Lecture 15 - The Genetics of Psychiatric Disorders, Personality and Intelligence

Question 1

Why do we use DNA?

Answer 1

• Readily accessible
• Stable over time: shows issue is with hormones/stress, not with person as DNA stays same

Question 2

What were early approaches to identifying genetic risk? (Exp)

Answer 2

• 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

Question 3

Describe linkage studies?

Answer 3

• 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

Question 4

What is LOD?

Answer 4

• Degree of co-segregation
• 3 is most suggestive
• Logarithms of odds score

Question 5

What were early successes in linkage studies?

Answer 5

• 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

Question 6

What are the limitations of early approaches of linkage studies?

Answer 6

• 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

Question 7

What were candidate gene association studies?

Answer 7

• Examines 1+ genes involved in pathways involved in disorder

Question 8

What were the two approaches of candidate gene association studies?

Answer 8

• 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.

Question 9

Limitations of candidate gene association studies?

Answer 9

• 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

Question 10

What is the Genome-Wide Association Studies (GWAS)?

Answer 10

• 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

Question 11

How else does GWAS help?

Answer 11

• 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

Question 12

What is heritability for personality?

Answer 12

• Influenced by genetics
• Heritability for most traits is about 50%
• Diff personality traits can vary by age (OCEAN)
• Generally stable

Question 13

How to identify genetic factors associated with personality types?

Answer 13

• 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

Question 14

Concordance of MZ twins for IQ?

Answer 14

• Increases, stays matching as they age
• DZ diverge and become more separate

Question 15

What are new biological insights?

Answer 15

• 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

Question 16

Limitations of GWAS:

Answer 16

• 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

Question 17

What are Copy Number Variants? How do you study this?

Answer 17

• 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

Question 18

What are insights from CNV studies?

Answer 18

• Confirmation of bio bias to psych disorders
• Some CNVs associated with higher risk

Question 19

What are limitations of CNVs?

Answer 19

• Rare and cannot explain risk in majority of cases
• Hard to make explicit single-gene behaviour associations

Question 20

What are new approaches?

Answer 20

• 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

Question 21

Limitations of new approaches?

Answer 21

• Expensive & labour-intensive
• Mutations rare and associations with phenotype only, amenable to animal model studies

Question 22

What are whole genome sequencing?

Answer 22

• Every base pair in the genome sequenced in cases & controls
• De Novo mutations are in particular interest
• Covers potentially functionally significant intergenic mutations

Question 23

Limitations of whole genome sequencing?

Answer 23

• Expensive and labour intensive
• Mutations rare and association with phenotype only; function of DNA between genes poorly understood