Genetics of Disease Susceptibility Flashcards
What are the components of a complex disease?
- Environment
- Epigenetic & regulatory events
- Genome allelic variants
The role of genetics in complex diseases is largely relegated to what?
Collection of family medical history (shared genetics + environment; raw estimate of overall risk)
The missing heritability problem is the variants discovered by GWAS only explain a (major/minor) fraction of expected heritability
minor
The missing heritability problem is the variants discovered by GWAS only explain a minor fraction of expected heritability. This may be because of the effect sizes….
are much smaller than previously thought
The missing heritability problem is the variants discovered by GWAS only explain a minor fraction of expected heritability. We may have (over/under) estimated the heritability
over
The missing heritability problem is the variants discovered by GWAS only explain a minor fraction of expected heritability. It is (common/rare) variants that contribute most of the variation
Rare
The missing heritability problem is the variants discovered by GWAS only explain a minor fraction of expected heritability. What accounts for much of the resemblance among relatives?
Epigenetic inheritance
The missing heritability problem is the variants discovered by GWAS only explain a minor fraction of expected heritability. Do the genotyping chips tag casual variants?
They do, but not very effective though
What is heritability?
Proportion of variance of phenotype in a POPULATION that can be attributed to genotypic differences
Example of discrete phenotype
Disease status
Example of categorical phenotype
Number of digits
Example of continuous phenotype
Height or biochemical measure
How can you estimate heritability using studies?
Use twin studies
Is heritability a statement about individuals?
Nope
Is heritability a statement about a single population?
Yurp
Is heritability the same as inheritance?
Nope
What is the Common Disease / Common Variant (CDCV) model?
Most disease susceptibility can be attributed to 10 to 20 specific loci (explains around 5% disease risk)
What is the subset model of CDCV?
Infinitesimal loci model
What is the infinitesimal loci model?
We carry thousands of weak susceptibility alleles
Those who are unlucky have too many and are at highest risk
Those who have rare variants or environmental triggers push us over the edge which implies a threshold
What is the Rare alleles of Major Effect (RAME) model?
Diseases are highly heterogenous with lots of rare mutations causing individual cases of disease
What are some cases for the CDCV model?
- Infinitesimal model is well validated in quantitative genetics
- Common variants capture most of genetic variance in GWAS
What are some cases against the CDCV model?
The missing heritability has not been account for in many common diseases
What are some cases for the RAME model?
- Evolutionary theory predicts that disease alleles should be rare
- Many rare familial disorders are due to rare alleles of large effect
What are some cases against the RAME model?
- Sibling recurrence rates are greater than postulated effect sizes of rare variants
- Epidemiological transitions cannot be attributed to rare variants
What is epigenetics?
- Histone modifications
2. Study of heritable changes that do not affect DNA sequence
(+/-) charged DNA is wrapped on (+/-) charged histones
Negative - DNA
Positive - Histones
What are the ways histones are chemically altered by?
- Acetylation
2. Methylation
Which histone change allows increased expression of DNA?
Acetylation
Histone acetylation allows what to DNA?
Increase expression (as a result of decreasing charge of histones + attraction to DNA)
Which histone change allows decreased expression of DNA?
Methylation
Histone methylation allows what to DNA?
Decrease expression (As a result of tightening of DNA coil + histones)
Can methylation patterns be inherited?
Yes
(T/F) Methylation of specific genes is heritable and impacts which copy of genes are expressed
True
(T/F) Acetylation of specific genes is heritable and impacts which copy of genes are expressed
False
Imprinting (promotes/prevents) complementation
prevents
Any mutation (as a result of imprinting) in the expressed gene will result in (phenotype/genotype)
phenotype
What is allelic heterogeneity?
Different mutations in the SAME gene
What is locus heterogeneity?
Mutations in several DIFFERENT genes
What is a modifier gene?
Genes that influence expression of other genes aka epistasis
What is pleiotropy?
One gene causes multiple phenotypes
What is penetrance/expressivity?
Varying proportion of phenotype observed given a particular geneotype
