Behavioural & Psychiatric Genetics Flashcards
Define a monogenic disorder.
A monogenic (‘single gene’) disorder is a disorder, the origins of which can be traced back to a single gene.
List a monogenic disorder or two.
Examples of a monogenic disorder would be ‘Fragile X Syndrome’ (FMR1), and ‘Huntington’s disease’ (HT).
Fragile X syndrome. What is it caused by?
FXS results from a copy-number variant in the 5’-untranslated region of the gene FMR1. FMR1 is critical to synaptic plasticity.
What does the 5’-untranslated region of a gene contain?
This region contains the ‘promotor region’, where chemicals bind to start the process of transcribing a gene into a protein.
Fill in the blanks: The expansion of ______ sequence of bases triggers _______.
The expansion of repeated CGG sequence of bases triggers methylation.
What does methylation do?
Methylation constricts the X chromosome and causes ‘fragile’ appearance.
Describe what the methylated promoter region does.
The methylated promoter region prevents transcription of the gene.
Define a polygenic disorder.
A polygenic (‘more than one gene’) disorder is a disorder, the origins of which can be traced back to/caused by several genes.
What does GWAS stand for?
Genome-Wide Association Studies.
What are GWAS used for?
Genome-Wide Association Studies (GWAS) are used to measure psychiatric disorders, psychological traits and cognitive traits.
What do GWAS examine?
GWAS examine the statistical association between a phenotype and many SNP markers throughout the genome, typically around 500,000 to 2,000,000 markers.
What is linkage disequilibrium?
Linkage disequilibrium (LD) is the correlation between two different SNPs.
True or False: There is no single gene for schizophrenia, autism, bipolar disorder, depression or anxiety.
True.
Why can we sample common variation sparsely (in a thinly dispersed manner; in small numbers)?
Because linkage disequilibrium (LD) allows us to observe indirect associations, chromosomes are mosaics and many variants are correlated.
What happens in a direct association?
The phenotype has a functional association with a non-genotyped SNP that is in LD with a genotyped SNP.
What is an allelic dosage model used for?
For quantatitive traits.
What is an allelic association model used for?
Categorical and binary traits.
What does a manhattan plot do?
Graphically summarises the results of all of our individual tests of association.
What does each point on a manhattan plot represent?
The outcome of a test for one SNP.
What is on the horizontal axis on a manhattan plot?
Physical location on the genome and within a chromosome.
What is on the vertical axis of a manhattan plot?
Transformed p value, lower p values are higher on the axis, emphasising the strongest associations.
Why are thresholds for significance stringent?
Because multiple comparisons increase the likelihood of Type 1 error.
What are the thresholds for significance typically set at?
Typically set around α = 5 x 10-8 (p
What does that threshold for significance correspond to?
The Bonferroni correction for around 1 million independent (uncorrelated) tests.
What does imputation predict?
Genotypes at non-genotyped SNPs.
What does imputation rely on?
On data from a reference panel of individuals genotyped at high density.
What patterns does imputation apply?
Applies patterns of linkage disequilibrium discovered in the reference panel.
What does genetic distance and recombination rate reflect?
The frequency with which two markers are inherited together, helps define the region likely to contain the functional variant.
What does conservation indicate?
The extent to which a sequence is maintained across species.
What does high conservation suggest?
An important function preserved during evolution
What can ‘skyscrapers’ be explained by?
Multiple SNPs in linkage disequilibrium with a functional SNP, multiple functional SNPs in the same gene.
What did a meta-analysis of bipolar disorder GWAS find?
Found an association with the ANK3 and CACNA1C genes.
What do the proteins transcribed from both of these gene regulate?
The flow of ions in and out of neurons during an action potential.
What are both the genes down-regulated by?
Lithium.
What does lithium do to the proteins?
Lithium reduces transcription of the protein.
What is lithium an effective treatment of?
Bipolar disorder (BP).
“Strong correlation between the sample size of a GWAS and…” (finish the sentence)
What does this mean?
Strong correlation between the sample size of a GWAS and the number of associated markers discovered.
This means that larger samples provide more statistical power to detect small effects.
What are one of the things GWAS can do?
GWAS can provide new evidence for existing hypotheses.
In regards to schizophrenia, how has GWAS provided new evidence for existing hypotheses?
Schizophrenia has previously been linked to abnormal dopamine signalling, antipsychotic drugs block dopamine receptors. DRD2, a dopamine-receptor gene, is associated with schizophrenia
What is another thing GWAS can do?
GWAS can raise new possibilities regarding understanding of behavioural and psychiatric genetics.
How has GWAS raised new possibilities?
GWAS has posited that the most significant association is the histocompatibility complex (MHC), MHC genes code for cell-surface proteins that allow the immune system to recognise foreign substances.
What is the last thing studies that GWAS can do?
GWAS can point out environmental factors regarding understanding of behavioural and psychiatric genetics.
How has GWAS pointed out environmental factors?
GWAS has posited that variants in the CHRNA5-A3-B4 gene cluster are known to be very strongly associated with heavy smoking. Encode subunits of a nicotine acetylcholine receptor, cholinergic receptors that also response to nicotine. Association of schizophrenia with CHRNA5-A3-B4 variants suggests heavy smoking may contribute to schizophrenia.
What do disorders consist of?
Complex GxE (Gene x Environment) interactions, diagnostic categories, measurement problems, interference from multiple deficits.
What do endophenotypes consist of?
More immediate relationships, single quantitative traits, psychologically normal participants.
What is an endophenotype?
A quantitative biological trait that reflects the function of a discrete biological system and is reasonably heritable.
What is a cognitive measure of endophenotypes?
The Wisconsin Card Sorting test.
What does the Wisconsin card sorting test involve?
Sort cards according to one rule, then having this rule change.
What are neurophysiological measures of endophenotypes?
Pre-pulse inhibition of startle response.
What is a psychomotor measure of endophenotypes?
The antisaccade oculomotor task.
What does the antisaccade motor task involve?
Watching a dot and look in the opposite direction of its movement when it moves.
What are some examples of endophenotypes?
Anomalies of basic visual perception, disturbances of visual sensitivity are associated with both schizophrenia and autism.
What did they find in a GWAS of visual sensitivity in a psychologically healthy population?
The strongest association signal was at a marker on chromosome 1q21.1
Where is the marker situated?
The 5’-untranslated region of the gene PDZK1
What does the 5’-untranslated region contain?
The promotor region
What happens if the functional SNP is situated in the 5’-untranslated region?
It likely affects protein transcription rather than protein structure
What do PDZ proteins do?
They hold other proteins in appropriate configuration for localisation on the surface of cells
What are the interactions between PDZK1 and NMDA receptors?
NMDA receptors play a critical role in contrast gain control in the retina, perceptual abnormalities in schizophrenia have been suggested to arise from NMDA receptor dysfunction
What are the interactions between PDZK1 and DLG4?
Disruption of Dlg4 in a mouse results in an ASD-related phenotype
What is the difference between DLG4 and Dlg4?
Human genes are all capital, rodent genes are title case
What may perceptual abnormalities observed in two different disorders be linked by?
Common genetic elements that affect synaptic function
How can endophenotypes of psychological disorders 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
