G15 Flashcards
what are CDCV
common diseases use to common variants
what are common variants
polymorphisms that occur at 1-5% in populations
what are the two hypotheses for common variants
- common diseases are due to common variants, several genes contribute, each polymorphism is of small effect - can be detected via association studies
- common diseases are due to rare alleles of large effect, - cant be detected via association studies
what is the more common correlation between effect size and allele frequency
more likley to get common variants with small effect sizes identified by GWAS
highly penetrant alleles for mendellian disorders are extremely rate with large effect sizes
what is the equation for linkage disequilibrium
D= PABPab - PAbPaB
How do you calculate the coefficient of disequilibirum
r^2 = D^2/ PAPaPBPb
what values can the coefficient of disequilbirum take
range from 0-1
0 = linkage equilibirum
1 = linkage disequilbirum
what do hotspots of recombination produce
blocks of LD in the genome - variation in each block is low
in theory how many SNPs do you need to analyze to determine if LD is complete
only 1 as if LD then should be same
what does local LD result in
SNPs being inherited in haplotype blocks
how are control groups selected in population based case/control studies
age matched sex matched ethnicity matched environment matched - so differences in marker allele freq in patient population its due to genotypwe
how do you calculate reltative risk of disease
P(disease|exposed to allele) / P(disease| no exposed to allele)
can calculate each using a(a/b) and c/(c+d)
a is case exposed
b is control exposed
c = case unexposed
d = control unexposed
what does RR of 1-1.5 tell you
small effect
what does RR of >2 tell you
large effect
what does a manhattan plot show you
human chromosomes shown, with SNPs associated with disease highlighted.
what does manhattan plot of T2D and FTO fat mass and obesity associated genes show
clusters of SNPs located within first intron associated.
position 16q12
one FTO SNP has high associated with very low P value
The risk allele frequency was at a higher frequency in the case group.
what did FTO studies in transgenic mice show
FTO deletion = lean
FTO dominant missense = lean
FTO over expression = increase fat mass, food intake and body weight
males 10% increase - females more
what did risk allele A of an SNP at rsl9939609 show
associated with increased BMI in eypreans homos = 16% pop are at high risk compared to TT homos
AA = eat more, especially fats
what are the issues with GWAS?
replication between studies isnt good
questionable clinical utility - hasnt got that dfar
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what did twn studies show about heritability for obestiy adn what did GWAS findings show
40-70%
GWAS found 75 vairants for obesity which explains 2-3% of the phenotypic variation - suggests CDCV doesnt hold.
what is an eQTL
genetic loci that affect mRNA expression level of other genes, measured mRNA or protein trait is almost always the product of a single gene with a specific chromosomal location
uses GWAS qtl mappinh approach but maps expression of a particular gene against SNP markers
what did eQTL studies for expression of FTO SNPs show
that SNPs associated with BMI are associated with IRX3 expression not FTO in human brain tissue.
