (or correlation) for MZ and DZ twins respectively.

Q8. Name the four CYP450 metabolizer phenotypes.

Answer: Poor metabolizer (PM), intermediate metabolizer (IM), normal/extensive metabolizer (NM), ultrarapid metabolizer (UM).

Q9. What HLA allele must be tested before starting carbamazepine in Asian patients, and what reaction does it predict?

Answer: HLA-B*1502. Predicts Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). FDA mandates testing before carbamazepine in patients of Asian ancestry.

Q10. What is the APOE e4 allele's relationship to Alzheimer disease?

Answer: APOE e4 is the strongest genetic risk factor for late-onset Alzheimer disease. One copy confers ~3x risk; two copies confer ~12x risk. It is a risk factor, not deterministic.

APPLICATION (Q11-Q22)

Q11. A patient of South Asian origin is started on carbamazepine and develops SJS. What genetic test should have been done before prescribing?

Answer: HLA-B*1502 genotyping. This allele is prevalent in South Asian, Southeast Asian, and East Asian populations and is strongly associated with carbamazepine-induced SJS/TEN. FDA guidelines recommend testing before prescribing carbamazepine to patients with Asian ancestry.

Q12. A patient stable on clozapine 400mg/day is admitted to a smoke-free psychiatric unit. After 5 days, they become excessively sedated with drooling. What happened?

Answer: Smoking induces CYP1A2, which metabolizes clozapine. When the patient stopped smoking upon hospitalization, CYP1A2 induction was lost, causing clozapine levels to rise and producing toxicity (sedation, sialorrhea). The clozapine dose should have been reduced by 25-50% upon smoking cessation.

Q13. A CYP2D6 poor metabolizer is prescribed nortriptyline at the standard dose. What clinical problem might arise?

Answer: Nortriptyline (a TCA) is metabolized by CYP2D6. A poor metabolizer cannot clear the drug normally, leading to accumulation and risk of cardiotoxicity (QTc prolongation, arrhythmias), excessive sedation, and anticholinergic toxicity. The dose should be reduced by approximately 50%, or an alternative not metabolized by CYP2D6 should be chosen.

Q14. An ultrarapid CYP2D6 metabolizer is prescribed codeine for pain after a dental procedure. She is also breastfeeding her infant. What is the risk?

Answer: CYP2D6 converts codeine to morphine. An ultrarapid metabolizer produces excessive morphine, which is secreted in breast milk. This can cause respiratory depression and death in the infant. Codeine should be avoided in CYP2D6 ultrarapid metabolizers who are breastfeeding.

Q15. A child is diagnosed with 22q11.2 deletion syndrome (VCFS/DiGeorge). The parents ask about the risk of psychiatric illness. What do you counsel?

Answer: 22q11.2 deletion confers a 25-30% lifetime risk of developing schizophrenia-like psychosis (25x the general population risk). It is the strongest known single genetic risk factor for schizophrenia. The child should be monitored for prodromal symptoms during adolescence. Other psychiatric risks include ADHD, anxiety disorders, and mood disorders.

Q16. A patient on fluoxetine 20mg is started on risperidone 2mg. After one week, the patient develops significant EPS. The dose of risperidone seems low for such side effects. What might explain this?

Answer: Fluoxetine is a potent CYP2D6 inhibitor. Risperidone is metabolized by CYP2D6. Fluoxetine inhibits risperidone metabolism, effectively converting the patient into a pharmacokinetic "poor metabolizer." This causes risperidone levels to rise, producing EPS at what would normally be a low dose. Either reduce risperidone dose, discontinue fluoxetine, or switch to an SSRI that does not inhibit CYP2D6 (e.g., sertraline, escitalopram).

Q17. A researcher finds a LOD score of 2.1 for linkage between a chromosomal region and bipolar disorder. What is the interpretation?

Answer: A LOD score of 2.1 is suggestive but does NOT reach the threshold for significant linkage (LOD >= 3.0). It warrants further investigation with larger samples but cannot be considered evidence of linkage. LOD <= -2.0 would exclude linkage.

