Behavioural and psychiatric genetics

Question 1

What is a monogenic disorder?

Answer 1

we can trace its origins to a single gene

e.g., Huntington’s disease (HT); Fragile X syndrome (FMR1)

Question 2

Where does fragile X syndrome result from

Answer 2

A copy-number variant in the 5′-untranslated region of the gene FMR1.
Expansion of repeated CGG sequence of bases triggers methylation, which constricts the X chromosome and causes ‘fragile’ appearance

(A methylated promotor region prevents transcription of the gene into protein)

Question 3

What does the 5′-untranslated region of a gene contains

Answer 3

the promotor region, where chemicals bind to start the process of transcribing a gene into a protein

Question 4

What is FMR1 critical to

Answer 4

FMR1 is critical to synaptic plasticity, which is what forms the neuron bases of learning

Question 5

What is polygenic disorder

Answer 5

Monogenic disorders are the exception to the rule in behavioural and psychiatric genetics
There is no single gene for schizophrenia, autism, bipolar disorder, depression or anxiety

Question 6

What is GWAS?

Answer 6

Genome-wide association studies (GWAS) examine the statistical association between a phenotype and many SNP markers throughout the genome

We look at how the genotype is associated with the phenotype, how the genotype at that particular SNP is associated with the phenotype

Question 7

Why can we rely on that sort of sparse sampling, won’t we potentially miss that particular functional SNP?

Answer 7

Because these SNPs are close-by on the genome, they will have very strong correlation with nearby SNPs including that functional SNP
The linkage disequilibrium (LD) allows us to observe indirect associations, to capture variation in that functional SNP
In a direct association, the phenotype has a functional association with a genotyped (measured) SNP
In an indirect association, the phenotype has a functional association with a non-genotyped SNP that is in LD with a genotyped SNP

Question 8

In GWAS, which model we use for phenotypes with quantitative traits

Answer 8

allelic dosage model

e.g., T/T; T/G; G/G. is there a statistical association between the phenotypic measurement and the number of copies of the minor allele?

Question 9

In GWAS, which model we use for phenotypes with categorical and binary traits

Answer 9

allelic association model

Is one of the two alternative alleles statistically over-represented in a phenotypic group?

Question 10

What is the most appropriate statistical model for Diagnosis of bipolar disorder

Answer 10

allelic association model

Question 11

What is the most appropriate statistical model for Frequency of alcohol use

Answer 11

allelic dosage model

Question 12

What is the most appropriate statistical model for Intelligence quotient (IQ)

Answer 12

allelic dosage model

Question 13

What is the standard way of representing results of GWAS in a figure

Answer 13

Manhattan plot
A Manhattan plot represents chromosomes (the location of that SNP on the chromosome) across the X axis, represents transformation of the p value (lower are higher) of that test of association across the Y axis
This plot graphically summarizes the results of all of our individual tests of association

Question 14

What is imputation in GWAS

Answer 14

Imputation predicts genotypes at non-genotyped SNPs
Relies on data from a reference panel of individuals genotyped at high density
Applies patterns of linkage disequilibrium discovered in the reference panel

Question 15

What can genetic distance and recombination rate reflect

Answer 15

The frequency with which two markers are inherited (correlated) together
Because we might be measuring the LD within the functional SNP
This helps define the region likely to contain the functional variant

Question 16

What can Conservation indicate?

Answer 16

The extent to which a sequence is maintained across species (how consistent these DNA are across multiple species)
High conservation suggests an important function preserved during evolution

Question 17

Why there is a strong correlation between the sample size of a GWAS and the number of associated markers discovered

Answer 17

Larger samples provide more statistical power to detect small effects

Question 18

Three main advantages of GWAS

Answer 18

Provide new evidence for existing hypotheses
Raise new possibilities;
Point to environmental risk factors

Question 19

What problems can Endophenotypes deal with

Answer 19

Many disorders aren’t just single disorders but collection of different disorders with similar symptomatology and perhaps very different underlying biology

On the one hand we have people who share no common symptoms but the same diagnosis;
On the other hand some disorders have overlapping features

Perceptual abnormalities observed in two different disorders may be linked by common genetic elements that affect synaptic function
But that is not something would necessarily be observable if the disorder would be studied in themselves rather than using endophenotypes

Question 20

In which ways Endophenotypes of psychological disorders can yield larger genetic effects than diagnoses

Answer 20

Avoids difficulties assigning diagnostic categories

Allows testing of psychologically normal participants

Underlying biological mechanisms are likely to be simpler than for psychological disorders