Lecture 15 - The Genetics of Psychiatric Disorders, Personality and Intelligence Flashcards
1
Q
Why do we use DNA?
A
- Readily accessible
- Stable over time: shows issue is with hormones/stress, not with person as DNA stays same
2
Q
What were early approaches to identifying genetic risk? (Exp)
A
- Juvenile offenders identified translocation in a boy with affective disorder
- Translocation is a swap of genetic material between chromosomes 1-11
- 33/74 family members had the same mutation and 16 of them had evidence of psychiatric illness
- Looked at mice with same mutation, which showed issues with schiz and their ventricles
3
Q
Describe linkage studies?
A
- Families in which psychiatric disorders are present in multiple members
- DNA selected across genome for each family member
- Markers get shuffled in each generation
- Test to see which marker co-segregates with the disorder
- Identified marker and genetic mutations causing the disorder are linked. This part of DNA can then be screened for mutations
- Narrow down the parts of the chromosome for you to look out
4
Q
What is LOD?
A
- Degree of co-segregation
- 3 is most suggestive
- Logarithms of odds score
5
Q
What were early successes in linkage studies?
A
- Linked a gene and alz
- Gene comes in 3 alleles - all transport lipoproteins, fat soluble vitamins and cholesterol into the lymph system and blood
- Different alleles show different disease risk
6
Q
What are the limitations of early approaches of linkage studies?
A
- Rare to identify chromosomal mutations on one gene
- Hard to identify families who have the illness throughout generations in linkage studies
- Little usage if disorder results in high mortality/impaired fertility
- Can be influenced by family environment
- Can only identify genetic changes that have high penetrance (high effect on risk)
- Not reproducible
7
Q
What were candidate gene association studies?
A
- Examines 1+ genes involved in pathways involved in disorder
8
Q
What were the two approaches of candidate gene association studies?
A
- Family-based design: find someone with illness, check if allele is transmitted from parent instead of chance
- Case-control design: Find population of cases and controls
- Single gene selected for analysis and looking for SNP/genetic variants between case & control
- Any variants that occur in cases more than controls is associated with increased risk.
9
Q
Limitations of candidate gene association studies?
A
- Assumes knowledge of underlying biology as choice of gene is subjective
- Family-based studies require DNA samples from parents and offspring
- Need to closely match case/controls - issues with population stratification
- Studies limited to gene itself - env factors or polymorphism ignored.
- Small sample sizes
- Poor replicability
10
Q
What is the Genome-Wide Association Studies (GWAS)?
A
- Compares large number of cases/control inc. companies e.g 23&me
- Genotypes millions of SNPs across the genome - analysis are not driven by hypothesis, completely independent from what we know previously
- Perform chi-squared test for each SNP to compare frequency
- Allows simple analysis and replication to prevent spurious results.
- Small p-values
- Represented in Manhattan plots
11
Q
How else does GWAS help?
A
- Compares subgroups within a clinical population e.g types of medications and effectiveness for illness
- Looks at people who have very traumatic environmental markers but have no psychological illnesses as controls to identify any protective genetic variants
12
Q
What is heritability for personality?
A
- Influenced by genetics
- Heritability for most traits is about 50%
- Diff personality traits can vary by age (OCEAN)
- Generally stable
13
Q
How to identify genetic factors associated with personality types?
A
- Genotype multiple people from population at particular genetic sites
- Look at score on personality measures
- Can look at number of alleles in particular groups of the population
14
Q
Concordance of MZ twins for IQ?
A
- Increases, stays matching as they age
- DZ diverge and become more separate
15
Q
What are new biological insights?
A
- Unbiased = implicated genes that could have been predicted apriori
- Explains variability in presentation within a disorder
- Clarifies symptom overlap in common genetic variations across disorders (comorbidity symptoms)
- Better therapies and diagnostics
16
Q
Limitations of GWAS:
A
- Identify risk variant but not causal of disorder
- Only examine common alleles
- Not all SNPs can be genotyped - imputation
- Polymorphisms on sex chromosomes are not examined
17
Q
What are Copy Number Variants? How do you study this?
A
- Relatively rare mutations in which a section of DNA has been deleted or duplicated
- Must do chi-squared to compare frequency in cases and controls
18
Q
What are insights from CNV studies?
A
- Confirmation of bio bias to psych disorders
- Some CNVs associated with higher risk
19
Q
What are limitations of CNVs?
A
- Rare and cannot explain risk in majority of cases
- Hard to make explicit single-gene behaviour associations
20
Q
What are new approaches?
A
- Exome sequencing: identifies small and rare mutations
- Compare number of cases/controls
- Every base pair of gene exon sequenced in cases and healthy controls, mutations that occur more frequently in cases than controls
- De Novo mutations show that genes are more likely to be causal
21
Q
Limitations of new approaches?
A
- Expensive & labour-intensive
- Mutations rare and associations with phenotype only, amenable to animal model studies
22
Q
What are whole genome sequencing?
A
- Every base pair in the genome sequenced in cases & controls
- De Novo mutations are in particular interest
- Covers potentially functionally significant intergenic mutations
23
Q
Limitations of whole genome sequencing?
A
- Expensive and labour intensive
- Mutations rare and association with phenotype only; function of DNA between genes poorly understood
