BG24 Flashcards
what is GWAS
- large populations
- identify cases with phenotype and controls without
- genotype all subjects with a high density panel of SNPs
- determine association
What is the odds ratio
- underlying probabilities
the association between an SNP and the phenotype = odds ratio.
- get odds for each SNP that it will appear in each group (O)
- P case = probability of SNPa occuring in these phenotype cases
- Pcont = probability of SNPa occuring in the controls
what are the odds of SNPa occuring in the phenotypic cases and in the control cases
Ocase = Pcont/1-Pcont Ocont = Pcont/1-Pcont
what is the odds ratio
OR = Pcase/1-Pcase/Pcont/1-Pcont
if
OR = 1
OR > 1
OR <1
OR = 1 SNP is equally likely to occur in case as controls
OR > 1 SNP is more likely to occur in cases than in controls
OR <1 SNP is less likely to occur in cases than controls
GIANT consortium
17k individuals 500 markerss OR = 1.2-1.5 found 24 new genes for diseases such as crohns and hypertension
Human height, the history of genetic association
2008: major studies identified 44 associated QTLs (found most chromosomes contain height associated QTLs)
2010: meta-analysis GWAS of european height by GIANT consortium accounting for 12% of the heritability of human height (180 subjects, 180 height QTLS)
2014: meta-analysis GWAS european height = 250k people, 700 SNPs, 400 height QTLs, 60% of heritbiality in height accounted for.
pathways or genes associated with humans height
- hypothalamus piturity growth axis = systemic growth reg in mammals
- dwarfs and giants due to abnormal signalling here - endochondral bone: many genes picked up giants are expessed in chondrocytes or MSCs, QTLS associated with signalling pathways that regualte chondrocyte proliferation
endochondral bones, growth and regulation
- formed by condensations of chondrocytes
- BMPs reg. chondrogenesis
(ectopic expression of BMP causes extra bone = FOP occurs due to gain of function bmp. - endochondral bone growth occurs around the growth plate - region of cell proliferation and hypertrophy
Diseases cinvolved in height mutations
- achondroplasia - dom gain of function FGFR3 - regs chondrocyte proliferation = heterozygous
- Thantophoric dysplasia = homozygous - severe skeletal disorder
- Bloomstrand chondroplasia - short limbs, enlarged skull = recessive loss of function in parathyroid related peptide.
cline in height
north south cline in height
height alleles differ in freq between northern and southern europe.
- too large drift to be due to drigt alone - weak selection rather than drift
Drosophila selection for fly size experiment
- start with outbred population of 1800 flies
- use sieves select for body size for 100 generations
- make 2 large, 2 small, 2 control pops
- pool 75 females from each population and resequence
candidate genes in drosophila
several IGF like ILS pathways are candidate for drosophila size
potential ILS involved in drosophila size
- IGF ligand
- IGF-R RTK
- chico-vertebrate IRS-4 homolog - insulin receptor suubstrate.
- TOR: target of rapomycin, ser/thr kinase - regs cell growth, proliferation, survival, protein synthesis and transcription.
results of drosophila fly experiment
41k SNPs differ between each pair of large and small lines
5.6k that differ are >95% in freq
1.2k distinct regions that differ in freq.
Only TOR ILS is thought to be important