Common Disease Intro 2

Human Genome Project

• Large number of inter-individual genetic variations in our genome 
• Novel sequences technologies and analytical tools
• Cost was originally $100 million dollars but now approx. $1000
• Development of genomics research
• Application of high-throughput technologies
• Large biological data sets
• Personalised medicine is a emerging field
• Discover aetiology, novel therapeutic targets, identification of biomarkers

Candidate SNP approach

Aim: discovery of new functional genetic associations (or absence of association) between functional SNPs within pre-specified genes of interest and disease

Approach: based on prior knowledge about the genes and SNPs in relation to disease = hypothesis driven, study small number of SNPs (1-20), genotyping of theses SNPs in a population (e.g. case-control study) and compare genotype frequency between cases and controls at each locus

Advantages: relatively cheap, small to medium size study population (100s-1000s) - cheap, look at functional impact of the SNPs, can account for SNP x SNP or SNP x Environment interaction 

Limits: need prior knowledge, small to medium size study population - is this representative for the whole population

Pathway approach and GWAS

SNP - known or unknown functionality

Large number of SNPs studied:

• multiple statistical test - risk of false positives
• requires corrections for multiple testing e.g if significant p-value threshold p<0.05 for 1 test then for n-tests i.e. n SNPS p<( 0.05/ n)
• increase statistical power so need to use a very large study population and reduce the number of SNPs to genotype: use of Tag SNPS

A Tag SNP is a representative SNP in a genome region with high LD that represents a group of SNPs (haplotype). Means you don't have to genotype all the SNPs reducing cost and number of tests required

Pathway Analysis

Aim: discover new genetic SNPs, disease associations within a given metabolic pathway, identify genes involved in the disease mechanism within this pathway

Approach: based on prior knowledge about the role…