Behavioural and psychiatric genetics Flashcards
What is a monogenic disorder?
we can trace its origins to a single gene
e.g., Huntington’s disease (HT); Fragile X syndrome (FMR1)
Where does fragile X syndrome result from
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)
What does the 5′-untranslated region of a gene contains
the promotor region, where chemicals bind to start the process of transcribing a gene into a protein
What is FMR1 critical to
FMR1 is critical to synaptic plasticity, which is what forms the neuron bases of learning
What is polygenic disorder
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
What is GWAS?
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
Why can we rely on that sort of sparse sampling, won’t we potentially miss that particular functional SNP?
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
In GWAS, which model we use for phenotypes with quantitative traits
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?
In GWAS, which model we use for phenotypes with categorical and binary traits
allelic association model
Is one of the two alternative alleles statistically over-represented in a phenotypic group?
What is the most appropriate statistical model for Diagnosis of bipolar disorder
allelic association model
What is the most appropriate statistical model for Frequency of alcohol use
allelic dosage model
What is the most appropriate statistical model for Intelligence quotient (IQ)
allelic dosage model
What is the standard way of representing results of GWAS in a figure
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
What is imputation in GWAS
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
What can genetic distance and recombination rate reflect
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
What can Conservation indicate?
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
Why there is a strong correlation between the sample size of a GWAS and the number of associated markers discovered
Larger samples provide more statistical power to detect small effects
Three main advantages of GWAS
Provide new evidence for existing hypotheses
Raise new possibilities;
Point to environmental risk factors
What problems can Endophenotypes deal with
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
In which ways Endophenotypes of psychological disorders can yield larger genetic effects than diagnoses
Avoids difficulties assigning diagnostic categories
Allows testing of psychologically normal participants
Underlying biological mechanisms are likely to be simpler than for psychological disorders
