EB - Risk factors of metal health disorders I Flashcards
Why do people suffer from neuropsychiatric disorders? (2)
- Risk; involves uncertainty and vulnerability/sensitivity.
- Genetic factors; a critical determinant.
What genetic models are used for understanding disease risk and why are they useful? (3)
Family diagrams:
Family studies
- Identify families with higher disease incidence.
- Measure recurrent risk ratio; the increased risk of a disease occurring in a relative of an affected individual compared to the general population
Twin studies
- MZ vs DZ
- Higher concordance in monozygotic twins suggests genetic contribution.
Linkage studies:
- Identify regions of the genome linked to disease inheritance
- Effective for Mendelian disorders.
- Less useful for polygenic conditions.
What are association studies, and how do they work? (4)
Candidate Gene Studies:
- Focus on specific genes linked to disease.
- Compare genetic variant frequencies in cases vs. controls.
Genome-Wide Association Studies (GWAS):
- Scan the genome for disease-linked variants.
- Effective for common variants with small effects.
Structural Variation Studies:
- Examine copy number and structural variations.
Sequencing Studies:
- Detect rare variants with large effects.
What are Gene-Environment Interaction (GxE) Studies? (2)
- Study genetic and environmental factor interplay in disease risk.
- Identify individuals at higher risk based on combined exposures.
What are Functional Studies in molecular genetics?
- Explores how genetic variants influence disease mechanisms.
Investigate:
- Gene expression.
- Protein function.
- Cellular pathways.
How are Animal Models used in genetic research? (2)
- Study genetic variant effects on disease progression.
- Example: Use mice to simulate human genetic conditions.
What are Clinical Studies, and what do they examine? (4)
- Investigate clinical implications of genetic findings.
Focus areas:
- Diagnostic test development.
- Prognostic marker identification.
- Creation of targeted therapies
What is the importance of Pathway Analysis? (2)
- Determines if genetic variants act within the same pathways.
- Identifies biological pathways influencing disease mechanisms.
What are the two types of mutations?
- Inherited variations: Passed through generations.
-
De novo mutations: New mutations linked to paternal age.
The number of de novo mutations in the person’s genome increases with paternal age
How does the timing of mutations affect cell impact? (5)
Parental gonad: All offspring cells affected.
Early embryo: Large proportion affected.
Embryo: A smaller portion of the offspring’s cells will carry the mutation
Fetus: An even smaller portion of the offspring’s cells will carry the mutation.
Post-birth: Tissue-specific effects.
What is penetrance in genetics? (3)
- Proportion of individuals with a genetic variant showing the phenotype.
- Inversely related to allele frequency
- Example: Huntington’s disease has 100% penetrance with triplet expansion.
What is linkage disequilibrium (LD)? (3)
- Non-random association of nearby alleles on a chromosome.
Causes:
- Genetic Linkage: Close alleles likely inherited together.
- Population History: Influences LD patterns.
What is the evidence for heritability? (4)
Monozygotic twin studies: Concordance rates for:
- Autism: 80%–90% (MZ) vs. 5%–15% (DZ).
- Monozygotic to dizygotic twin concordance ratios for drug addictions are approximately 2:1
- Psychiatric disorders: Highly polygenic.
- There are common variants with small effect sizes.
What are the three groups of genetically related psychiatric disorders identified by GWAS?
- Mood/Psychotic: Depression, bipolar, schizophrenia.
- Neurodevelopmental: Autism, ADHD, OCD.
- Compulsive Behaviors: Anorexia, Tourette’s.
What are GWAS challenges? (3)
- Sample size; small effect sizes, making them difficult to detect with smaller sample sizes.
- Sample ancestry; Different populations may have different genetic risk factors
- Disease definition; a lot of diagnosis is based on self reporting of specific traits
How does genetic architecture influence psychiatric conditions? (3)
- Common SNPs (≥1% allele frequency).
- Rare variants (<1% frequency).
- Structural variations.
What is the Genetic Heterogeneity of CNS Disorders? (3)
- No damaging genetic variant appears in more than a few cases.
Analysis focuses on:
- Identifying trends and commonalities.
- Studying specific genes/mutations to understand disease biology
What genetic associations have GWAS studies revealed about ASD-linked genes? (4)
- Strong associations found with SNPs in genes like NEGR1, PTBP2, CADPS, KCNN2, KMT2E, MACROD2.
- Genes are Highly expressed in the developing cortex.
- Genes are Most active prenatally, influencing early brain development.
- There are genetic correlations with other traits
What is Shared Heritability in psychiatric disorders? (2)
- Psychiatric disorders often share genetic and environmental risks.
- Shared heritability highlights overlapping biological pathways.
What are challenges of shared heritability? (2)
- Diagnosing individuals with multiple disorders.
- Assortative mating, where individuals with similar phenotypes mate.
What are Pleiotropic Loci? (3)
- Pleiotropic loci are genetic loci associated with multiple psychiatric disorders.
- Example: 109 genetic loci linked to shared biology in psychiatric conditions.
- Suggest potential shared treatment targets
What is the role of the DCC Gene in psychiatric disorders? (3)
- DCC Gene Function: Encodes netrin-1 receptor, crucial for axonal growth during neurodevelopment.
- Suggests axonal disruptions contribute to psychiatric disorder risk.
- SNP rs8084351 within the DCC gene is linked to eight psychiatric disorders.
What is the evolutionary paradox of Schizophrenia and the possible reasons for this phenomenon? (3)
- Despite reduced fecundity (fertility), schizophrenia risk alleles persist.
Possible reasons:
- Recent Evolution: Some genes associated with schizophrenia are located in regions of the genome that have undergone recent evolutionary changes.
- Genetic trade-offs, e.g., enhanced creativity or cognition in other contexts (advantagous).
What are Human Accelerated Regions (HARs), and their relevance to neuropsychiatric disorders? (3)
- HARs: Genomic regions with rapid evolutionary change in humans.
Linked to:
- Neural development and SCZ risk.
- De novo CNVs affecting HARs found in ASD cases.
What polymorphisms are associated with Substance Use Disorders (SUDs)? (4)
- OPRM1: µ-opioid receptor, influences opioid dependence and treatment response.
- ALDH1/2, DRD2, PDE4B: Related to addiction mechanisms.
How do Enhancers regulate genes in neurodevelopment? (4)
functions:
- Control pluripotency; ability of a cell to become any type of cell in the body.
- neuronal differentiation.
- neuronal development
- adult neuron function.
Note: Majority of SNPs are outside genes – may affect regulatory regions e.g. enhancers