Q18. A patient with schizophrenia has a family history of schizophrenia in his father and paternal uncle. His GWAS-based polygenic risk score is in the 95th percentile. He asks if his children will definitely develop schizophrenia. How do you counsel?

Answer: A high PRS increases risk but is NOT deterministic. Schizophrenia is polygenic with incomplete penetrance. The baseline risk for a child of one affected parent is ~10%. PRS adds statistical risk at the population level but cannot predict individual outcomes with certainty. Environmental factors (cannabis, stress, obstetric complications) also modulate risk. Genetic counseling should emphasize probabilistic risk, not certainty.

Q19. A researcher wants to study whether a specific SNP is associated with schizophrenia. She has 200 cases and 200 controls. Is this adequate for a GWAS?

Answer: No. GWAS requires very large samples (tens of thousands of cases and controls) to achieve adequate power, because individual SNPs have small effect sizes (OR 1.05-1.2) and the significance threshold is stringent (p < 5 x 10^-8). A sample of 200 cases would only be adequate for a candidate gene study (not GWAS) and even then would be underpowered for small effects.

Q20. A patient with schizophrenia who is a heavy smoker (20 cigarettes/day) on stable clozapine is prescribed ciprofloxacin for a urinary tract infection. What drug interaction should you anticipate?

Answer: Ciprofloxacin is a CYP1A2 inhibitor. While smoking induces CYP1A2, ciprofloxacin inhibits it. The net effect is a rise in clozapine levels, potentially causing toxicity. Monitor clozapine levels and consider dose reduction during the ciprofloxacin course.

Q21. The Caspi et al. (2002) study found that MAOA-L allele carriers who experienced childhood maltreatment had higher rates of antisocial behavior. A colleague argues this means the MAOA gene "causes" violence. How do you respond?

Answer: The MAOA-L allele does not "cause" violence. This is a gene-environment interaction: the gene modulates the effect of an environmental exposure (maltreatment). Without maltreatment, MAOA-L carriers do not show increased antisocial behavior. The gene creates a vulnerability that is only expressed under specific environmental conditions. Additionally, the effect size is modest, and many MAOA-L carriers exposed to maltreatment do NOT become antisocial.

Q22. A 45-year-old patient with bipolar disorder on carbamazepine 600mg BD is also started on ketoconazole for a fungal infection. A week later, he develops ataxia, diplopia, and nausea. What is the likely mechanism?

Answer: Carbamazepine is metabolized by CYP3A4. Ketoconazole is a potent CYP3A4 inhibitor. Inhibition of CYP3A4 by ketoconazole causes carbamazepine levels to rise, producing signs of carbamazepine toxicity (ataxia, diplopia, nausea, nystagmus). Carbamazepine levels should be checked and the dose reduced.

ANALYSIS (Q23-Q30)

Q23. Why does the high heritability of schizophrenia (~80%) not translate to simple Mendelian inheritance?

Answer: Because schizophrenia is polygenic (hundreds of genes contribute small effects), exhibits genetic heterogeneity (different genetic variants can produce the same phenotype), has incomplete penetrance (carrying risk alleles does not guarantee illness), and involves gene-environment interaction. High heritability means genetic factors explain most of the variance in liability, but the architecture involves many common variants of small effect plus rare variants of larger effect, rather than a single gene with a clear inheritance pattern.

Q24. The MZ twin concordance for schizophrenia is ~48%. What does the remaining ~52% discordance tell us?

Answer: The 52% discordance in genetically identical individuals indicates that non-genetic factors contribute significantly. These include: (1) environmental factors (prenatal insults, obstetric complications, cannabis, urbanicity, stress), (2) epigenetic divergence (MZ twins accumulate different methylation patterns over time), (3) stochastic developmental variation (random events in brain development), and (4) gene-environment interactions where the same genotype produces different outcomes depending on environmental exposure.

Q25. Why is the C4/MHC finding from GWAS considered such an important advance in schizophrenia genetics?

