Week 3 - Genes and heritability - BB

Genes and Heritability

  • Presented by Dr. Alyson Dodd (PY0549)

Lecture Structure

  • Behavioural Genetics

  • Molecular Genetics

  • Gene x Environment Interactions

Learning Outcomes

  • Understand genetic challenges to early development

  • Critically evaluate the relationship between family history, genes, and psychopathology

Recap of Developmental Psychopathology

  • Developmental Topics:

    • Developmental Cascades:

      • Effects within and across domains of development.

    • Developmental Pathways:

      • Typical and Atypical Development

      • Concepts of Continuity, Equifinality, and Multifinality

    • Early development is a predictor of lifelong psychopathology.

Biological Models of Psychopathology

  • Origins:

    • Terminology: Mental illness, psychopathology, patients

    • Diagnostic classification manuals

    • Neuroscience

  • Assumptions:

    • Symptoms arise from specific diseases with defined causes, courses, and prognoses.

    • Involves aspects of genetic, brain biochemistry, and brain structure.

Behavioural Genetics Revisitation

  • Key Definitions:

    • Genotype: Genetic makeup passed down from parents.

    • Phenotype: Observable characteristics influenced by genes.

    • Heritability: Genetic contribution to trait variability, ranging from 0-100% based on population studies.

Methodologies in Behavioural Genetics

  • Studies include:

    • Adoption and family studies

    • Twin studies: Comparison of monozygotic (MZ, 100% shared genes) vs. dizygotic (DZ, 50% shared genes) twins.

Concordance in Twin Studies

  • Definition:

    • Measurement of how many pairs (MZ vs. DZ) share traits like eye and hair color, height, or psychopathological conditions.

    • Relative differences in concordance rates help to infer genetic influences while assuming similar environmental factors.

Limitations of Twin Studies

  • Concordance rates are not absolute; MZ twins do not always show 100% similarity.

  • Differences noted when clinical samples vs. population samples are analyzed.

  • Diagnoses are considered end-points and may not reflect complexity.

Liability Threshold Models

  • Describe complex traits, attributing variability to:

    • Genetic factors

    • Shared and non-shared environmental influences

    • Measurement errors

  • Concept of a Continuum: Everyone has a liability score impacting diagnosis potential.

Heritability of Autism Spectrum Disorder (ASD)

  • Studied using a population-based sample to reduce bias.

  • Heritability Range: 56 – 95%, indicating significant genetic influences.

  • Emphasis on both categorical diagnosis and spectrum of traits.

Heritability of Psychosis

  • Data from a nationwide sample over 40 years observing onset during ages 18-25.

  • Findings:

  • Low concordance (0.33 MZ)

  • High heritability:

    • 79% for schizophrenia

    • 73% for schizophrenia spectrum.

Twin Studies Summary

  • Observations confirm higher concordance in MZ twins compared to DZ.

  • Findings support the idea of heritable psychopathological traits, yet questions about specific genes remain.

Molecular Genetics Approach Assumptions

  • Involves searching for specific genes, which may be monogenic or polygenic.

  • It emphasizes the independent role of genes but disputes total determinism by environment.

Chromosomal and Genetic Disorders

  • Examples of single-gene disorders include:

    • Phenylketonuria, Down’s syndrome, Tay-Sachs, Williams syndrome, Fragile X, Prader-Willi syndrome.

Williams Syndrome Characteristics

  • Characterized by 'elfin' facial features, health issues, intellectual disability, strong language abilities, and hypersociability due to gene deletions on chromosome 7.

Commonality of Unknown Genetic Causes in Psychopathology

  • Many psychopathologies lack clearly identified genetic causes.

  • Reference to the 'missing heritability' problem indicating complexity in understanding neurodevelopmental disorders.

Genome-Wide Association Studies (GWAS)

  • Aim to identify genetic variants associated with traits across individuals.

  • Requires large sample sizes for accurate results.

Types of Genetic Variants Identified

  • Copy Number Variants (CNVs): Variations in the number of DNA segment copies.

  • Single Nucleotide Polymorphisms (SNPs): Variation at a single DNA location with differential effects.

Genetics of Dimensional Psychopathology in Youth

  • Multiple GWAS targeting internalizing symptoms have shown no genome-wide significance yet indicate genetic correlations with categorical psychology.

Genetic Studies of Diagnosed Disorders

  • Multiple GWAS with over 30,000 cases of various disorders have pinpointed significant SNPs, demonstrating polygenic nature and common biological processes among disorders.

Understanding Polygenic Risk Scores (PRS)

  • PRS calculates contribution to psychopathological traits by aggregating the effects of genetic variants.

  • Signals a continuous risk across the population; higher scores correlate to increased risk.

Specificity of PRS in Adult Psychopathology

  • Relationship between PRS in disorders, symptom severity, and functional outcomes. Differences noted in phenotypes for bipolar disorder and depression.

Current State of Molecular Genetics and Psychopathology

  • Complexity and polygenic nature of disorders emphasized, with both common and rare variants at play.

  • Highlighting cross-disorder analysis and pleiotropy - illustrating genetic interaction across disorders.

Challenges in Understanding Biological Mechanisms

  • Biological mechanisms behind genetic influence remain unclear; they do not directly code behavior but may affect it through broader developmental pathways.

The Missing Heritability Problem

  • There is a discrepancy between SNP heritability and estimated heritability from twin studies, mainly due to undetected rare variants and gene-environment associations.

Gene x Environment Interactions

  • Discusses diathesis-stress models highlighting how genetic predispositions interact with environmental factors, albeit with inconsistent findings across studies.

Development and Gene Interaction

  • Karmiloff-Smith (1998) notes the significance of development processes on gene expression and brain specialization.

Summary of Findings

  • Heritability is not absolute; contributions vary across common and rare variants.

  • Findings challenge strict diagnostic boundaries, acknowledging variability in genetic disorders and implications for risk identification and prevention.

Example Exam Question

  • Critically evaluate: "Psychopathology is in our genes."

Core Reading & Recommendations

  • Essential readings highlighted from renowned journals and studies within the field of psychiatric genomics, emphasizing the integration of genetic research within psychopathology.

References for Further Study

  • Comprehensive list of studies addressing heritability in psychopathology, offering insights into genetic contributions and methodologies utilized in the realm of psychiatric research.