Lecture 17 - The genetics of psychiatric disorders, intelligence and personality Flashcards
(20 cards)
Why do family, twin, and adoption studies reveal about the heritability of psychiatric conditions, intelligence, and personality traits?
They indicate a substantial genetic component, with heritability estimates ranging from 50% to 90%
How is the overall genetic risk for psychiatric disorders explained?
Through a combination of:
- Few, rare genetic variants with large effects (high penetrance)
- Many, common genetic variants with small effects (low penetrance)
How do allele frequency and relative risk relate in genetic variants?
- Common variants (low penetrance) have high allele frequency and low relative risk
- Rare variants (moderate penetrance) have low allele frequency and moderate relative risk
- Rare variants (high penetrance) have low allele frequency and high relative risk
What was discovered in the 1970s cytogenetic study involving Scottish juvenile offenders?
- A translocation between chromosomes 1 and 11 was identified in a boy with an affective disorder
- 33 out of 74 family members had the same translocation
- 16 of these showed evidence of psychiatric illness, demonstrating pleiotropy
What gene was implicated in the translocated study?
DISC1 (Disrupted in Schizophrenia) located at 1q42.1
How do linkage studies identify genetic mutations associated with psychiatric disorders?
- BY genotyping markers across the genome in families with multiple affected members and testing for co-segregation of marker with the disorder
- Significant linkage is indicated by a LOD score >3
What was a significant finding from early linkage studies in Alzheimer’s disease?
-The identification of linkage between the APOE gene (chromosome 19) and familial Alzheimer’s disease
- Different APOE genotypes confer varying levels of disease risk
Describe the two main designs in candidate gene association studies?
1) Family-based design: Analysing trios (two parents and an affected offspring) to see if a particular allele is transmitted more frequently than expected by chance
2) Case-control design: Comparing the frequency of genetic variants between cases (affected individuals) and controls (unaffected individuals)
What are the limitations of candidate gene association studies?
- They assume prior knowledge of disease biology
- They may suffer from population stratification
- They often have small sample sizes
- Many findings lack replicability
How do Genome-Wide Association Studies (GWAS) differ from candidate gene studies?
GWAS are hypthesis-free, scanning the entire genome for associations without prior assumptions, and typically involve large sample sizes to detect common variants with small effects
What is required for a finding to be considered genome-wide significant in GWAS?
A p–value less than 5 x 10^-8, along with replication in independent samples
What was a notable GWAS finding in psychosis research?
The identification of a risk variant in ZNF804A associated with schizophrenia and bipolar disorder
How has GWAS contributed to understanding Alzheimer’s disease?
A meta-analysis identified 20 polymoprhisms significantly associated with sporadic late-onset Alzheimer’s disease
What is the Wilson Effect in the context of intelligence?
The observation that the heritability of IQ increases with age, from about 20% in infancy to approximately 80% in adulthood
What are Copy Number Variant Studies (CNVs), and how are they studied?
- CNVs are deletions or duplications of DNA segments
-They are studied using array-based assays to compare their frequency in cases versus controls
What have CNVs revealed about psychiatric disorders?
- Large CNVs are more frequent in children with ADHD compared to neurotypical controls
- Certain CNVs, like the 22q11 deletion, are associated with multiple conditions like intellectual disability, autism spectrum disorders, and schizophrenia
What is the focus of exome sequencing studies?
Sequencing all exons (protein-coding regions) in the genome to identify rare, potentilly functional variants with disorders
How does whole-genome sequencing differ from exome sequencing?
Whole-genome sequencing covers the entire genome, including non-coding regions, providing a more comprehensive view of genetic variation
What do epigenome-wide studies investigate?
They examine epigenetic modifications, such ad DNA methylation, across the genome to understand how gene expression is regulated in relation to psychiatric disorders
Why are Genome-Wide Association Studies (GWAS) more useful than candidate gene association studies?
- GWAS are hypothesis-free and scan the entire genome, allowing for the discovery of novel genetic associations without prior assumptions
- In contrast, candidate gene studies focus on pre-selected genes based on existing knowledge, which may be incomplete or biased, and often suffer from small sample sizes and lack of replication