Answer: The C4/MHC finding (Sekar et al., 2016) is important because it provides a mechanistic bridge between a GWAS statistical signal and a neurobiological process. C4A overexpression leads to excessive complement-mediated synaptic pruning in adolescence. This single finding connects: (1) the strongest GWAS association to (2) a specific molecular mechanism to (3) the neurodevelopmental model of schizophrenia to (4) the clinical observation of adolescent onset and (5) the neuropathological finding of reduced synaptic density and grey matter. It transformed a statistical association into a biologically interpretable and potentially druggable pathway.

Q26. How do common variants (GWAS) and rare variants (CNVs) each contribute to schizophrenia risk, and why do we need to study both?

Answer: Common variants (identified by GWAS) are individually of small effect (OR 1.05-1.2) but collectively explain a substantial portion of genetic risk through polygenic mechanisms. Rare variants (CNVs, de novo mutations) are individually rare but have large effects (OR 2-40x). Studying both is necessary because: (1) they capture different parts of the genetic architecture, (2) rare variants point to specific genes and biological pathways more directly, (3) common variants help build polygenic risk scores, and (4) together they explain more variance than either alone. The "missing heritability" gap may partly lie in rare variants not captured by GWAS.

Q27. Why has the 5-HTTLPR x stress interaction for depression been controversial, and what lesson does this teach about GxE research?

Answer: Caspi et al. (2003) reported that the short allele of 5-HTTLPR interacted with stressful life events to increase depression risk. However, a large collaborative meta-analysis (Culverhouse et al., 2018) with over 40,000 subjects found no support for this interaction. The controversy teaches several lessons: (1) initial GxE findings may be false positives due to small samples and publication bias, (2) environmental measures and genotype categorizations affect replicability, (3) very large samples are needed to detect genuine GxE effects, and (4) replication in well-powered studies is essential before clinical application.

Q28. A colleague says "if schizophrenia is 80% heritable, then environment only contributes 20%." Is this correct?

Answer: This is a common misunderstanding. Heritability is a population-level statistic that describes the proportion of variance in liability attributable to genetic factors in a specific population at a specific time. It does NOT mean the environment contributes only 20% in any individual case. Also: (1) heritability does not account for gene-environment interaction or gene-environment correlation, which may inflate the genetic estimate, (2) epigenetic effects (environmentally induced) may be captured in the "genetic" portion, (3) heritability can change if environmental variance changes (e.g., in a more stressful environment, the environmental contribution increases), and (4) high heritability does not mean the condition is immutable or that environmental interventions are futile.

Q29. Schizophrenia reduces reproductive fitness, yet it persists at ~1% prevalence globally. How can this be explained genetically?

Answer: Several hypotheses explain this paradox: (1) Balancing selection: Risk alleles may confer advantages in certain contexts (e.g., creativity, divergent thinking, immune function). (2) Polygenic mutation-selection balance: Many variants of small effect are constantly generated by new mutations at a rate that balances selection against them. (3) De novo mutations: A substantial fraction of schizophrenia may arise from new mutations (especially CNVs) each generation, replenishing the pool. (4) Antagonistic pleiotropy: Variants that increase schizophrenia risk may benefit other traits (e.g., CACNA1C variants may have immune or metabolic benefits). (5) Relaxed selection in modern environments: Reduced mortality from other causes allows psychiatric risk alleles to persist.

Q30. What are endophenotypes, why are they important in schizophrenia genetics, and give three examples?

Answer: Endophenotypes (intermediate phenotypes) are heritable, quantifiable traits that lie on the pathway between genes and the clinical phenotype. They are important because: (1) they are closer to gene action than the complex clinical syndrome, making genetic associations easier to detect, (2) they are present in unaffected relatives (indicating genetic mediation), (3) they are more biologically homogeneous than the clinical diagnosis. Three examples in schizophrenia: (1) Smooth pursuit eye movement abnormalities (found in 50-80% of patients and 25-40% of unaffected relatives), (2) P50 auditory sensory gating deficits (reduced suppression of the second auditory stimulus; linked to CHRNA7 gene), (3) Working memory deficits (related to DLPFC dysfunction and COMT Val158Met polymorphism).